2002-2006

PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME FRAMEWORK FUNDED UNDER THE SIXTH PROJECTS CANCER RESEARCH

PROJECT SYNOPSES PROJECT

CANCER RESEARCH CANCER CANCER RESEARCH CANCER

KI-NA-23471-EN-C c expertise from the laboratory to the clinic, the clinic, to the laboratory from c expertise c knowledge in cancer research. in cancer c knowledge PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME (2002-2006) FRAMEWORK FUNDED UNDER THE SIXTH PROJECTS to validate new innovative tools for detection and early prognosis, and early prognosis, detection for tools innovative new validate to and cure. prevent to cancer to related catalogue includes 108 projects, present The who and beyond Europe from includes 1 500 researchers research, Cancer the ‘Combating to participate projects their research through in the major diseases research combating part of the EU’s initiative’ programme. Sixth framework research collaborative of European in the forefront are projects These and achievements progress information, providing currently and are on scientifi inter- disease with multiple causation, complex is a complex Cancer the At but also at population level. organism actions at the cell, collaborative research interdisciplinary same time a challenge for better, understand to and clinical level transnational basic to from scientifi integrate to CANCER RESEARCH CANCER RESEARCH ???????? Interested in European research?

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European Commisssion Directorate-General for Research Directorate F – Health Unit F.2 – Medical and Public Health Research Area: Cancer

Contact: Dominika Trzaska E-mail: [email protected] European Commission Offi ce CDMA 2/46 B – 1049 Brussels CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME (2002-2006)

Edited by ELENGO MANOUSSAKI

2008 Directorate-General for Research – Medical and Public Health Research EUR 23471 EN Acknowledgements The catalogue has been produced thanks to the input of the coordinators involved in FP6 research, to the colleagues from Genomics and System Biology, Health Biotechnology and Horizontal aspects units of Health Directory. To the continuous encouragement of Manuel Hallen and dedication of Maria Vidal-Ragout. However, it would not have been possible to conceive and produce the catalogue without the input of colleagues who left, and new colleagues who arrived, especially: Olaf Kelm, Stefan Junglbluth, Christel Jaubert, Joana Namorado, Cornelius Schmaltz, Jessica Tengelidou, Dominika Trzaska, Alfredo Cesario and Jan van de Loo.

Elengo Manoussaki

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Printed in Belgium PRINTED ON WHITE CHLORINE-FREE PAPER TABLE OF CONTENTS

FOREWORD – CANCER: COMBATING A COMPLEX DISEASE 7 Biology 9 Aetiology 85 Prevention 97 Early detection, Diagnosis and prognosis 105 Treatment 161 Cancer control, Survivorship, and outcomes research 231 Scientifi c model systems 243 Indices – Keywords 250 Indices – Partners 254 Indices – Organisations 264

Contact details for activities related to cancer research

European Commission Directorate General Research Directorate Health – F Unit Medical and Public Research-F2

MANUEL HALLEN, Acting Director, Health Directorate ([email protected])

MARIA JOSE VIDAL-RAGOUT, PhD, Deputy Head of unit ([email protected]) ALFREDO CESARIO, MD, Scientifi c Offi cer, SNE ([email protected]) ELENGO MANOUSSAKI, PhD, Scientifi c Offi cer ([email protected]) DOMINIKA TRZASKA, PhD, Scientifi c Offi cer ([email protected]) JAN-WILLEM VAN DE LOO, PhD, Scientifi c Offi cer ([email protected])

3 TABLE OF CONTENTS

Biology 9 Active p53 10 ANGIOTARGETING 13 Anti-tumour targeting 15 BRECOSM 17 CAPPELLA 19 COMBIO 2 1 CONTICANET 23 DIAMONDS 26 DNA Repair 28 ENLIGHT 30 EPISTEM 32 EPITRON 34 EuroBoNeT 36 EuroCSC 38 GROWTHSTOP 40 INTACT 42 KidsCancerKinome 45 Lymphangiogenomics 47 MetaBre 49 MitoCheck 51 MOL CANCER MED 53 MSCNET 55 Mutp53 57 Nano4Drugs 60 ONCASYM 62 ONCODEATH 64 PRIMA 66 Regulatory Genomics 68 SENECA 70 SIROCCO 72 SMARTER 75 TCAC in Cancer 77 THOVLEN 79 TransDeath 81 TRKCancer 82 Tumour-Host Genomics 83

Aetiology 85 AIDIT 86 CARCINOGENOMICS 88 GenoMEL 91 INCA 93 POLYGENE 95

4 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Prevention 97 EPIC 98 EUROCADET 100 MAMMI 102

Early Detection, Diagnosis and Prognosis 105 BAMOD 106 BioCare 108 BMC 1 1 1 CANCERDEGRADOME 113 COBRED 116 DASIM 118 DISMAL 119 DNA METHYLATION 121 Drop-Top 123 E.E.T.-Pipeline 127 eTUMOUR 129 GLYFDIS 131 HI-CAM 133 HighReX 135 MCSCs 137 MMR-related cancer 139 MolDiag-Paca 140 NEMO 142 OVCAD 144 P-MARK 146 POC4life 148 PROMET 150 PROTHETS 153 STROMA 155 TRANSFOG 157

Treatment 161 ANGIOSKIN 162 ANGIOSTOP 164 Apotherapy 166 ATTACK 168 BACULOGENES 170 CancerGrid 172 CANCERIMMUNOTHERAPY 175 CHEMORES 177 CHILDHOPE 179 DC-THERA 182 DC-VACC 184 Dendritophages 186 DEPPICT 188

TABLE OF CONTENTS 5 EMIL 190 ENACT 194 European LeukaemiaNet 196 European MCL Network 201 EUROXY 203 FIRST 205 GIANT 207 HERMIONE 209 Immuno-PDT 2 1 1 LIGHTS 213 MAESTRO 215 TEMPO 217 THERADPOX 219 TRANSBIG 222 TRIDENT 225 VITAL 227

Cancer control, Survivorship and outcomes research 231 CCPRB 232 EPCRC 234 EUROCAN+PLUS 236 EUSTIR 238 NORMOLIFE 240

Scientifi c Model Systems 243 ESBIC-D 244 ZF-TOOLS 246

6 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME CANCER: COMBATING A COMPLEX DISEASE

Human cancer is one of the oldest documented diseases. The oldest written evidence of the disease is found in Egyptian papyri from the period 3000 to 1500 BC which describe ulcers and breast cancer. The oldest specimen is a bronze age (1900-1600 BC) female skull suggesting head and neck cancer, whereas skeletal remains of a Peruvian – INCA – woman suggest melanoma.

Breast cancer, melanoma, as well as head and neck cancer and other solid cancers, are still present across the world today. Cancer is an increasingly important health burden, both for patients and public health systems with signifi cant societal and psychological consequences.

In recognition of this, a global eff ort to fi ght and control cancer has been set. Recently, the European Parliament published a resolution on Combating cancer in the enlarged Europe(1) and the council of the European Union in its conclusions on reducing the burden on cancer(2), invited the European Commission to extend knowledge of cancer epidemiology and cancer risk factors, early detection, diagnosis, treatment, survival and palliative care, as well as to include translational research under the Seventh Framework Programme.

In addition, the World cancer declaration 2008, calls for a concerted strategic action to reduce the global cancer burden and outlines the steps needed to begin to reverse the global cancer crisis by 2020. Moreover, it sets specifi c priority actions on health policy, prevention and early detection, cancer treatment, and cancer research(3).

The European Union’s strong research community is well placed to advance the understand- ing and treatment of cancer. Traditional approaches such as surgery, radiotherapy and chemotherapy are constantly improving, whilst genomic and immunological research off er innovative prospects for future treatment. In addition, new screening and detection methods are making it possible to confront the disease at an increasingly early stage. Furthermore, palliative care is increasingly recognised as important in ensuring cancer patients and their families to receive the best possible care and quality of life.

The European Union supports cancer research in order to prevent cancer and to improve patients’ survival chances and their quality of life. The ‘Combating Cancer’ initiative was part of the EU’s Combating Major Diseases research. Within the ‘Life Sciences, Genomics and Bio- technology for Health’ thematic priority of the Sixth Framework Programme, 2002-2006 some € 480 million of funding for cancer research has been made available to the European research community through the programme.

It aimed to combat cancer by developing improved patient-oriented strategies, from prevention to earlier and more eff ective diagnosis, to better treatment with minimal side eff ects. It supported initiatives aimed at translating knowledge of basic research into applications to improve clinical practice and public health actions.

This distinctive patient-oriented approach included four interlinked components, focusing on: • Establishing facilities and developing initiatives for the exploitation of cancer research in Europe, encouraging the development of evidence-based guidelines for good clinical practice and improved public health strategies by accelerating the translation of existing research results into applications.

(1) http://www.europarl.europa.eu/sides/getDoc.do?pubRef=-//EP//NONSGML+TA+P6-TA-2008-0121+0+DOC+WORD+V0//EN (2) Adopted 10/06/08, www.consilium.europa.eu/Newsroom (3) http://www.uicc.org/wcd/wcd2008.pdf

FOREWORD 7 • Supporting clinical research, particularly early stage (phase I and II) clinical trials, targeted at validating new and improved interventions. • Funding translational research that takes basic knowledge through to applications in clinical practice and public health. • Other cancer related issues, such as ageing and cancer, gender related cancer; regional diff erences, psycho-social aspects, palliative care, and guidance for support groups.

During the lifetime of FP6, many research groups applied and 108 projects were selected for fund- ing. Among the funded ones are 37 large Integrated Projects (IP) or Networks of Excellence (NoE); 64 Specifi c Targeted Research Projects (STREP) and 7 Coordination or Support Actions (CSA).

The EU is committed to funding excellence in European biomedical research. All submitted proposals were subject to a rigorous, transparent and equitable peer-reviewed evaluation carried out by independent international panels of high-level experts from academia, public and private research organisations, and industry.

Connecting European academic excellence with innovative research-based industry is the key to the success of translational research. Therefore, the Commission particularly encouraged small and medium-sized enterprises (SME) to participate in its research programmes.

The present catalogue includes cancer projects on a variety of topics. No less than 1 500 research teams are collaborating in European Union Member States and other European countries associ- ated with the Framework Programme, as well as selected third countries, such as USA, Chile, Australia, Russian Federation etc., thus consolidating an important critical mass to fi ght cancer. In fact, virtually all major European cancer research centres are taking part in one or several of the Commission-funded support schemes.

The presentation of the catalogue follows the Common Scientifi c Outline (CSO) fi rst presented as a classifi cation system of scientifi c interest in cancer research, in the framework of the Cancer Research Portfolio (CRP) of the National Institute of Health, USA.

They include 7 broadly defi ned research areas: • Biology • Aetiology (causes of cancer) • Prevention • Early detection, diagnosis and prognosis • Treatment • Cancer control, survivorship and outcomes research • Scientifi c model systems

The division into the diff erent groups is not always straightforward; therefore some of the projects could be classifi ed in one or more of the above areas. The essential fact is that these projects are all present in the catalogue and represent the enormous eff ort and constant devotion of the European research society to fi ght cancer.

Manuel Hallen Maria José Vidal Ragout Acting Director Health Research Deputy Head of Unit DG Research, European Commission Medical and Public Health Research DG Research, European Commission

8 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Biology

CancerCancer is a diseasediseaseet thatthat is chcharacterizedararacterized by uncuncontrolledncontrolled growth and spread of abnormal cells. Trans-Tranns- formationforrmation of a nornnormalmalal cecellll intinintoo a cancer ccellell is a comcomplexplep x multistemultistepp pprocessrocess inin whichwhichhc cellscelle s acquireacquuire capabilities tot didividevide iindefindend fi nitelynitely independentlyindependend ntly ofof growthgrorowth signals,signals, evade programmedprorogrammemed cellcell death,ded ath, invade neighbouringneighbououring tissuestissues andand metastasisemetatastasise to otherother partsparts ofof thethe body.body. DuringDuring thisthis transformationtransformmationo nnumerousumerous changeschahangnges occuroccur atat tthehe momolecular,lecular, bbiochemicaliochemical aandnd celcellularlular level.levle el. AllAll cancerscancn ers arise dueduue toto aaccumulationccumum lationon ofo gegeneticnetic and epepigeneticpigeg netic changes. SomSoSomee mmutationsutaatiotit ns mayy be presepresentntt in the gegermlinermlmlinine thuthusus iincreasingncreasasing ththehe rriskiisk ooff cacancerncer ddevelopment,evelopment, butb mamanyany occooccurur durduringingg ththee indiindividual’sviddual’s lilifefe iinn ttheheh somsosomaticatia c ccells.ells. TheTherehere are mammanynny aetaaetiologicaliollogical ffactorsactorss invinvolvedolvedd inn cancer, inclincludingudid ng ininfection,fectiono , exposureexposurre toto chchechemicalsmicm alss anandd ootherther eenvironmentalnvnvironmenmem tal ririskisks factors aandnd herediheredity.ty.y.y ThTThee past yyearsears hhahaveve witwitnessednesssed a dradramaticamattic proprogressgregr ss in understandingundu erstatanndining thethe mechanismsmece hanh isms ofof transformationtranr sformation of a normanormall ccellell into a cancercancer cellcell thatthath iss expexpectedececte ed to lealeadd ttoo mmajorajoor iimprovementsmproveveemenm ts in thetherapy.rrapra y. YetYYet,, oourur knoknknowledgewleedged is still fafarr ffromromr cocompleteompletee and muchmum chc remainsrememainns toto bebe discovered.discoovereded. ThiTThirtyrty sixsix projectsprojojects presentedpresr enten ede in thisthis sectionsection investigateinvestigate mechanismsmechaninisms thatthat underlieunderlie cancercancnceer initiation,iniitiation,n prproprogressiongreg ssion andnd memetastasisetasta tasis anand cocompareompare thethemm wwithith ththeireir nonormalrmal ccounterparts.ounterparts.ts A numnumberbeber of ththemem focfocusus on molmomolecularecular memechanisms,chanisms,s inincludingcluudding DDNANA reprepair,aira , ooncogenes,ncogenes, tutumormor susuppressorppresses orr genggenes,es, chchromosomeromososomee altalterations,erations,ns tetelomerelomere mamaintenance,intntenance, eepigenetics,pigenetics, and prprogrammedogrammmede celcelll ddeath.eath. Due tot availabilityavailability ooff tthehe comcompleteplel te humhumanan gengenomeomeom anandd rrapidapid iincreasencrease iinn pproteomicroteomeoomicc anda trtranscriptomicansan cririptop micic datdataa aann integrative aapproachpprpp oachih iiss nneeded.eedee ed. A grogroupup of proprojectsjects prepresentedsented in ththisis secsectionction eemploymploy syssysystemstems andnd compucomputationaltattiono al biobbiologylogyay aapproachespproaches anandd hhigh-throughputigh-throughput anaanalyseslyses to invinvestigateestigagatee comcomplexplex nnetworketwork off intiinteractionseractitions in ththee ccell.ell. MorMoreover,oreover, FP6FP6 ssupportsupppportssr rresearchesearch oonnnt ttheheh devdevelopmentelopment of sopsophisticatedhisticated ttoolsools aandnd novnovelel tectechnologies,hnohn loglo ies, fforor exampleexe ample analysesanalyses and imagingimaging inn situ,situ, thatthat wwillilll enenableable rresearchersesearchers ttoo iinvestigatenvenv stigate nnormalormmal funfufunctioningctioning off the cellcec ll and thethhe changeschhanges that lealeadead ttoo ccancerancer iniinitiationtiation aandnd proprogression.gressiss on.o ‘Kn‘KnowKnnow your eenemy’nemmy’y – ssaidaid SunSuun TzuTzu inn the ‘The‘The Art off War’.War’.r. ResearchResearch on cancercancen r biologybiologyog is crucialcrucial in our fifig gghtht with canccancer.er.r. ExExploringpplorinng tthehe key ggegenetic,netic, biochemical and cellulacellularr cchangeshahanges ininvolvedvolved in cancercancer initia-initia- tiotionion and progressionprogressisionn willwill yieldyiele dnd newnew disease biomarkers and targets forfor treatmenttreaatmetm nt and ultimatelyultimatelyl pavpavee the wayay to new ttherapies.herapipieses.

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9 Keywords | Tumour suppression | p53 | p73 | p63 | inhibitors | activators |

Active p53 Problem

Manipulating tumour suppression: Cancer is the second leading cause of death in European countries, and one of the most imminent health problems in a key to improve cancer treatment the developed world. The p53 protein is generally recog- nised as the key determinant of tumour suppression. It has been declared by the European Union that ‘a large co- Summary operative eff ort is needed to ensure that every European citizen will rapidly profi t from the revolution of knowledge in The prevention of human cancer development depends on cancer management’ (Philippe Busquin). The presence of the integrity of a complex network of defence mechanisms wild type p53 is particularly prevalent in breast cancer, the that help cells to respond to various stress conditions. A key type of cancer that stands at the centre of the European player in this network is the p53 tumour suppressor protein. cancer policy. Since breast cancer aff ects mostly (though By inducing effi cient growth inhibition, p53 eliminates can- not exclusively) women, breast cancer research is also an cer cells thereby preventing the development of human important task to implement the gender dimension into malignancies. These functions of p53 often determine the basic research. For these reasons, we will choose breast effi cacy of anti-cancer therapies. Although p53 is frequently cancer as one of our focuses in this block of work. Moreover, mutated in some cancers, in about 50% of all human can- a non-mutated but inactive p53 is also found in a high per- cers p53 is non-mutated and could, in principle, be activated centage of the most frequent intracranial tumour of children, to prevent tumour progression. This situation is prevalent neuroblastoma. Since paediatric tumours are particularly among a wide range of cancers, notably breast carcinoma. dramatic events for patients and their families, it appears However, p53 activity is hampered by malfunction of its appropriate to put another focus on this tumour species. many modulators, such as Mdm2 or p73, which govern p53 tumour suppressive activity by acting upstream and/or s downstream of p53. There is therefore a crucial need to 53 im p Homologues il o a t ri understand how p53 modulators contribute to human s t WB3 ie ie t s malignancies. Based on this information, we propose to i t r o a l develop rational therapeutic approaches to manipulate i p 5 m i 3 p53 modulators, thereby wakening the sleeping tumour s suppression activities of p53, allowing it to eliminate can- Activators Activators cer cells. This carefully structured consortium comprising WB1 p53 WB2

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i e identify relevant signalling pathways that impair or mediate d and technology tumour suppression by p53. These analyses will include p53 WB4 activators and inhibitors, p53 homologues p73/p63, and dissection of p53 target genes mediating apoptosis and growth arrest. Our links with highly profi led clinical partners The four blocks are linked as outlined. These links are formed according to the biological and our access to large, well-characterised and clinically activities governing p53 and, therefore, the scheme simultaneously depicts biological documented sample collections will enable the evaluation dependencies as well as the mode of collaboration within the consortium. Activators of p53 of diagnostic expression profi les, and their potential prog- frequently act by antagonising p53 inhibitors, and vice versa; this will be taken into account by nosis value in cancer. Particular emphasis will be directed networking accordingly between the blocks 1 and 2. Activators and inhibitors of p53 may act on towards translating the information on p53 regulation into p73 and p63 as well and this was shown to be true in a number of cases. Therefore, each the development of new anti-cancer therapies. p53 regu- regulator of p53 will be assessed regarding its impact on p53-homologues as well by latory proteins will be used for the identifi cation of new collaborative eff orts between block of work 3 with blocks 1 and 2. Finally, the assessment of p53 molecular targets for drug discovery. downstream activities, and the development of cutting-edge technologies to analyse them, will be used throughout the consortium. Therefore, block of work 4 forms a basis not only for reaching excellence on its own, but also to eff ectively advance the progress of blocks 1, 2 and 3. © C. AND M. KAGE

10 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME p53-homologues deltaNp73/p63 Partner 2 p73/p63 ligands Partner 9 p73, c-Abl, p300 Partner 11 p73TA and YAP Partner 15

p53 activators ASPP Partner 5 Clinical Biotech SMEs p53 inhibitors NFkappaB Partner 6 units Mdm2 and p14Arf Partner 7 Pin1 Partner 14 genomics Mdm2 and c-Abl Partner 3 HIPK2 Partner 14 patient data proteomics Mdmx Partner 12 Chk1/Chk2 Partner 10 specimens drug leads Mdm2 drug traget Partner 17,2 JMY/Strap/p300 Partner 8 therapy Integrin avb3 Partner 13

p53 activity and technology intrabodies Partner 15 apoptosis Partner 4 senescence Partner 7 V.R. DNA structure Partner 16 DNA binding in vivo Partner 3, 15 Outline of the consortium. targets/regulators Partner 18, 1

Aim • whether and how p53 modulators can be targeted by therapeutic strategies, and be manipulated towards The principal aim of this proposal is to ease both diagnosis regaining tumour suppression; and prognostic classifi cation, as well as the eff orts towards • disseminate the knowledge that will be produced to novel therapy regimens to treat patients suff ering from practically all the interested parties including medical breast cancer and neuroblastoma. Overall, the integrated doctors, and managerial staff in the industries; action of our consortium is aiming at re-establishing tumour • familiarise SMEs with scientifi c research work and state- suppressor activity in cancer, thereby translating basic of-the art technology that will provide the necessary knowledge of functional oncogenomics into cancer diag- know-how for the improvement of their services and noses and treatment, and contributing to leadership in competitiveness. European health technology. Potential applications Expected results The ultimate general objective of this research proposal is to The overall goals of this integrated eff ort are to understand: provide a basis for the re-activation of tumour suppression • which modulators determine the tumour-suppressive and the design of novel therapeutic approaches to combat activities of the p53 family members; cancer. In particular, we are aiming at modulating p53 family • by what mechanisms these modulators aff ect the tumour activities to decrease resistance of tumour cells to anti-cancer suppression activities; treatments. Thus, the ultimate goal of this research proposal • how the expression and activity of p53 modulators is is the identifi cation of novel drug targets and strategies for regulated; induction of p53-mediated apoptosis in therapy-resistant • whether p53 modulators aff ect the biological characteris- cancer cells. The participation of the SMEs is expected to tics of tumour cells; play a key role to the practical application of the knowledge • whether the status of p53 modulators correlates with that will be produced. the clinical outcome and can be used to determine the individual prognosis;

BIOLOGY 11 Coordinator Project number LSHC-CT-2004-503576 Giovanni Blandino Varda Rotter/Moshe Oren Gianni Del Sal Translational Oncogenomics Unit Weizmann Institute of Science Università degli Studi di Trieste EC contribution Molecular Medicine Department Molecular Cell Biology/Biology Dipartimento di Biochimica € 6 000 000 Regina Elena Cancer Institute Rehovot, Israel Biofisica e Chimica delle Macromolecole Via Elio Chianesi, 53 Trieste, Italy Duration Rome, Italy Nicholas B. La Thangue 60 months [email protected] University of Oxford Richard Iggo Oxford, United Kingdom University of St. Andrews Starting date St. Andrews, United Kingdom 01/12/2004 Partners Gerry Melino Medical Research Council Wolfgang Deppert Instrument Matthias Dobbelstein Leicester, United Kingdom Heinrich-Pette-Institut für Experimentelle IP Georg-August-Universität Göttingen Virologie und Immunologie an der Göttingen, Germany Jiri Bartèk Universität Hamburg Project website Danish Cancer Society Dept. of Tumour Virology www.europeire.it/ Ygal Haupt Dept. of Cell Cycle and Cancer Hamburg, Germany Activep53/intro.htm The Lautenberg Center for General Institute of Cancer Biology and Tumour Immunology Danish Cancer Society David Lane/Sonia Lain The Hebrew University – Hadassah Copenhagen, Denmark University of Dundee Medical School Dept. of Surgery and Molecular Oncology Jeruslem, Israel Massimo Levrero Nethergate Fondazione Andrea Cesalpino Dundee, United Kingdom Guido Kroemer Laboratory of Gene Expression INSERM Institut National de la Santé Rome, Italy Simona Greco et de la Recherche Médicale Biotecgen s.r.l. Paris, France Aart Gerrit Jochemsen Dept. of Biological Sciences Dept. Molecular and Cell Biology Institute of Physiology Xin Lu Tumour Suppressor Group Lecce, Italy Tumour Suppressor Group Leiden University Medical Center Ludwig Institute for Cancer Research Leiden, The Netherlands Cristina Fregonese London, United Kingdom INNOVA spa Galina Selivanova Tecnopolo Tiburtino Karen Voudsen Karolinska Institute Rome, Italy The Beatson Institute for Cancer Research Dept. of Laboratory Medicine Tumour Suppressor Laboratory Stockholm, Sweden Roberto Mantovani Glasgow, United Kingdom GeneSpin srl SME Milan, Italy

12 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Angiogenesis | vasculogenesis | blood vessels | tumour | endothelial cells | clinical trials | microarrays | proteomics molecular targets |

ANGIOTARGETING Targeting non-cancer cells that feed and drain the tumour and form channels through which tumour cells can disseminate, Multidisciplinary research to explore rather than targeting the neoplastic cells themselves, repre- sents an approach to cancer therapy that holds particular and validate molecular targets promise because these cells are genetically stable, and there- fore less likely to accumulate mutations that allow them to for innovative treatments develop drug resistance. The fi rst meaningful clinical eff ects of antiangiogenic therapy in human cancer have recently been demonstrated. However, in spite of some highly encouraging results, most angiogenesis inhibitors, reported to suppress Summary tumour growth in animal models, have thus far failed in human clinical trials. In our view, this refl ects that no standardised Solid tumour growth depends on the recruitment of new tools and models have been identifi ed that reliably refl ect the blood vessels that will provide the cancer cells with nutri- complexity of tumour angiogenesis mechanisms in humans. ents and oxygen. The ANGIOTARGETING project intends to The successful translation of potential angiogenesis inhibitors fi nd new targets on the tumour vasculature. The project will to clinical application depends partly on the transfer of exper- then defi ne these targets and develop new therapeutic tise from scientists who are familiar with the biology of strategies towards them. angiogenesis to clinicians, as well as an active feedback from the clinicians to the scientists. The apparent limited success in translating angiogenesis research into the clinic is, in our view, based on the fact that ANGIOTARGETING aims at the identifi cation and validation the research fi eld has been fragmented, and no standard- of new therapeutic targets in tumour vasculature, develops ised tools and models have been identifi ed that reliably new therapeutic strategies and implement such strategies refl ect the complexity of tumour angiogenesis mechanisms in pre- and clinical trials. A strong focus on translational in humans. research and clinical implementation will convert R&D results into direct public and economic benefi ts. ANGIOTARGETING will identify and validate new thera- peutic targets directed towards tumour vascular-matrix interactions, develop new therapeutic strategies and imple- Aim ment such strategies in pre- and clinical trials. The project represents a virtual research institute in Europe and con- The objective is the identifi cation and validation of new sists of 14 highly competent research centres within the therapeutic targets directed towards tumour vascular- fi eld of angiogenesis research. To defi ne and validate new matrix interactions. targets related to the tumour vascular transcriptome and proteome, the consortium will establish high throughput functional screening technologies for the identifi cation of Expected results novel secreted factors that regulate endothelial cell growth and survival. This includes the use of robotic platforms that • The project will increase our understanding of how will be used to identify cDNAs with specifi c cellular func- tumours generate a vascular supply. tions. In this project, basic science, translational research • The project will develop new technologies to defi ne and clinical activities are strongly integrated, in order to and validate key molecular targets that control tumour validate defi ned targets and to develop new therapeutic vascularisation and invasion. principles for clinical implementation. • The project will identify potential therapeutic targets towards the tumour vascular and invasive transcriptome and proteome. Problem • The project will develop comprehensive bioinformatics tools for the analysis of high throughput gene and pro- The signifi cant role of neovessel formation in health and dis- tein data from defi ned cell populations within tumours. ease has been clearly demonstrated during the last decade. • The project will develop state-of-the-art platforms for The molecular mechanisms that lead to the establishment of preclinical and clinical assessment of newly developed functional blood vessels are also key factors that regulate compounds. tumour progression. Considerable eff orts have been devoted • The project will provide new information on how poten- to research identifying the mechanisms that regulate the tial antivascular therapies shall be evaluated in the clinic. recruitment of blood vessels to tumours. Under normal This includes the development of surrogate markers to conditions, the establishment of blood vessels is a highly evaluate therapeutic effi cacy. complex and coordinated biological process.

BIOLOGY 13 Potential applications Project number LSHC-CT-2004-504743 The project will lead to the identifi cation of a number of potential targets towards the tumour vasculature. Within the EC contribution ANGIOTARGETING consortium there are a number of activi- € 6 000 000 ties aiming at developing novel therapeutic strategies towards identifi ed and validated targets. Some of these strategies will Duration be applied and assessed in preclinical and clinical trials. 54 months

Starting date 01/11/2004 Coordinator Instrument Rolf Bjerkvig Adrian Harris IP University of Bergen University of Oxford Bergen, Norway United Kingdom Project website [email protected] [email protected] www.uib.no/med/ angiotargeting/ Partners Henk Broxterman Vrije Universiteit Medical Center Amsterdam Helge Wiig, Karl-Henning Kalland Amsterdam, The Netherlands and Inge Jonassen [email protected] University of Bergen Bergen, Norway Taina Pihlajaniemi [email protected] University of Oulu [email protected] Oulu, Finland [email protected] [email protected]

Francesco Bertolini Eva Sykova European Institute of Oncology Institute of Experimental Medicine Milan, Italy Prague, Czech Republic [email protected] [email protected]

Lena Claesson-Welsh Simone Niclou University of Uppsala Centre de la recherche public de la santé Uppsala, Sweden Luxembourg [email protected] [email protected]

Peter ten Dijke Karl Tryggvason and Yihai Cao Leiden Medical University Center The Karolinska Institute Leiden, The Netherlands Stockholm, Sweden [email protected] [email protected] [email protected] Michael Kubbutat Proqinase/KTB Tumorforschungs GmbH Peter Vajkozcy Freiburg, Germany Charité-Universitatsmedizin [email protected] Berlin, Germany [email protected] Arjan W. Griffioen and Johannes Waltenberger Leo Hofstra University Hospital Maastricht PharmaTarget BV Maastricht, The Netherlands Maastricht, The Netherlands [email protected] [email protected] [email protected]

14 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Tumour-host interactions | tumour targeting |

Anti-tumour targeting The strategies to target the tumour will be based on gene, cell and immune therapy methods. They will include the use of: Modulation of the Recruitment of • adenoviruses for the expression of angiogenesis inhibitors following targeted delivery of the viruses to the tumour the Vessels and Immune Cells by vasculature; • the genetic modification of murine embryonic and human Malignant Tumours: Targeting of Tumour umbilical cord/bone marrow progenitor cells and their directed homing into the tumour; Vessels and Triggering of Anti-Tumour • the use of genetically-engineered immune cell products or the transduction of immune cells to activate targeting of Defence Mechanisms the tumours by innate and adaptive anti-tumour defence mechanisms. We expect that this project will contribute to innovation on three levels. Firstly, we will gain basic addi- tional novel knowledge on important pathways and Summary regulatory molecules for the recruitment of host cells to the tumours and their functional interaction with the All malignant tumours acquire the capacity for efficient tumour. Secondly, we will use this knowledge to test novel recruitment of blood vessels, which are absolutely neces- ways of targeting viruses and (transduced) cells to the sary for tumour growth beyond a certain size. They also tumours. Finally, we will evaluate whether, by a combina- frequently stimulate lymphangiogenesis supporting dis- tion of anti-angiogenesis therapy with directed anti-tumour semination of tumour cells, not only via the blood vasculature immunotherapy, it would be possible not only to inhibit but also via the lymphatic system, leading to metastasis. tumour growth, but also to eradicate residual disease. Vessel growth is promoted by sprouting angiogenesis and the homing of bone marrow progenitor cells into the tumours and tumour vessels. The extensive vascularisation Problem facilitates the invasion of cells of the innate and adaptive immune system, which stay largely functionally suppressed Despite significant improvements in diagnosis, surgical tech- by the tumour environment, and even contribute to angio- niques, general patient care, and local and systemic adjuvant genesis and tumour growth by cytokine and growth factor therapies, many solid tumours remain a major cause of death. secretion. Among the most prevalent and fatal forms are carcinomas of the breast, colon and prostate. Most deaths from cancer are We propose in this application to: due to metastases, seeded from the primary tumour via the • further investigate key regulatory pathways by which blood and lymph vasculature, which are resistant to conven- tumour-secreted molecules promote vascularisation tional therapies. The main barrier to the non-surgical treatment and inhibit immune cell function; of the primary neoplasm and its metastases is the genetic • develop methods to inhibit tumour growth and metas- instability and biological heterogeneity of cancer cells leading tasis by blocking vessel and tumour cell growth; to the rapid development and growth of resistant cells. Since • achieve tumour clearance by additionally promoting the expansion of solid tumours and their metastases beyond activation and homing of functional immune cells to the a minimal size is absolutely dependent on the formation of tumours. new blood vessels, anti-angiogenesis therapies constitute a promising alternative. In this case the genetically normal The project will comprise the collaboration of laboratories endothelial cells of the tumour vessels are targeted, avoiding with complementary expertise. It will include experts in blood the problem of resistance development. Furthermore, immune vessel and lymph vessel angiogenesis, metastasis formation, therapies are based on the ability of the immune system, progenitor cell incorporation into tumours and tumour evolved over evolutionary times, to cope with an almost unlim- vessels, anti-tumour defence mechanisms of the immune ited number of antigens, thus opening the possibility to find system and viral transduction techniques. The final goal will a mechanism to target any tumour variant as long as the be the preclinical evaluation of strategies in murine models inhibitory milieu of the tumour environment can be overcome. of three of the most prevalent forms of human cancer, Therefore angiogenesis and immune therapies remain among i.e. carcinomas of the breast, colon and prostate. the most promising fields of cancer therapy.

BIOLOGY 15 Aim Coordinator Project number LSHC-CT-2005-518178 The general aim of the project is to design and evaluate strate- Erhard Hofer gies of anti-tumour angiogenesis and anti-tumour immune Dept. of Vascular Biology EC contribution therapies and their combination in murine models of some of and Thrombosis Research € 3 005 000 the most prevalent forms of human solid tumours. It will Centre for Biomolecular Medicine include the identification, modification and use of key regula- and Pharmacology Duration tory molecules of vessel growth and immune defence and the Medical University Vienna 36 months development of methods to specifically and efficiently target Vienna, Austria tumours and their metastasis. [email protected] Starting date 01/11/2005

Expected results Partners Instrument STREP We will undertake a concentrated eff ort to identify targets Seyedhossein Aharinejad and develop methods for interference with vessel growth. University of Vienna Project website Furthermore, we will develop techniques to target tumour Vienna, Austria www.tumortargeting.eu endothelium by viruses and progenitor cells,methodsthat [email protected] could be usedto also reachdistant metastases via the blood stream and not only the primary tumour. In addition, we will Michael Detmar explore the use of innate receptors of NK cells to detect malig- Institute of Pharmaceutical Sciences nant cells and to boost the T-cell response of the immune Swiss Federal Institute of Technology system with the help of dendritic cells. Weanticipate thata- Zurich, Switzerland single method,depending on the individual tumour, may not [email protected] be sufficient, but the development of several techniques based on diff erent principles and their tumour-specific or Hidde Haisma combined application may be successful. University of Groningen Groningen, The Netherlands For this purpose we combine laboratories with diff erential [email protected] expertise, each having either identified a specific target mole- cule or developed a specific technique for targeting tumours. Peter Vajkoczy We will combine the expertise, molecules and techniques and Charité Universitätsmedizin comparatively evaluate diff erent strategies in corresponding Berlin, Germany models of human carcinomas. [email protected]

Ofer Mandelboim Potential applications Hebrew University Hadassah Medical School The results of this project will be disseminated and exploited Jerusalem, Israel on three levels: [email protected] • basic molecular medicine research level: all expected findings with the angiogenesis inhibitors and immune Karsten Mahnke stimulators will be important to improve understanding University of Heidelberg of the role of vessel formation and of anti-tumour Heidelberg, Germany immune responses for cancer. These basic findings will [email protected] be published in quality scientific journals; • clinical level: it is anticipated that our findings and devel- Melvyn Little oped preclinical methods will have impact on the design Affimed Therapeutics AG and further development of clinical protocols for the Heidelberg, Germany treatment of cancer; [email protected] • company level: key novel molecules, findings and tech- niques will be patented and, together with patents Karl-Heinz Preisegger available, used to develop reagents and protocol for EccoCell Biotechnology and gene-therapy of solid tumours. Stem Cell Therapy GmbH Graz, Austria [email protected]

Project number

16 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Breast | metastasis | gene expression profi ling |

BRECOSM Problem

Identifi cation of molecular pathways Breast cancer is a major health issue and is highly gender rel- evant. It is the most often diagnosed female cancer, and the that regulate the organ-specifi c majority of cases are already invasive at diagnosis. More than 17% of cancer deaths result from breast tumours, making metastasis of breast cancer breast cancer a major societal problem. Treatment involves radical and disfi guring surgery, often with long-term side eff ects such as the development of lymphedema of the arm, and radiotherapy and chemotherapy, again associated with Summary severe side eff ects. The eff ects of metastatic spread of the tumour cells and the formation of secondary deposits in The objectives of this project are to identify genes, proteins a wide variety of organs are the cause of death due to breast and molecular pathways involved in regulating the metastasis cancer. Metastases to organs such as bone and brain are of breast cancer to specifi c organs. To achieve these major causes of suff ering in terminally ill patients. objectives we will use a combination of gene expression profi ling, bioinformatic analysis, histology of human female The incidence of breast cancer increases sharply between breast cancer samples, genetic manipulation of transplantable the ages of 30 and 50 meaning that many women in the tumor cells and transgenic mouse technology. In addition to prime of life are aff ected by this disease. Not only does this fi nding new genes, we aim to analyse to what extent genes mean that many families are traumatised, but it also has already known to play a role in breast cancer metastasis severe economic consequences, removing economically specify which organs breast tumors metastasise to. We will active women from society. Further economic consequences also establish how the currently known genes that are arise as a result of the high health care costs associated associated with breast cancer dissemination and the new with treating breast cancer patients. ones we identify fi t together into pathways that regulate organ-specifi c metastasis. These fi ndings will be coupled Clearly improvements in the treatment and management of with the analysis of clinical trials in which participants in this breast cancer would have impact on both health and the consortium are involved. Further deliverables include the economy. By analysing molecular mechanisms that regulate development of improved animal models for the study of organ-specifi c metastasis in breast cancer, the BRECOSM breast cancer metastasis, and the development of diagnostic project will identify tools that will contribute to improved methods for determining whether primary tumours already clinical decision-making, prognostic evaluation and therapy have metastatic potential. Together, the work packages in in breast cancer. this project will establish a pipeline of activities that unite basic research into the organspecifi c metastasis of breast cancer with target validation and clinical application. Aims

• To identify genes that are specifi cally up- or down- regulated in breast cancer metastases in specifi c organs. • To identify gene expression signatures in primary breast tumours that predict metastasis to specifi c organs or predict the prognosis of ductal carcinoma in situ (DCIS). • To determine whether genes already associated with breast cancer invasiveness and metastasis are expressed in metastases in all or only a subset of organs. • To demonstrate whether genes found to be specifi cally expressed in breast cancer metastases to given organs play a functional role in organ-specifi c metastasis. • To elucidate molecular pathways that regulate breast cancer metastasis to specifi c organs. • To develop improved animal models for studying organ- specifi c metastasis of breast cancer. • To produce a prototype microarray chip for diagnostic/ prognostic evaluation. Wholemount staining of the epithelial ductal structure in a mouse mammary gland. • To apply the fi ndings on organ-specifi c metastasis in the The lymph nodes are also visible as densely-stained spheroidal structures. clinical setting.

BIOLOGY 17 Expected results Coordinator Project number LSHC-CT-2004-503224 • The results of this project will begin to explain the molec- Jonathan Sleeman ular basis for organ-specifi c metastasis in breast cancer. University of Heidelberg EC contribution • This project will identify regulatory pathways and cellu- Medical Faculty Mannheim € 3 430 273 lar events that coordinate organ-specifi c metastasis of Centre for Biomedicine and Medical breast cancers. Novel targets for therapy will thereby be Technology Mannheim (CBTM) Duration identifi ed. Mannheim, Germany 42 months • This project will identify gene expression signatures in [email protected] tumours associated with metastasis to particular organs. Starting date This will be an important advance in understanding the 01/07/2004 underlying genetic changes that regulate organ-specifi c Partners metastasis in breast cancer. Instrument • This project will bring together European experts working Frans Van Roy STREP on diff erent aspects of the molecular basis of tumour Dept. for Molecular Biomedical Research metastasis. As a result of coordinated eff orts, pathways VIB – Gent University Project website that regulate metastasis to specifi c organs will be deter- Gent, Belgium http://igtmv1.fzk.de/ mined, and genes that play a functional role in organ-specifi c [email protected] www/brecosm/ metastasis will be identifi ed. • This project will generate improved animal models for Gerhard Christofori the further study of breast cancer metastasis to specifi c Institute of Biochemistry and Genetics organs. Dept. of Clinical-Biological Sciences Peter ten Dijke • This project will identify gene expression signatures in University of Basel The Netherlands Cancer Institute primary breast tumours that predict patterns of metas- Basel, Switzerland Division of Cellular Biochemistry tasis. The application of these fi ndings will assist clinical [email protected] Amsterdam, The Netherlands decision making and prognostic evaluation. & Leiden University Medical Center (LUMC) Eugene Lukanidin Leiden, The Netherlands Danish Cancer Society [email protected] Potential applications Institute of Cancer Biology Copenhagen, Denmark Roland Stauber The gene expression signatures in primary tumours identi- [email protected] Chemotherapeutisches Forschungsinstitut fi ed in this project that predict organ-specifi c metastasis Frankfurt am Main, Germany and the prognosis of DCIS will have obvious potential for Jean-Paul Thiéry & Johannes Gutenberg Universität Mainz clinical application in diagnosis and prognostic assessment. CNRS – UMR 144 Mainz, Germany Gene expression signatures in primary tumours associated Institut Curie [email protected] with either organ-specifi c metastasis or progression of DCIS Cell Biology Department will be extensively validated retrospectively and as a prelude Paris, France Massimo Zollo to introducing these gene expression signatures into clinical [email protected] TIGEM-Telethon diagnosis and prognostic evaluation, we will perform pro- Naples, Italy spective studies to demonstrate the effi cacy of examining Bernd Hentsch & CEINGE Biotecnologie Avanzate, S.c.a.r.l. gene expression signatures in primary breast cancers for TopoTarget Germany AG Naples, Italy predicting the likelihood and location of metastases and the Frankfurt am Main, Germany [email protected] probability that DCIS will progress and metastasise after [email protected] partial mastectomy. The prototype microarray chips we cre- Peter Schlag ate based on gene expression profi les produced as part of Agnès Noël Charité Universitätsklinikum Berlin this project will be applied in the clinical setting to investi- Laboratoire de Biologie des Tumeurs Berlin, Germany gate their diagnostic and prognostic value for breast cancer et du Développement [email protected] in a prospective study. This will constitute a major step Liège, Belgium towards exploitation of the results. It is also highly likely that [email protected] genes are identifi ed in this project will be candidate targets for the development of novel cancer therapies. The develop- John Collard ment of such therapies lies outside the time-frame and The Netherlands Cancer Institute scope of the proposal. Division of Cell Biology Amsterdam, The Netherlands [email protected]

18 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Identifi cation of novel compounds | natural products | inhibition of protein-protein interactions | high-throughput screening |

CAPPELLA Expected results

Combating cancer through novel Innovative tools for designing PPI inhibitors • Five diff erent PPI-inhibitor library creation tools, based approaches to protein-protein on fi ve complementary approaches: • in silico; interaction inhibitor libraries • genetic chemistry; • advanced natural product technologies; • retro-synthesis of natural scaff olds; • ADME improvement. Summary • Cross-fertilisation of approaches so that each of the fi ve approaches learns lessons from the others and incorpo- The inhibition of protein-protein interactions (PPI) is one of rates relevant leanings into its approach. the most promising approaches to the development of novel • Three high-content assay systems for three important cancer therapies. This project brings together some of PPI cancer targets (p53-Mdm2, Beta catenin-TCF4, Europe’s leading biotech SMEs and several highly recognised BRCA2-RAD51). academic institutes. By combining fi ve distinct chemical • Design rules for PPI inhibitor compound libraries (mass, approaches and testing them on three diff erent targets (all diversity composition, lipophilicity, compound class etc.) from diff erent partners) a series of innovative small-ligand generated from 15 complementary data sets. tools and libraries that allow new approaches to the inhibi- tion of PPI in cancer will be developed. The project is a unique Novel small-ligand libraries and pre-clinical candidates opportunity to integrate novel in silico, chemical, genetic • Several ‘PPI inhibitor’ compound libraries. and ADME-based approaches to the design, synthesis and • Diff erent candidate compound families from within these optimisation of libraries and compounds. libraries that can subsequently be taken forward into pre-clinical testing by the SME partners. Problem

Most protein-protein interactions occur within the cell and thus can only be targeted by small molecules. Furthermore, PPI diff er structurally from more classic drug targets such as enzymes and receptors, and consequently existing compounds have generally delivered disappointing results. Therefore, new approaches are needed to develop novel small molecules which inhibit PPI in cancer.

Aim

The objective of this project is to develop a series of innova- tive smallligand tools and libraries that allow new approaches to the inhibition of protein-protein interactions in cancer. A key theme is the utilisation of structural motifs found in natural PPI-inhibitor compounds. This is coupled with high content testing of the resultant structures on three distinct PPI targets relevant to diff erent types of cancer, to allow compound rule- sets to be developed and improved. We want to develop small-ligand libraries focused on PPI inhibitors of relevance to cancer. Furthermore, we will develop innovative tools that allow improved library design in this area by integrating in silico approaches, bio-informatics, new approaches to compound synthesis and pharmacology. The project will also cover the scientifi c areas such as in silico prediction of drug-like proper- ties, prediction of ADME parameters, predictive toxicology and creation of virtual libraries. Libraries containing extracts of biological material off er great chemical diversity.

BIOLOGY 19 Coordinator Project number LSHC-CT-2006-037251 Sanne Jensen Birger Lindberg Møller Tanja Thybo Royal Veterinary EC contribution Evolva SA & Agricultural University € 3 361 300 Basel, Switzerland Copenhagen, Denmark [email protected] Duration Carmen Cuevas 36 months Pharmamar SA Partners Sociedad Unipersonal Starting date Madrid, Spain 01/01/2007 Hajo Schiewe AnalytiCon Discovery GmbH Ashok Venkitaraman Instrument Potsdam, Germany University of Cambridge STREP – SME Cambridge, United Kingdom Lise Madsen Project website BioLigands ApS Ariel Ruiz i Altaba www.cappellabio.eu Odense, Denmark University of Geneva Geneva, Switzerland Thierry Langer Inte:Ligand Juhan Sedman Software-Entwicklungsund University of Tartu Consulting GmbH Tartu, Estonia Vienna, Austria

20 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Systems biology | modelling | simulation | functional genomics |

COMBIO Aim

An Integrative Approach to Cellular It is not our goal here to come out with a new software package, or to simulate a whole cell. Rather our project aims Signalling and Control Processes – to bring computer models and simulations to the experi- mental community. To do so we will focus on two systems Bringing Computational Biology involving diff erent aspects of biological systems: networks and self-organisation and we will apply diff erent simulation to the Bench approximations to both of them. This will enable us to iden- tify both the modelling and the simulation strategies that are better suited for a particular experimental problem. Summary Expected results The project combines a unique group of experimentalists, bio- informaticians and simulation groups in order to gain detailed The expected result will be a set of guidelines specifying understanding of key processes: the P53-MDM2 regulatory which, and how, simulation methods should be used, given network and the self-organisation process whereby chromatin the problem at hand. These guidelines will also indicate controls microtubule nucleation and organisation. A major how best simulations and experimental procedures might objective will be to benchmark the ability of current modelling be combined to answer key questions about biological and simulation methods to generate useful hypotheses for function. experimentalists and to provide new insights into biological processes of realistic complexity. Potential applications

Problem The generation of the guidelines described above should make a fundamental contribution to the area of functional It is increasingly being recognised that the progress of mod- genomics, and provide ways for elucidating the mechanisms ern day biology will require understanding and harnessing of action of pharmacological compounds. the network of interactions between genes and proteins, and the functional systems that they generate. Given the complexity of even the most primitive living organism, and our still very limited knowledge, it is unreasonable to expect that we might, in the near or even medium term, reach such understanding at the level of an entire cell. However, signifi - cant progress towards a system-level understanding should be achievable by applying an integrated approach to the analysis of a set of well-defi ned and biologically important cellular processes.

BIOLOGY 21 Coordinator Project number LSHG-CT-2004-503568 Isabelle Vernos Edgar Wingender Centre for Genomic Regulation (CRG) University of Göttingen EC contribution Barcelona, Spain Dept. of Bioinformatics € 1 998 000 [email protected] Göttingen, Germany Duration Béla Novák 42 months Partners Technical University of Budapest Molecular Network Dynamics Starting date Francois Nedelec Research Group 01/03/2004 European Molecular Biology Budapest, Hungary Laboratory (EMBL) Instrument Cell Biology and Biophysics Unit Alfonso Valencia STREP Heidelberg, Germany National Centre for Biotechnology Protein Design Group Project website Olga Kel-Margoulis Madrid, Spain www.pdg.cnb.uam.es/ Edgar Wingender COMBIO/ BIOBASE Pathway Databases Cayetano Gonzales Wolfenbüttel, Germany Parc cientific de Barcelona Cell Division Laboratory Uri Alon Barcelona, Spain Weizmann Institute of Science Dept. of Molecular Cell Biology Luis Serrano Rehovot, Israel Systems Biology Research Unit Barcelona, Spain Marcelle Kaufman [email protected] Université Libre de Bruxelles Centre for Nonlinear Phenomena and Complex Systems, Brussels, Belgium

22 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Oncology | anticancer therapy | clinical pharmacology | uncommon cancer | sarcomas | GIST | children | adults |

CONTICANET Problem

Connective Tissue Cancers’ Network Scientifi c challenges • Connective tissue tumours: a collection of rare tumours. to integrate the European Experience • Molecular characterisation is routine for few tumours, in progress for other tumours but unknown for most in Adults and Children tumours. • There is a need for harmonisation of research activities in the following fi elds: • molecular characterisation of these tumours, Summary • functional genomics. • Pharmacology: target characterisation and validation. Connective tissue cancers, and more specifically sarcomas, • Promotion of clinical and translational research. GIST, aggressive fibromatosis and hamartomas, are uncom- • Improvement of medical practices. mon cancers with an incidence below 2/100 000 per year in • Education of the physicians for CPGs. the EU aff ecting children, young adults and adults. At a national • Epidemiology and medical economics. level, the limited number of cases (about 7/10 000 in Europe each year) does not allow Europe to have a critical mass of Medical challenges researchers and the supporting environment to progress in • Demonstrated ‘proof of concept’ for several connective the disease understanding and management and to have tissue subtypes. access to new drugs and treatments. Europe, however, has • Targeted oncogene treatments are active treatments. proven with research made on GIST, through the EORTC-STBSG • Harmonisation of research activities, medical practices group, that gathering workforces can achieve significant and education in a context where: progress. CONTICANET will create the critical mass of key • patients are not always treated in specialised centres; stakeholders to overcome the current difficulties in terms of • most patients are not treated according to CPGs; lack of data and data fragmentation, mobility of researchers, • structured clinical research and TR in large centres heterogeneity of methodologies and legislations. and network. • Medical practices do not follow clinical practice guidelines CONTICANET will: for more than 60% of patients in most western countries • start by providing the required environment for develop- so there is a need for education of physician and patients. ing joint research activities through the development of standard operating procedures (SOP), distributed data- Economical challenges bases, tissue banks and harmonisation of ongoing and Health: previous research projects, to promote complementarity Inappropriate management results in increased costs. and perform parallel research programmes according to Survival and functional disabilities in adults and children. similar SOPs; Identifi cation of novel targets and treatment: • provide the infrastructure to test several drug candidates Generate intellectual propriety. and perform European wide exploratory clinical trials while Commercialisation of new agents. implementing a federated research policy; Transfer towards industrial partners: • further lead to an integrated sustainable structure – a Euro- Perform rapid proof of concept clinical trials. pean research foundation – able to support integrated Generate synergy between European academia and industry. research actions and make new treatments available. Political challenges Involving 20 partners – major comprehensive cancer cen- Strengthen and harmonise European research in tres, academia and private companies – over a period of these rare tumours: five years, CONTICANET will gather the critical mass of Establish the network as the worldwide leading force for resources and knowledge in the understanding, diagnosis research in these rare tumours. and clinical management of connective tissue cancers, at Promote academic and industrial collaborations: the same time opening new therapeutic options. Generate a network with integrated joint research progra m mes. Include new partners from academia, industry and patients CONTICANET will spread excellence in several directions: advocacy groups. enlarging the network with other academic and private organ- Ensure the long term viability of the network. isations; developing working sessions with EMEA, health authorities and insurances in order to optimise the availability of new therapeutic options; supporting and collaborating with patients through advocacy groups and cancer leagues.

BIOLOGY 23 Aim and expected results • but also with international societies: the world wide Connective Tissue Oncology Society – CTOS (UCBL, CONTICANET aims at setting up a Network of Excellence as IGR, ICR, ERASM, INT, MAUNIHEI); a vehicle to create the critical mass of researchers, clinicians • and European organisations such as orphanet and industrialists able to: Europe, research directorate by contributing to the • improve the understanding of carcinogenesis and tumour European eff ort on rare diseases (www.cordis.lu/ progression of connective tissue cancers in adults and lifescihealth/major/rare-diseases.htm). children and specifi cally of sarcomas, GIST, aggressive • inform, get feedback from, collaborate with and support fi bromatosis and hamartomas; patients advocacy groups (SOS-Desmoides, Jeunes Soli- • develop new diagnostic tools, prevention strategies and darité Cancer, Life Raft); treatments for these connective tissue cancers in adults • interact with EMEA, health authorities, social security and children. and insurances; • involve other pharmaceutical, biotech and academic cen- The main goals of CONTICANET are to: tres in the EU to enlarge the capacity of the network; • create the critical mass of key stakeholders from transla- • reinforce collaborations outside Europe, in particular with tional, pharmacological and clinical research to make a Canada (McGill University), Russia (NCI Moscow), Israel real breakthrough in connective tissue cancer diagnosis (Weizman Inst.), USA (MSKCC) and Australia (Peter Mac- and management, both for adults and children; Callum Cancer Institute) Finally CONTICANET will generate • capitalise on pre-existing collaborations to set up, imple- three diff erent types of results: ment and update a joint research programme and then a • an organisation gathering key stakeholders in con- European-wide organisation covering pre-clinical and nective tissue cancer research and able to perform clinical research on connective tissue cancers with a signifi cant progress in the disease understanding patient to patient approach; and management through jointly performed studies • make available to all participants a strong network of in the fi elds of epidemiology, molecular biology facilities accelerating research output. research, clinical research, drug development. This organisation will take the form of an international From this integration, CONTICANET will provide a basis for non-profi t association gathering all network partici- the development of new treatments and, from an industrial pants. This association will then in a second step point of view, to: evolves towards a research foundation open to new • establish synergisms between data and models acquired members and to sponsors. By involving pharmaceu- by academics and drug development from the pharma- tical companies and with the objective of extending ceutical industry to improve therapeutic options for both the approach to other uncommon cancers, such adults and children; a foundation will be self-sustained through the con- • validate some of those options with competent authori- tributions of its members and the support to be ties as a model for orphan disease. obtained form the industry through the develop- ment of orphan disease models; CONTICANET will spread the excellence achieved in the • the delineation of methods, tools and activities which network to: will be developed within the network and supporting • improve training of health professionals in charge of the integration of the research activities of the par- diagnosis and multidisciplinary primary care of the Euro- ticipants and which will be shared among participants pean patients through the production of guidelines and and ultimately beyond the network to strengthen reference for medical practice. In particular, strong rela- research in this fi eld: tionships already exist – and will be reinforced – between – distributed standardised repository of tissues, the consortium and: data, information supporting research activities; • the European Society of Medical Oncology – – standardised Operating Procedures (SOP) at Euro- ESMO (all); pean level; • the EORTC (ERASM, UCBL, IGR, INT, ICR, MAUNIHEI); – common pool of facilities: instruments, platforms, • the European Society for Surgical Oncology – ESSO drugs, diagnostic tools, etc.; (INT, UCBL, IGR, ICR, MAUNIHEI); – collaborative platform for data transfer and valida- • the European Society for Therapeutic Radiation tion and collaborative work; Oncology – ESTRO (UCBL, SLS, IGR, UNIPD, ICR); – network for pharmacodynamics based clinical • the European Musculo Skeletal Oncology Society – trials; EMSOS (INT, IGR, SLS); – standardised validated screening tools (ex vivo & • the European paediatric Soft tissue Sarcoma Group in vivo); – EpSSG (UNIPD, ICR, IGR, CURIE, BERGONIE); – pharmacovigilance network;

24 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME • public health research coupled with education aim- Project number ing to understand the determinants of medical LSHC CT-2005-018806 practice in order to propose innovative education strategies to improve patient management and fol- EC contribution low up. Knowledge gained in this fi eld will be € 9 432 600 disseminated within the network and beyond by the key opinion leaders present in the network in their Duration respective countries. 60 months

Once these goals are achieved for sarcomas, GIST, aggres- Starting date sive fi bromatosis and hamartomas, the consortium will 01/02/2006 choose other types of uncommon connective tissue tumours (primary CNS tumours, mesotheliomas) and ultimately aim Instrument at contributing to integrated research in the fi eld of uncom- NoE mon epithelial cancers (neuroendocrine cancers, adenoid cystic carcinomas). Thus the CONTICANET network is expected Project website to develop on the long term a stable structured European www.conticanet.eu research organisation on uncommon cancers and could possibly serve as a model for other rare diseases.

Coordinator

Jean-Yves Blay Javier Olaiz Christian Auclair Patrick Schöffski Université Claude Bernard Lyon 1 Lyon I Ingénierie École Normale Supérieure de Cachan Katholieke Universiteit Leuven Villeurbanne, France Lyon, France Cachan, France Leuven, Belgium [email protected] [email protected] Ian Judson Rudolph Zvonimir J.-M. Coindre The Institute of Cancer Research Institute of Oncology Ljubljana Institut Bergonié London, United Kingdom Ljubljana, Slovenia Bordeaux, France Partners Axel Lecesne Jean-Pierre Bizzari Olivier Delattre Eric Papon Institut Gustave Roussy Sanofi-Aventis General Affairs Institut Curie Arttic SA Villejuif, France Valorisation & Innovation Paris, France Paris, France Bagneux, France Nadia Zaffaroni Peter Hohenberger Gerald O’Sullivan Istituto Nazionale per lo Studio Michel Marty Ruprecht-Karls-Universität Heidelberg National University of Ireland e la Cura dei Tumouri Centre Hospitalier Mannheim, Germany University College Cork Milano, Italy Universitaire Saint-Louis Cork, Ireland Paris, France Fabienne Hermitte Jaap Verweij Ipsogen SAS Carlo Ricardo Rossi Erasmus University Medical Centre Marseille, France Università degli Studi di Padova Rotterdam, The Netherlands Padova, Italy

BIOLOGY 25 Keywords | Functional genomics | systems biology | regulatory networks | dynamical modelling |

DIAMONDS the processes that regulate cell division is therefore of prime importance for human health, welfare and sustainable Dedicated Integration and Modelling development. The approach taken by DIAMONDS consti- tutes a pioneering step toward the application of a systems of Novel Data and Prior Knowledge biology approach for genetic network analysis, and as such will contribute to the maturation of systems biology into to Enable Systems Biology a general approach, complementary to the traditional gene- by-gene approach. With the rapid increase in genome sequences, published literature and databases on proteomic and transcriptomic data, it is obvious that integrative analy- Summary sis, bringing together various complementary data types for the identifi cation of network motifs, should be tested We will demonstrate the power of a systems biology on well-defi ned biological models to assess the potential of approach to study the regulatory network structure of the a systems biology approach. most fundamental biological process in eukaryotes: the cell cycle. An integrative approach will be applied to build a basic model of the cell cycle in four diff erent species Aim including S. cerevisiae (budding yeast), S. pombe (fi ssion yeast), A. thaliana (weed, model plant) and human cells. To The overarching objective of this multidisciplinary project is do this, a consortium has been assembled of leaders in the to demonstrate the power of a systems biology approach to fi elds of cell cycle biology, functional genomic technolo- study fundamental biological processes. We focus on eukary- gies, database design and development, data analysis and otic cell cycle regulation, and will develop and implement integration technology, as well as modelling and simulation a computational model that will function as a hypothesis- approaches. The project combines a number of complemen- generating engine in a systems biology ‘wet-lab’ environment. tary data sets toward an advanced mining and modelling The work will be done in a number of wet-labs and dry labs, environment, designed to assist the biologist in building on yeast, plant and human cells, to make sure that the and amending hypotheses, and to help the investigator approach is validated across widely diff erent organisms. The when designing new experiments to challenge these main target of the project consists of two parts: hypotheses. By doing these simultaneously in widely diff er- • a cell cycle knowledge base and an integrated platform ent organisms, we will ensure that the tools are generally of data mining, modelling and simulation tools that will applicable across species. By bringing together biologists, allow the integrated analysis of that data in a systems bioinformaticians, biomathematicians and (commercial) biology approach; software developers in the design phase, we will ensure • the development of a basic model, the use of this model that a user-friendly, intuitive data analysis environment is to design new experiments, the production and analysis created. The main data streams generated de novo within of novel data, and the integration of these into a refi ned the project concern transcript profi ling and proteomics model. data (Y2H and TAP). These data will be complemented with information extracted through comparative genomics, and The knowledge base and tools will be made available and prior knowledge coming from literature mining (text mining introduced to the European research community. tools). The project will bring together a number of existing technologies to build a knowledge warehouse in a relational The principle method to reach this target is to harvest and/ database designed to contain cell cycle regulatory network or produce a large body of cell cycle-related biological information, accessible through an intuitive user platform knowledge. This will function as the central resource for the (GUI) with embedded modelling tools. This platform will modelling and simulation environment that will be devel- enable both top-down and bottom-up hypothesis-driven oped. As mentioned above, the knowledge warehouse will research, and will serve as a basis to develop more rigorous constitute one of the major deliverables of the project, ena- dynamical models for cell cycle variants. bling future hypothesis-driven research. The project will showcase the fact that a systems biology approach towards analysis of a fundamental biological process can in fact Problem become mature today, and hinges on an integrated data analysis pipeline, extended with modelling and simulation Cell division is regulated by highly conserved genetic net- tools. The essential elements of such a pipeline will be: works. Occasionally the cell division machinery becomes functional genomics data production (transcriptome and unstable, resulting in an uncontrolled proliferation of cells. In proteome); literature mining; comparative analysis of genes humans, the uncontrolled division and growth of cells can and networks; a visualisation, modelling and simulation envi- lead to cancer. Cell division is also at the core of biomass ronment, and a web service-based data integration layer. production and agricultural yield. A better understanding of

26 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Expected results Project number LSHG-CT-2004-512143 We will construct an integrated toolbox for the analysis of functional genomics data, and the modelling of cell cycle EC contribution information for simulation purposes. We will also deliver a € 2 500 000 knowledge base (GIN-db) containing detailed information about core cell cycle genes. Duration 36 months

Potential applications Starting date 01/01/2005 The concerted eff orts in DIAMONDS will allow extensive data integration and modelling, and will deliver new insights Instrument in cell cycle regulation and the mechanisms that prevent the STREP uncontrolled proliferation of cells, opening the way to novel anti-tumour drugs and strategies. The potential for appli- Project website cations of life sciences and biotechnology promises to be www.SBcellcycle.org a growing source of wealth creation in the future, leading to the creation of jobs, particularly in the areas of highly skilled labour, and new opportunities for investment in further research.

Coordinator

Martin Kuiper Alvis Brazma Dept. of Biology European Bioinformatics Institute Faculty of Sciences and Technology Cambridge, United Kingdom NTNU Trondheim, Norway Michal Linial [email protected] The Hebrew University of Jerusalem Jerusalem, Israel

Partners Eivind Hovig PubGene AS Kristian Helin Oslo, Norway University of Copenhagen Copenhagen, Denmark Marta Acilu Noray Bioinformatics, S.L. Denis Thieffry Bilbao, Spain Université de la Méditerranée Marseille, France Alfonso Valencia The National Centre of Biotechnology Søren Brunak Madrid, Spain Technical University of Denmark Copenhagen, Denmark Jurg Bahler The Wellcome Trust, Sanger Institute Cambridge, United Kingdom

BIOLOGY 27 Keywords | DNA damage | genome (in)stability | cancer pre-disposition | genomics | proteomics | mouse models |

DNA Repair Background

DNA Damage Response The pleiotropic eff ects, inherent to the time-dependent ero- sion of the genome and the complexity of the cellular responses and Repair Mechanisms to DNA damage, necessitate a comprehensive, multi-discipli- nary approach, which ranges from molecule to patient. At the level of structural biology and biochemistry, individual com- ponents and pathways will be analysed to identify new Summary components and clarify reaction mechanisms. The interplay between pathways and cross talk with other cellular processes This project focuses on unravelling the mechanisms of DNA will be explored using both biochemical and cellular assays. damage response and repair, an area with a major impact on human health, notably cancer, immunodefi ciency, other ageing related-diseases and inborn disorders. The project Aim brings together leading groups with multi-disciplinary and complementary expertise to cover all pathways impinging To get to grips with the vast problem of DNA damage, an upon genome stability, ranging from molecules to mouse integrated, multidisciplinary approach is imperative. The level models and human disease. of understanding of many individual pathways has strongly increased through worldwide research in which European The main objective is to obtain an integrated perception of teams have played a prominent role. The main questions and the individual mechanisms, their complex interplay and challenges ahead are: biological impact, using approaches ranging from structural • moving from understanding distinct pathways towards the biology to systems biology. The translation of the results complex interplay between the various genome stability that we obtain is expected to contribute to an improved systems putting these pathways in an integrated cellular quality of life through: context, perfectly fi tting into the concept of integrated • possible identifi cation of genetic markers for assessment projects; of susceptibility to occupational hazards and disease; • insight into the clinical impact of the systems individually • discovery of promising targets for therapy; and collectively from the cellular level to that of intact • improved diagnostic and prognostic procedures for organisms, and extending to the human population; genetic disorders; • translation of this knowledge into practical applications • early diagnosis and prevention of cancer and other in terms of improved diagnosis, eff ective therapy and ageing-related diseases. We have also included a strong prevention or postponement of diseases associated with training component in the project to invest in young the functional decline of the genome. talented students for the future.

To understand the function and impact of DNA damage Expected results response and repair systems in living organisms better, we will take full advantage of our existing unique and extensive • A detailed understanding of the biochemical mechanism collection of models (mutant yeast cells and mice), and engi- of DNA repair and checkpoint pathways. neer and analyse new mutants impaired in genome stability. The rapid growth in genomic and proteomic technologies • Insight into the cellular functioning and consequences of will be exploited to identify novel genes involved in genome defects in one of the genome surveillance pathways. surveillance. We will use bioinformatics and high-throughput systems for analysis of gene expression, and proteomics to • Identifi cation of new components of DNA damage identify putative functions of such genes and their proteins, response pathways. as well as similar global genome analytical tools to identify interactions with, and eff ects on, other cellular processes. • Extension of knowledge from model organisms to The ‘drugability’ of potential targets to improve anti-cancer humans. This will be accomplished by the investigation therapy will be tested in collaboration with SMEs. Through of patients and cells from patients suff ering from genome existing contacts with clinicians we will continue to analyse instability, cancer predisposition and premature ageing patients with previously identifi ed defects in DNA damage syndromes, and also by an extensive comparison of response and repair mechanisms, and use our clinical contacts mouse mutants with human diseases involving genome to screen for new disorders. instability, cancer predisposition and premature ageing.

28 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Potential applications Project number LSHG-CT-2005-512113 Our DNA is under constant attack from physical and chemi- cal agents that compromise its integrity and form a potential EC contribution danger for genomic stability, which may result in cancer and € 11 500 000 other health problems. A large number of chemical com- pounds in our food have a potentially harmful infl uence on Duration our genetic make-up, especially under conditions in which 48 months the DNA repair capacity is sub-optimal. The proposed research will be of prime importance to assess potential risks Starting date posed by environmental hazards (such as food components 01/05/2005 or environmental pollutants). Instrument A better understanding of the genome-wide responses to IP genotoxins in relation to the DNA repair status of an organ- ism will enable evaluation of possible risks to consumer health Project website and thereby help eliminate sources of danger to human erasmusmc.nl/ health. Our genomics and proteomics approaches have dna-repair/index.php applications for the assessment of the health risks of such compounds for specifi c subgroups carrying subtle mutations in DNA repair genes and for the ageing population. Thus, the advances in insight generated by the integrated project have the potential to be of major importance for rational risk assessments pertaining to drug development, environmental pollutants and occupational hazards.

Coordinator

J. Hoeijmakers Stephen Jackson Marco Foiani Magnar Bjørås Erasmus MC Head of Cancer Research UK Laboratories IFOM Fondazione Istituto FIRC Centre of Molecular Biology and Dept. of Genetics The Wellcome Trust/Cancer Research UK di Oncologia Molecolare Neuroscience and University of Oslo Rotterdam, The Netherlands Gordon Institute Milan, Italy Rikshospitalet-Radiumhospitalet HF [email protected] Cambridge, United Kingdom Dept. of Molecular Biology Paolo Plevani Institute of Medical Microbiology Alan Lehmann Università degli Studi di Milano Oslo, Norway Partners Genome Damage and Stability Centre Dipartimento di Scienze Biomolecolari University of Sussex e Biotecnologie Noel Lowndes Jiri Bartèk Brighton, United Kingdom Milan, Italy Genome Stability Laboratory Institute of Cancer Biology Dept. of Biochemistry Danish Cancer Society Stephen West Karl-Peter Hopfner National University of Ireland Copenhagen, Denmark Cancer Research UK Gene Centre Galway, Ireland Clare Hall Laboratories University of Munich Leon Mullenders South Mimms, United Kingdom Munich, Germany Jean-Marc Egly Leiden University Medical Center CERBM-GIE/IGBMC Dept. of Toxicogenetics Josef Jiricny Hans Krokan Illkirch, France Leiden, The Netherlands University of Zurich Norwegian University of Science Institute of Molecular Cancer Research and Technology Graeme Smith Zurich, Switzerland Dept. of Cancer Research KuDOS Pharmaceuticals Ltd and Molecular Medicine Cambridge, United Kingdom Trondheim, Norway

BIOLOGY 29 Keywords | Cancer | biomarker | in situ analysis | technology development | proximity ligation | padlock probing |

ENLIGHT nucleic acids and to distinguish closely similar sequence vari- ants, while the proximity ligation assay (PLA) is applied to New molecular methods and image analyze individual proteins, interactions between proteins, analysis tools for analysis of cancer and post-translational protein modifi cations. As a second aim we will develop automated image analysis biomarkers in situ procedures to complement the molecular methods. The objective is to achieve quantitative information about what molecules or molecule complexes are present in the sample and their tissue or sub-cellular localization (i.e. in which Summary cellular substructures).

The ENLIGHT project has the purpose to develop analyti- The third aim is to use the new methods and image analysis cal procedures with the sensitivity and specifi city required procedures to clarify the role of molecular biomarkers in to study individual nucleic acid and protein molecules, tumourigenesis, primarily concerning the AP-1 and HER and also interacting molecules, in their normal context in protein families and for mitochondrial DNA. The methods cells and tissues (in situ) and in tissue lysate microarrays. will also be tested in a high-throughput microarray analysis A spectrum of reagents will be developed for the analysis system. The cancer biomarker will primarily be investigated of specifi c markers of particular interest in oncology. Fur- in a research setting, but we will also explore the utility of thermore, we will establish software and algorithms for the markers for diagnostic analyses. automatic user-independent in situ image analysis of sin- gle molecule-events. These methods and algorithms will be applied to evaluate candidate biomarkers of special Expected results relevance for tumour biology and cancer pathology. This project is expected to provide new means to study biomarkers for oncogenesis, and to generate novel insights Problem in cancer biology. We expect that the in situ techniques developed in this project, and the scientifi c knowledge In situ analysis of cells and tissues has been an essential part created, in the longer run will lead to improved disease of pathological research and diagnosis primarily within can- prevention, more rapid and accurate cancer diagnosis, and cer for many years, and a number of specifi c biomarkers of better treatment opportunities. predictive and prognostic value for various cancers have been identifi ed. In situ analysis of nucleic acid sequences is New analytical means will be developed to analyse cancer dominated by in situ hybridization, while in situ analysis of biomarkers in situ. Relative to state-of-the-art procedures, proteins is dominated by immunohistochemistry where sec- these methods are expected to provide signifi cantly tions of tissues are tested for the presence of proteins by improved in situ analyses in terms of specifi city, sensitivity specifi c antibodies. Due to limitations in these technologies (single molecule detection), possibility to study biomarker there is a signifi cant need in the scientifi c community for localisation, analysis of protein interactions and protein new effi cient techniques and procedures for more advanced modifi cations, and an opportunity for simultaneous analysis analyses. A major challenge is to develop improved means of multiple markers (multiplex analysis). Automated image for more detailed studies of biomolecules in situ, in order to analysis procedures will be developed, i.e. software-based determine their abundance, sub-cellular localization, and classifi cation of molecules and their localisation in tissues secondary modifi cations, as well as how they interact with or cells. The software will provide a rapid way to analyse other molecules and participate in signalling and control of many samples as well as user-independent, unbiased data cellular function. classifi cation.

The results from this project are furthermore expected Aims to provide new commercial opportunities for products addressing signifi cant market needs, thereby allowing the The fi rst aim is to develop new molecular methods and participating European SMEs to build sustainable businesses assays for the analysis of individual DNA and protein mole- at the forefront of biotechnology. cules in situ. The project is based on two fundamental technological inventions, padlock probing and proximity ligation. These are the fi rst technologies to off er the sensitiv- Potential applications ity and specifi city required for studies of single bio-molecules in situ. The padlock probe technology is used to interrogate Cancer biology and diagnosis.

30 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHB-CT-2006-037545

EC contribution € 2 978 810

Duration 36 months

Starting date 01/08/2006

Instrument STREP

Project website www.olink.com/ enlight.html

Microscopic examination of tissue sections.

Coordinator

Björn Ekström Henrik Winther John Bartlett Anders Alderborn Dako Denmark A/S The University of Edinburgh Olink AB Glostrup, Denmark Edinburgh, United Kingdom Uppsala, Sweden [email protected] [email protected] [email protected] [email protected] Anders Larsson Anton Raap Immunsystem I.M.S. AB Hans van Dam Uppsala, Sweden Leiden University Medical Center Partners [email protected] Leiden, The Netherlands [email protected] Mats Gullberg Niels Foged [email protected] Olink AB Visiopharm A/S Uppsala, Sweden Hørsholm, Denmark [email protected] [email protected]

Ulf Landegren Olli Kallioniemi Ewert Bengtsson VTT Technical Research Uppsala University Centre of Finland Uppsala, Sweden Turku, Finland [email protected] [email protected] [email protected]

BIOLOGY 31 Keywords | Epithelial stem cell | keratinocyte diff erentiation | p63 and family members | EEC-related syndromes |

EPISTEM Aim

Role of p63 and Related Pathways in • Collecting and culturing of keratinocytes from EDS patients with p63 mutations and extensive analysis of Epithelial Stem Cell Proliferation and phenotype-genotype correlation. These keratinocytes will be used to uncover the role of p63 proteins and path- Diff erentiation and in Rare EEC-Related ways in normal and abnormal skin development. • Building relevant in vitro and in vivo skin disease models Syndromes for studying the role of p63 in EDS disease and the genetic assessment of novel pathways discovered dur- ing this project. These models will also be used for drug assessment. Summary • Provide insight into the regulation and involvement of p63 and related pathways in skin diff erentiation, the main- The focus of EPISTEM is to generate new knowledge and tenance of the proliferative capacity of epithelial stem translate it into applications that enhance human health. To cells and the transition of ectodermal cells to epidermal this end both fundamental and applied research will be stem cells. involved. EPISTEM integrates multidisciplinary and coordi- • Screening for, and design of, novel therapeutic drugs, nated eff orts to understand the molecular basis of factors based on three-dimensional p63 models, that will refold/ involved in epidermal stem cell generation, maintenance and reactivate or inhibit p63 mutants and induce biological diff erentiation and skin disease. Moreover, the core molecule responses in relevant disease models. that will be studied in this Integrated Project is p63 (and related pathways), a molecule genetically proven to be involved in the development of rare skin diseases. Collectively, Expected results the prevalence of ectodermal dysplasia syndromes (EDS) is estimated at seven cases in 10 000 births. Currently there is First of all, the EPISTEM consortium will generate a thor- no cure for these patients. By creating the EPISTEM consor- ough insight into the molecular biology of a rare disease tium, we want to address, from diff erent angles (i.e. via such as EDS, for which no cure is currently available. Sec- genetics, gene profi ling, molecular and cellular biology, ondly, characterising and understanding how epidermal structural biology, drug design and bioinformatics), the stem cell maintenance is regulated by p63 could be benefi - molecular pathways involved in epidermal dysplasia syn- cial for the treatment of burn victims since these stem cells dromes making use of diff erent technologies (mutation could be used for tissue regeneration. So, in the long run, the analysis, micro-array, ChiP, transgenes, proteomics, in vitro EPISTEM research proposal may have a far broader impact skin cultures, crystallography, etc.). Our consortium brings on clinical practice and the biomedical industry than is cur- together leading European clinicians, geneticists, molecular rently estimated. Thirdly, this integrated project will generate and cellular biologists, structural biologists, a drug designer knowledge and technology that is not only applicable to and bioinformatics specialists in the fi eld of p63 (and related p63 itself, but also to its family members p53 and p73; p53 molecules) research. is an important target that is mutated in most cancers and p73 is an important molecule for neurogenesis. Finally, from a technological point of view, the EPISTEM proposal will Problem invest in the development of chIP (chromatin immunopre- cipitation) on chip technology. The core molecule that will be studied by the EPISTEM con- sortium is p63 (and related pathways), a molecule genetically proven to be involved in the development of rare skin Potential applications diseases such as EEC syndrome (Ectrodactyly-ectodermal dysplasia – clefting), Hay-Wells (AEC) syndrome, Limb-mam- Drug-development for the cure of skin diseases, cancer, etc. mary syndrome, ADULT syndrome, Rapp-Hodgkin syndrome and a wound-healing treatment. and non-syndromic split hand-split foot malformation. Currently there is no cure for these patients.

32 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHB-CT-2005-019067

EC contribution € 8 130 000

Duration 48 months

Starting date 01/01/2006

Instrument IP

Project website www.epistem.be

Pluripotent embryonic stem cells are cultivated on glass coverslips coated with fi broblast-secreted matrix proteins (and probably trapped growth factors and cytokines). Undiff erentiated ES cells are induced to diff erentiate by removal of LIF (Leukaemia Inhibitory Factor) and the addition of BMP-4 (Bone Morphogenetic Protein-4). These cells were transfected with transduction-competent (TAp63) and transduction-incompetent (Np63) expression vectors. The presence of ES-derived keratinocytes is scored using an antibody against the cytokeratin-14 intermediate fi lament. These experiments show that TAp63 is capable of inducing keratinocyte diff erentiation starting from a stem cell population. Which cellular programmes are involved in this process remains to be determined.

Coordinator

Peter Vandenabeele Gerry Melino Klas Wiman Daniel Aberdam Flanders Interuniversity Institute for Vincenzo De Laurenzi Karolinska Institutet Institut National de la Santé Biotechnology Università degli Studi di Roma Tor Vergata Stockholm, Sweden et de la Recherche Médicale Gent, Belgium Rome, Italy [email protected] Nice, France [email protected] [email protected] [email protected] [email protected] [email protected] Volker Doetsch [email protected] J.W. Goethe-Universität Frankfurt am Main Luca Lorenzi Gian Paolo Dotto Frankfurt, Germany GeneSpin SrL University of Lausanne [email protected] Milano, Italy Partners Lausanne, Switzerland [email protected] [email protected] Roberto Mantovani Hans van Bokhoven Università degli Studi di Milano Pongsak Angkasith Gijs Schaftenaar John McGrath Milan, Italy Chiang Mai University Martijn Huynen King’s College London [email protected] Chiang Mai, Thailand Radboud University Nijmegen London, United Kingdom Nijmegen, The Netherlands [email protected] M. Gulisano Xie Sheng-Wu [email protected] Istituto Oncologico del Mediterraneo Shanghai Jiaotong University [email protected] Viagrande, Italy Shanghai, China [email protected] [email protected]

BIOLOGY 33 Keywords | Epigenetic | apoptosis | diff erentiation |

EPITRON Aim

Epigenetic treatment The overall goal of EPITRON is to validate and extend the concept of ‘epigenetic therapy’ of cancer. For this a pipeline of neoplastic disease will be established, which extends from the analysis of epi- genetic (de)regulation in cancer to the study and generation of epi-drugs in a multiplicity of in vitro, ex vivo and in vivo mouse models. We will develop and use mouse models that Summary accurately reproduce the human disease. The particular goals of EPITRON are: Chromatin is epigenetically modifi ed to regulate gene • to study the epigenetics of cancer cells (with a focus on expression. Upstream signals induce complex patterns of leukaemia, breast and colon cancer), and defi ne the enzyme-catalysed modifi cations of DNA and histones, mechanisms of (cancer selective) action of epi-drugs; key protein components of chromatin. These epigenetic • to establish the basis of the cancer-selectivity of TRAIL/ modifi cations create docking sites and form a code that TRAIL receptor action; specifi es transient or permanent (and heritable) patterns • to identify novel epi-drug targets; of genome function. In addition, epigenetic enzymes • to synthesise novel epi-drugs with increased effi cacy/ modify the activity of major transcription factors. Emerg- tumour selectivity; ing evidence causally links altered epigenetic functions • to validate epi-drug target therapy of cancer in vitro to oncogenesis, and suggests that chromatin regulators (primary normal and tumour cells), ex vivo (leukaemic and upstream pathways are critical targets for develop- blasts vs. normal progenitors) and in vivo (mouse mod- ing novel anti-cancer drugs (epi-drugs). EPITRON will els which accurately reproduce human cancer; the focus defi ne and validate the concept of ‘epigenetic cancer will be on APL/AML but also solid cancer models will be treatment’ from the molecular mechanism(s) to animal used or established). models reproducing human cancers. EPITRON will estab- lish a programme from drug target exploration and drug Taken together, EPITRON will not only provide information development to preclinical validation in vitro, ex vivo and about epigenetic modifi cation imposed upon cancer cells, in vivo. Epi-drugs are amongst the most important novel validate existing and generate novel epi-drugs, but most drugs that have been generated to treat cancer, as can be importantly engage upon a major challenge of cancer therapy concluded already from the existing results obtained with by devising treatments that kill cancer, but not normal cells. HDACi’s, some of which performed very well in phase I and phase II clinical trials. EPITRON is unique in its eff orts to strengthen European biomedical and pharmaceutical Expected results competitiveness. It fosters an exchange of biomedical knowledge, technology and materials among European To validate and extend the concept of ‘epigenetic cancer laboratories, provides opportunities for education and therapy’, EPITRON will follow six axes of research, focused training – and creates jobs. on preclinical models. • Mechanisms of anti-leukaemic action of epigenetic drugs. We will defi ne the anti-leukaemogenic potential Problem and the corresponding mechanistic basis of existing epi- genetic drugs used alone or in combination, and in Elucidating the ‘signatures’ of cancer cells is one of the four combination with other signalling drugs, such as nuclear so-called ‘extraordinary opportunities for immediate invest- receptor ligands. The impact of chromatin modifi cation ment’ defi ned by the National Cancer Institute of the United (DNA, histones) that correlates with tumourigenesis and States of America. These four priorities (defi ning the signa- underlying recognition principles will be studied. tures of cancer cells, cancer genetics, preclinical models of • Oncofusion genetic and epigenetic programmes. We will cancer and imaging technologies) were selected as top pri- use cell lines, patients’ blasts and mouse models to orities to receive privileged attention and funding. Thus the understand the altered gene programming due to the EPITRON project aims to contribute at multiple levels to the oncogenic fusion protein(s). defi nition of epigenetic signatures of cancer.

34 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME • Decryption of the leukaemia cell-selective apoptogenic Project number action of TRAIL. Based on the original fi nding of mem- LSHC-CT-2004-518417 bers of this consortium that several anti-leukaemogenic treatments activates the TRAIL death pathway, and the EC contribution observation that TRAIL signalling induces apoptosis in € 10 904 474 tumour, but not normal cells, the molecular mechanism(s) underlying this fascinating potential will be defi ned in Duration suitable cellular models using a plethora of genomic 60 months technologies. • Therapeutic potential and toxicities of TRAIL in animal Starting date models. Based on regulable TRAIL expression systems, 01/11/2005 EPITRON will establish mouse models to assess the spectrum of anti-cancer activities and possible toxicities Instrument of TRAIL in vivo using both ubiquitous and tissueselec- IP tive expression paradigms. At the same time ‘reporter mice’ will be created, which will allow monitoring activa- Project website tion of the TRAIL signalling pathway by (epi-)drugs. www.epitron.eu • Generation and validation of novel epigenetic drugs. Crystal structures and innovative chemistry will be used to generate compounds that (selectively) modulate the activity of epigenetic enzymes/machineries. • Models for epigenetic therapy of solid cancers. Among Coordinator the several tumour mouse models used by EPITRON, studies will be performed to assess effi cacy and mecha- Hinrich Gronemeyer Adriana Maggi nisms of HDACi and novel EPITRONgenerated epi-drug CERBM-GIE Centre Européen Università degli Studi di Milano actions in breast cancer models. In these studies, primary de Recherche en Biologie Milano, Italy cell cultures derived from the above mouse models (and et Médecine – Groupement their normal counterparts) will also be used. Moreover, d’Intérêt Économique Tony Kouzarides EPITRON will establish as a novel tool matched pairs of Illkirch, Strasbourg, France University of Cambridge primary normal and cancer cells from the same patients [email protected] Cambridge, United Kingdom to assess (epi-)drug action, especially tumourselective activities. As an example of a gender cancer, primary Olli Kallioniemi patient-matched cultures of normal and breast cancer Partners University of Turku epithelial cells will be studied. Turku, Finland Saverio Minucci Pier Giuseppe Pelicci Kurt Berlin Potential applications Istituto Europeo di Oncologia Epigenomics Milano, Italy Berlin, Germany In their entirety, the studies performed in AML, breast, skin and colon cancer preclinical models will provide a frame- Henk Stunnenberg Tiziana Cataudella work for a detailed molecular defi nition of ‘epigenetic Stichting Katholieke Universiteit Congenia therapy’, which will pave the way to more focused and Nijmegen, The Netherlands Milano, Italy appropriate protocols for future clinical trials. Angel De Lera Holger Hess-Stumpp Universidad de Vigo Schering AG Vigo, Spain Berlin, Germany

Lucia Altucci Abbie Harris Seconda Università Abcam degli Studi di Napoli Cambridge, United Kingdom Napoli, Italy

Hugues de The Centre Nationale pour la Recherche Scientifique Paris, France

BIOLOGY 35 Keywords | Bone tumour | chondrosarcoma | osteosarcoma | giant cell tumour of bone | Ewing’s sarcoma | osteochondroma | Paget disease of bone | chondrogenesis | osteogenesis |

EuroBoNeT The 2002 WHO classifi cation recognises 32 diff erent enti- ties of bone tumours. Achieving signifi cant numbers to European Network to Promote Research study the diff erent types of bone tumours, which are already rare as a group, is diffi cult. The research into these tumours into Uncommon Cancers in Adults is often performed in relatively small research groups, which are inherently hampered by the lack of availability of sub- and Children: Pathology, Biology stantial numbers of cases, as well as lacking a critical technical and/or multidisciplinary mass. Interestingly, despite and Genetics of Bone Tumours their rareness, these tumours provide excellent examples for unravelling oncogenic mechanisms. The main problems are: • collecting enough tumours to obtain reliable signifi cant Summary statistical results, also when comparing subtypes based on locations, grade, etc.; Primary bone tumours are rare, accounting for ~0.2% of the • since osteogenic and Ewing’s family of tumours are con- cancer burden. Children and young adolescents are fre- sidered orphan diseases, pharmaceutical companies will quently aff ected. The aggressiveness of these tumours has not invest in developing new drugs; a major impact on morbidity and mortality. Though progress • chemotherapeutic treatment can be toxic for the patient or has been made in pathological and genetic typing, the aeti- not eff ective, and there are no tools that predict which ology is largely unknown. Advances in therapeutic approaches patients are hypersensitive or which tumours are refractory; have increased survival rates, but a signifi cant numbers • cartilaginous tumours are resistant to treatment other than of patients (~40%) still die. Within the EuroBoNeT, staff surgery. This can be mutilating and it is not always feasible exchange, share of material and technologies, as well as the to remove the whole tumour (for instance in the pelvic organisation of training courses, will be used to increase and area); disseminate knowledge of primary bone tumours. Exchange • a small percentage of benign cartilaginous tumours devel- of material, standard operating protocols, and the use of op into malignant chondrosarcomas, but there are no clues technology platforms will enable us to obtain statistically to recognising the ones that will deteriorate; signifi cant datasets. A joint programme will contribute in • the biological behaviour of giant cell tumours is variable and obtaining molecular portraits of tumours, separated into four cannot be predicted so far. In a small proportion of tumours, research lines: RL1: cartilaginous tumours; RL2: osteogenic synchronous or metachronous metastases develop; tumours and related sarcomas; RL3: osteoclastogenesis and • the biology of normal chondrogenesis and osteogenesis is giant cell tumours of bone; and RL4: the Ewing family of complex. A better under-standing of the pathways involved tumours. The tumours will be examined by genome-wide could provide clues to the biology of bone tumours. expression, genomic aberration studies, and specifi c hypo- thesis-driven approaches (RNA/protein expression and mutation analysis). In vitro studies will be used to obtain Aim knowledge of normal growth and diff erentiation, and this may help to identify markers for malignant transformation The above-mentioned major problems will be handled by and/or progression, as well as identifi cation of therapeutic EuroBoNeT in the following ways: targets. Dissemination of knowledge will be achieved by • to overcome the spread of samples and lack of critical training courses on bone and soft tissue pathology. This is technical and/or multidisciplinary mass in some of the essential since patients do not normally present themselves institutes, the main objective will be to reach integration at centres, and it is important to share such knowledge. through sharing of samples, sharing of technologies and incorporating all information gathered by the diff erent partners. This will be done through staff exchange, core Problem facilities, a virtual BioBank and combining each others’ experimental results; Bone sarcomas are rare and represent a group of cancers • the EuroBoNeT will characterise the tumours in the dif- that occur predominantly in children and young adults. ferent research lines by proteomics, genome-wide Intrinsic to their aggressive behaviour, these tumours are expression analysis, and genomic array. This will provide lethal in about 40% of patients despite modern multimodal- a large data set, which can be compared within and ity therapy. Although substantial progress has been made between the diff erent tumour (sub)types. These data over the last 10 years in understanding these tumours at the will be used for: biological, pathologic and genetic level, this has not been • identifi cation of loci involved in conferring hypersen- translated into more eff ective therapies so far. sitivity or chemotherapy resistance;

36 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME • identifi cation of molecular targets for therapy; Project number • identifi cation of markers involved in malignant trans- LSHC-CT-2006-018814 formation; • identifi cation of genes/pathways involved in disease EC contribution progression. € 13 218 960 • by studying the molecular mechanisms involved in osteoclasto genesis and chondrogenesis (using in vitro Duration models), EuroBoNeT aims to identify new mechanisms 60 months that could also play a role in bone tumourigenesis, and provide clues for the identifi cation of new diagnostic Starting date and/or prognostic markers. 01/02/2006

Instrument Expected results NoE

The establishment of a lasting network in which samples will Project website be exchanged and results combined and discussed, and that www.eurobonet.eu will be able to: • provide uniform guidelines for bone tumour pathology; • play a role in the development of: • new diagnostic markers, • new prognostic markers, • markers to predict the eff ect of chemotherapeutics, • new drug treatment.

Coordinator

Pancras CW Hogendoorn Antonio Llombart-Bosch Fredrik Mertens Jos Joore Leiden University Medical Center University de Valencia University of Lund Pepscan Systems BV Dept. of Pathology Valencia, Spain Lund, Sweden Lelystad, The Netherlands Leiden, The Netherlands [email protected] Chris Poremba Thomas Aigner Jan Schouten Heinrich-Heine-University Düsseldorf University of Leipzig MRC-Holland Düsseldorf, Germany Leipzig Germany Amsterdam, The Netherlands Partners Pierre Mainil Raf Sciot Zsolt Hollo Piero Picci University of Bern Catholic University of Leuven Solvo Biotechnology, Inc. Istituto Ortopedico Rizzoli Bern, Switzerland University Hospital Budapest, Hungary Bologna, Italy Leuven, Belgium Nick Athanasou Peter Riegman Sakari Knuutila University of Oxford Horst Bürger Erasmus Medical Center University of Helsinki Oxford, United Kingdom Westfalische Wilhelmuniversity Münster Rotterdam, The Netherlands Helsinki, Finland Münster, Germany Enrique de Alava Adrienne Flanagan Lars-Gunnar Kindblom University de Salamanca-CSIC Angelo Paolo Dei Tos University College of London Royal Orthopaedic Centro de Investigacion del Cancer Hospital of Treviso London, United Kingdom Hospital NHS Trust Salamanca, Spain Treviso, Italy Birmingham, United Kingdom Ola Myklebost Miklös Szendröi Ramses Forsyth University of Oslo Semmelweis University Budapest N Goormaghtigh Institute of Pathology Norwegian Radium Hospital Budapest, Hungary Gent, Belgium Oslo, Norway Wiltrud Richter Wim Wuyts Søren Daugaard Stiftung Orthopadische University of Antwerp Rigshospitalet Universitatsklinik Heidelberg Antwerp, Belgium Copenhagen, Denmark Heidelberg, Germany

BIOLOGY 37 Keywords | Cancer | stem cells | leukaemia | breast cancer |

EuroCSC Problem

Targeting Cancer Stem Cells for Therapy Human tumours are currently treated primarily with drugs with cytotoxic eff ects against proliferating cells. This therapy is effi cient against cells with the properties of rapidly prolif- erating progenitors. However, the realisation that many Summary tumour types contain malignant cells with stem cell proper- ties, in that they are able to initiate and sustain a tumour but Cancer remains one of the leading causes of death in the proliferate infrequently, provides a potential explanation for western world and, while chemotherapy has provided the ability of many tumours to recur even after the eradica- a major improvement in survival for a wide array of malig- tion of the bulk tumour mass. The ability to identify and nant diseases, lethality remains high in most cancers and pharmacologically target these cancer stem cells would sig- side-eff ects are severe, including developmental impairment nifi cantly enhance the effi cacy and reduce the side-eff ects when used in childhood malignancies, infertility as well as of cancer therapy. damage to non-malignant tissues with resulting diminished quality of life for a large proportion of survivors. Aim Recently, the realisation that several tumour types contain rare populations of cancer stem cells (CSCs) which are capa- We will use functional analysis and gene profi ling of purifi ed ble of reforming the tumour upon transplantation while their human cancer stem cells and genetic modelling in the mouse progeny are not, have opened the possibility of using CSCs to identify molecular targets that may be used to selectively as targets for directed molecular therapies that could lead to eradicate or inactivate the malignant stem cells that sustain improved tumour eradication, as well as reduced side-eff ects tumours. These targets will be validated by knockdown and of treatment. genetic ablation in mouse model systems. Finally, we will initiate the identifi cation of lead compounds with activity The goal of the present project is to perform a thorough against these targets. characterisation of AML, cALL and breast cancer CSCs, as well as a systematic comparison of these with their normal stem cell and progenitor counterparts, using gene profi ling Expected results to identify putative molecular targets in CSCs. In parallel, we will use mouse genetic modelling to obtain information We expect to identify and validate target molecules with about genes regulated by oncogenic changes in stem and activity against cancer stem cells in AML, call and breast progenitor cell populations. Directly oncoprotein-regulated carcinoma. CSC targets will be validated in vitro and, where relevant, in vivo. The fi nal outcome will be identifi cation of the nature and hierarchical position of CSCs in three major cancers, and Potential applications a set of identifi ed and validated CSC molecular targets with activity against the eff ects of leukemogenic oncoproteins on These results are directly applicable to the development of hematopoietic stem cell/progenitor populations. drugs targeting human cancer stem cells.

38 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME A Coordinator Project number LSHC-CT-2006-037632 Claus Nerlov LT-HSC European Molecular Biology Laboratory EC contribution MEP + Monterotondo, Italy € 1 900 000 [email protected] LT-HSC CMP Duration GMP 36 months MPP Partners CLP Starting date Sten Eirik W. Jacobsen 01/01/2007 B University of Lund Lund, Sweden Instrument STREP CSC Dominique Bonnet MEP Cancer Research UK Project website + Partially London, United Kingdom www.embl-monterotondo.it/ differentiated CSC CMP research/projects/nerlov/ myeloid cells GMP Tariq Enver eurocsc.html MPP* MRC Molecular Hematology Unit Oxford, United Kingdom CLP

Roger Patient C MRC Molecular Hematology Unit Oxford, United Kingdom

“L-CMP” Ole W. Petersen + University of Copenhagen “L-CMP” MEP Copenhagen, Denmark Partially differentiated “CMP” Jon Tinsley myeloid cells GMP Vastox Oxford, United Kingdom

The Cancer Stem Cell hypothesis: Human tumors contain cells that are able to re-initiate tumor formation at distant sites (when metastases form) or when tumors relapse after chemotherapy. As illustrated in the Figure using acute myeloid leukemia as an example, these Cancer Stem Cells are self-renewing (CSC; panel B), and may phenotypically resemble the normal self-renewing stem cells (Long-term hematopoietic stem cells; LT-HSC; panel A) of the tissue from which they arise. However, Cancer Stem Cells may also have phenotypes of more committed progenitors (as exemplifi ed by the leukemic Common Myeloid Progenitor, or L-CMP; panel C), which have acquired ectopic self-renewal capacity, and thus able to perpetuate the malignant clone. Both normal and cancer stem cells reside at the top of a diff erentiation hierachy; however, while normal stem cells maintain the tissue by providing the cells which sustain its function Cancer Stem Cells give rise to defective progeny that when allowed to accumulate can lead to tissue failure.

LT-HSC: Long-term hematopoietic stem cell; MPP: multipotent progenitor; CLP: common lymphoid progenitor; CMP: common myeloid progenitor; GMP: granulocyte-macrophage progenitor; MEP: megakaryocyte-erythroid progenitor.

BIOLOGY 39 Keywords | Apoptosis | cell death | cell imaging | tumour models | kinase inhibitors | pharmacophore inhibitors | scaff old inhibitors |

GROWTHSTOP Problem

Identifi cation, development and Cancer is a major challenge to European health care. Each year nearly two million people are diagnosed with cancer in validation of novel therapeutics the EU, and over one million deaths result from this disease. Each case can have a tremendous impact on the health and targeting programmed cell death wellbeing of the aff ected person, his or her family and per- sonal environment. In addition, a high percentage of cases in tumours have major economic impacts, both for the individual and for the health care provider. As a result, improvements in cancer therapy remain of prime importance for the wellbe- ing of Europeans and for the future development of the Summary Union.

Mounting evidence indicates that the acquired ability to Cancer is caused by mutations in a relatively small and iden- resist apoptosis is a hallmark of most, and perhaps all types tifi able number of genes, which fall into two categories: of cancer. As scientists learn more about how apoptosis is proto-oncogenes, which provide critical proliferative or sur- thwarted by cancer cells, they are also gaining a greater vival signals to cells and which are inappropriately activated understanding of why many tumours are resistant to the by mutation during tumourigenesis; and tumour-suppressor apoptosis-inducing eff ects of radiation and chemotherapy. genes, which restrain cell growth and proliferation, and which These insights will guide eff orts to overcome treatment are lost or inactivated by mutations during the development resistance and off er important clues about new drugs that of a tumour. target genes and protein products in the apoptosis path- ways to encourage selective cell death. Importantly, mutations in individual genes do not cause tumours, since the human genome harbours failsafe mecha- GROWTHSTOP is exploring how apoptosis is regulated and nisms that protect normal cells from the consequences of how it can be selectively triggered to induce suicide in can- deregulated proliferative stimuli. Two such failsafe mecha- cer cells while sparing normal cells. The GROWTHSTOP nisms are known. The fi rst is an irreversible growth arrest, Consortium applies a combination of high resolution bio- termed cellular senescence, which is activated by deregu- imaging techniques, proteomics, cellular models, and in vivo lated oncogenic signals through the Ras pathway: one key tumour models towards: example is the often lifelong lack of proliferation of melano- • the understanding of the pathways that signal apoptosis cytic naevi despite the presence of mutations in B-Raf, in solid tumours; a downstream eff ector of Ras proteins. The second is apop- • their validation as viable targets for tumour suppression tosis, or programmed cell death, which is activated by many or regression in animal models in vivo; forms of de-regulated proliferative signals. Tumours can • the discovery and validation of a novel, alternative class only develop when secondary mutations that disable these of inhibitors that specifi cally targets protein interactions failsafe programmes arise; as a consequence, many muta- rather than, or in addition to, enzyme activity. The goal tions that are found in human tumours are involved in of the GROWTHSTOP project is to exploit apoptotic pathways that control either senescence or apoptosis. pathways as a viable therapeutic strategy.

Importantly, more than 30% of the applied EU budget will Aim be reserved for SMEs that deliver expertise and chemical screening in order to ensure a rapid translation of novel Strategies that aim at restoring these failsafe programmes, screens and assays into an effi cient search for specifi c drugs in particular apoptosis, in established solid tumours have manipulating pro-apoptotic pathways. emerged as an important approach to cancer therapy. The promise of this approach is that such strategies create a therapeutic window, killing tumour cells while sparing normal cells. The key aim of this project is therefore to devise, test and implement strategies that restore apoptosis as a failsafe programme to solid human tumours.

40 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2006-037731

EC contribution € 3 531 507

Duration 48 months

Starting date 01/10/2006

Instrument STREP

Project website X-ray diff raction of target drug complexes at high resolution. www.cemit.at/ growthstop

More specifi cally, the following aims will be addressed: Coordinator • advanced cancer mouse models, hepatocellular carci- noma and squamous cell carcinoma (SCC) will be used Lukas Huber Piero Crespo Baraja to dissect the contribution of individual kinase pathways Innsbruck Medical University Consejo Superior de to the survival of tumour cells; Innsbruck, Austria Investigaciones Cientificas • understanding of the signalling mechanisms used by [email protected] Santander, Spain human tumours to counteract apoptosis will be improved; • a lucid and structured pathway to exploit these fi ndings Walter Kolch for therapeutic intervention will be provided, by address- Partners Beatson Institute ing the problems that hinder the effi cient translation of for Cancer Research knowledge about kinase pathways into therapeutic Manuela Baccarini Glasgow, United Kingdom approaches. University of Vienna Vienna, Austria György Kéri Vichem Chemie Research Ltd. Expected results Martin Eilers Budapest, Hungary Philipps University of Marburg Through the integrated approach of the project, the follow- Marburg, Germany Martin Ried ing results are expected: CRELUX GmbH • an understanding of the pathways that signal apoptosis Maria Sibilia Munich, Germany in solid tumours; Medical University of Vienna • their validation as viable targets for tumour suppression Vienna, Austria Armin Peter Czernilofsky or regression in animal models in vivo; Baden, Austria • and the discovery and validation of a novel, alternative Rony Seger class of inhibitors that specifi cally targets protein interac- Weizmann Institute of Science Blair Henderson tions rather than, or in addition to, enzyme activity, with Rehovot, Israel Center of Excellence in Medicine & IT GmBh the fi nal goal of establishing the manipulation of apoptotic Innsbruck, Austria pathways as a viable strategy for cancer therapy. Tony Ng King’s College London London, United Kingdom Potential applications

Proliferative diseases.

BIOLOGY 41 Keywords | Cancer biology, high-throughput screening | RNA interference screening | knowl- Keywords | Cancer biologyedge-based | high-throughput | cancer therapyscreening | RNA interference screening | knowledge-based cancer therapy |

INTACT Aim

Identifi cation of novel targets The scientifi c and technological objectives are: • use large-scale functional genomics, in particular genome- for cancer therapy wide lossof-function screens, to identify novel mechanisms, including novel oncogenes and tumour suppressor genes, involved in the development of human cancer; • to generate novel tools in the form of RNAi retroviral librar- Summary ies (mouse and human), cell-based assays, mouse models and reagents that will be distributed on a non-profi t Despite intensive worldwide research eff orts, cancer remains cost-charge to academic researchers in the European a devastating, often poorly treatable disease. We propose to Community; develop and apply new functional genomic technologies • to develop novel technologies for target validation in that will provide unique approaches to the design of new mouse and to develop mouse models to validate the role pathway-specifi c cancer therapies. To reach the objectives of the identifi ed genes in the development of cancer; outlined below, we have formed a multidisciplinary research • to develop cell-based assays for cancer-relevant genes consortium, including top scientists with extensive experi- that will serve as a starting point for the identifi cation ence in developing innovative genomics technologies and of anti-cancer agents through the screening of chemi- with an excellent track-record in identifying key signalling cal compound libraries. At the end of the four-year molecules involved in cancer, as well as SMEs with experi- programme, collaboration with large pharmaceutical ence in identifying cancer-relevant genes and in screening compa nies will lead to further refi nement of lead-com- chemical compound libraries. The location of most of the pounds and the possible introduction of novel anti-cancer partners at leading European cancer centres will ensure agents into clinical trials; optimal conditions for the development of novel cancer- • to develop novel technologies to study gene function specifi c treatments. This proposal provides new possibilities in vitro and vivo, and to distribute these technologies of ‘translating basic knowledge of functional oncogenomics within the consortium and subsequently to researchers into cancer diagnosis and treatment’ in compliance with the in the European Community. main goal in the LifeSciHealth call in the Sixth Framework Programme. Expected results

Problem Translating basic knowledge of functional oncogenomics into cancer diagnosis and treatment. Until now, genomic The availability of the complete human genome sequence information has been used mainly to develop expression has provided unparalleled opportunities to examine changes array technologies. Such technologies have been commer- in both DNA sequence and gene expression in normal and cialised and are being applied in many laboratories; indeed, cancer cells. Several major projects are underway to identify members of this consortium have published key profi ling cancer specifi c mutations by largescale sequencing or cancer papers on several human tumours. The central weakness specifi c alterations in gene expression by micro-array tech- of this approach is that expression profi ling gives no indi- nology and providing important information. However, these cation of gene function and is, therefore, not suited for the technologies have severe limitations in that they provide only functional annotation of the human genome. As such, an inventory of cancer-associated alterations without shed- expression arrays have been useful in defi ning prognostic ding light on the functional implications of these changes. profi les for multiple forms of cancer: however, they have Delineating how, or even whether, the alterations identifi ed rarely given insight into potential therapeutic strategies through these methodologies play a real role in malignant for disease. development will be a massive task. We are therefore propos- ing to make use of the most advanced technology developed In contrast, the technology platforms developed by this within the groups of the programme to move a step further consortium aim immediately at the determination of gene and apply new high-throughput functional screens for the function on a genomewide scale. Two key technological swift identifi cation of new targets that are critical for survival developments form the basis of this consortium. First, of tumour cells carrying distinct, frequently occurring gene scientists in this consortium have developed retroviral defects. Building on the expertise of other members of the screening technologies to allow phenotypic screens that programme we will be able to validate these targets in in vivo have specifi c cellular or organismal phenotypes as read- mouse and human xenograft models, which closely mimic out. Genes are therefore annotated by their contribution the human disease condition and form the basis for new to specifi c cellular phenotypes. Within this consortium, experimental intervention-intervention strategies. these screens will be adopted to specifi c cancer pathways

42 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME using pathway-specifi c reporter cell lines. Therefore, genes Secondly, RNAi technology, in combination with reporter are screened at high throughput and are annotated imme- screens, will identify novel genes that control downstream diately by their functional contribution to individual cancer eff ector functions of tumour suppressor pathways. Such pathways. Second, the development of RNAi screens and genes (for example novel regulators of the p15Ink4b gene) bar-code screens will allow us to conduct for the fi rst time will identify novel entry points for targeting cancer path- systematic loss-of-function screens in mammalian cells. ways. Specifi cally, the aim of the analysis is to identify candidate genes that allow the restoration of tumour sup- Using these technology platforms, the work carried out in pressor function in the presence of inactivating mutations. this consortium addresses all three key aims of this specifi c The inclusion of RNAi libraries and bar code screens will topic: it will help to identify novel potential oncogenes and ensure that the analysis identifi es negative regulators of tumour suppressor genes and will provide insights into the tumour suppressor pathways. Such genes will provide role of telomere shortening and genomic stability (p53) in immediate candidates for drug screening approaches. tumour biology. Most importantly, however, it fi lls a key technological gap in the identifi cation of novel targets for tumour therapy. The identifi cation of strong dominant Potential applications oncogenes like bcr-abl has subsequently led to spectacu- lar successes in the development of drugs that specifi cally This consortium will develop novel high-throughput tech- target the mutated gene product. Thus, as highlighted by nologies for the functional annotation of the human the paradigm drug Gleevec, insights into the molecular genome and will apply these technologies to develop pathways that control cancer development can lead to the novel therapies to treat human cancer. We believe that development of highly cancer-specifi c drugs. In recent these technologies allow us to address a key problem of years, it has become clear that disruption of a limited translating current cancer research into therapy and thus number of tumour suppressor pathways, such as the TGF-β, our work in collaboration with SMEs will pave the way for pRB, the p53 or the APC pathways, is causal for the devel- more effi cient development of knowledge-based cancer opment of most human tumours. However, fi ndings drugs therapeutic intervention. that specifi cally target cancer cells with disruption of any of these pathways has been much more diffi cult to achieve. Clearly, current technologies are unable to identify drug target genes on a genome-wide scale. The technology developed in this consortium addresses this need and will allow the systematic identifi cation of two classes of genes:

First, we will identify genes that show synthetic lethality with disruptions in known tumour suppressor pathways. Synthetic lethal genes are genes whose disruption by themselves cause little or no phenotype, but become lethal in the presence of a second mutation. The existence of this class of genes as well as the feasibility of using them as targets for anti-tumour strategies is clearly docu- mented: for example cells transformed by Myc, in contrast to normal cells, critically depend on the presence of anti- apoptotic genes for survival. Inhibition of anti-apoptotic genes therefore selectively kills Myc-transformed cells. However, a systematic way for the identifi cation of syn- thetic lethal genes for tumour suppressor pathways is at present not available. The development of resources required to identify synthetic lethal genes for human tumour suppressor pathways on a genome-wide scale is the fi rst key aim of this consortium. Using this technology, the consortium will specifi cally identify and subsequently validate those genes that will cause lethality in the pres- ence of a disrupted p53, APC or TGF-β pathway. These genes defi ne the key entry points for rational drug devel- opment of most solid tumours.

BIOLOGY 43 Coordinator Project number LSHC-CT-2003-506803 Kristian Helin Manuela Baccarini Karen Vousden Biotech Research and Innovation Centre Institute of Microbiology and Genetics Beatson Institute for Cancer Research EC contribution Copenhagen, Denmark University of Vienna Glasgow, United Kingdom € 8 200 000 [email protected] Vienna, Austria [email protected] [email protected] Duration Anne Dejean 48 months Partners Clemens Schmitt Institut Pasteur Max-Delbrück-Centre for Molecular Paris, France Starting date Pier Giuseppe Pelicci Medicine [email protected] 01/01/2004 Istituto Europeo di Oncologia Charité, Campus-Virchow-Klinikum Milan, Italy Hematology-Oncology Bernhard Sixt Instrument [email protected] Berlin, Germany Agendia BV. IP [email protected] Amsterdam, The Netherlands Anton Berns [email protected] Project website René Bernards Martin Eilers www.imt.uni-marburg. Maarten van Lohuizen Philipps-Universität Marburg György Kéri de/intact Nederlands Kankerinstituut Institute for Molecular Biology Vichem Chemie Research Ltd Antoni van Leeuwenhoek Ziekenhuis and Tumour Research Budapest, Hungary Amsterdam, The Netherlands Marburg, Germany [email protected] [email protected] [email protected] [email protected] [email protected] Andreas Trumpp Michel Aguet Maria Blasco ISREC Manuel Serrano Epalinges, Switzerland Centro Nacional de Investigaciones Oncológicas [email protected] Madrid, Spain [email protected] [email protected] [email protected]

44 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Kinases | pediatric pancers | new drugs |

KidsCancerKinome Aim

Selecting and validating drug targets The overall aim of the KidsCancerKinome project is to sys- tematically explore the human kinase family for targeted from the Human kinome for high risk therapy development for children with cancer can be broken paediatric cancers down in the following objectives. • In silico analysis of the ITCC microarray database (in which we established the expression profi les of 600 childhood tumours), for expression profi les of all Summary protein kinase family members. The expression patterns will be used to prioritize the analyses of the protein Selecting and validating drug targets from the human kinases. kinome for high risk pediatric cancers. KidsCancerKinome • Functional high-throughput screening of the full >500 will make a comprehensive analysis of the human protein member kinase gene family for essential protein kinases kinase family. Protein kinases are already excellent targets in 24 childhood cancer cell lines, using a kinase-specifi c for many small inhibitory molecules and antibodies designed viral siRNA library and bar-coding-based read out for adult tumors. system. • Screening of extended cell line panels of the six selected Six aggressive childhood tumors (neuroblastoma, medullob- tumour types for dependency on known cancer-related lastoma, rhabdomyosarcoma, osteosarcoma, Ewing tumor, protein kinases and the protein kinases identifi ed in acute lymphocytic leukemia) will be addressed, which are step 2, by single-kinase siRNA. responsible for 50% of childhood cancer deaths. Viral shRNA • Mutation analysis of ‘tumour-driving’ protein kinases libraries will be applied to test the entire human kinase gene (identifi ed in steps 1-3) in series of paediatric tumour family for tumor-driving kinases in cell lines. They will subse- samples. quently be analyzed for mutations and functional parameters • Analysis of large clinical series of tumour samples for in large cohorts of tumor samples. siRNA mediated inactiva- presence and activation status of protein kinases identi- tion in larger cell line panels will critically validate suitable fi ed in step 1-3 by immunohistochemistry. kinases as drug targets. • In vitro testing of available small molecules for inhibition of the protein kinases identifi ed in step 1-3. Novel kinase inhibitors being developed for adult oncology • In vitro testing of LNA kinase inhibitors for protein kinas- will be tested for in vitro activity against the tumor-driving es identifi ed in step 1-3 for which no small molecule kinases. When no inhibitor is available, a novel generation of drugs are available. siRNA based nucleic acid drugs (LNAs) will be applied. • Validation of selected small molecule and LNA kinase Successful compounds will be taken further to in vivo vali- inhibitors in nude mouse transplants of childhood dation in established xenograft models of the six childhood tumours. tumor types. • Pharmacokinetic and pharmacodynamic studies of LNA’s for protein kinases selected in step 1-7 to identify LNA antagonist kinase inhibitor for the drug development Problem pipeline of Santaris.

Each year 15 000 European children are diagnosed with cancer and 25% die of this disease. Survivors frequently Expected results suff er from late side-eff ects of current treatments regimes. KidsCancerKinome will contribute to a better under- Translational research of childhood tumors to identify standing of the unique pediatric tumor biology and to molecular targets for novel generations drugs is therefore the development of new drugs. urgently needed. In addition, novel targeted drugs currently developed for adult tumors have to become available for children. Indeed, the EU launched in 2007 a paediatric Medi- Potential applications cines Regulation to stimulate drug evaluation in children. Nine European research centers devoted to molecular- Identifi cation of new drugable targets and development biologic and pharmacologic studies of childhood cancers of new specifi c treatments for childhood malignancies. and two SMEs therefore engaged in the KidsCancerKinome project.

BIOLOGY 45 Project number LSHC-CT-2006-037390

EC contribution € 3 415 414

Duration 36 months

Starting date 01/11/2006

Expression of human kinases in 6 pediatric malignancies (neuroblastoma, medulloblastoma, Instrument rhabdomyosarcoma, osteosarcoma, Ewing tumours and acute lymphoblastic leukemias). STREP

Project website www.KidsCancer Kinome.org Coordinator

Gilles Vassal Olivier Delattre Institut Gustave Roussy Institut Curie Villejuif, France Paris, France [email protected] Claudia Lanvers-kaminsky Westfälische Wilhelms- Partners Universität Münster Münster, Germany Huib Caron Academisch Medisch Centrum Torsten Pietsch Emma Children’s Hospital Amc Universitätsklinikum Bonn Amsterdam, The Netherlands Bonn, Germany

Steve Clifford Massimo Serra University Of Newcastle Upon Tyne Istituto Ortopedico Rizzoli Newcastle Upon Tyne, United Kingdom Bologna, Italia

Monique Den Boer Olivier Degrand Erasmus Mc France Europe Innovation Sophia Children’s Hospital Le Vesinet, France Rotterdam, The Netherlands Troels Koch Janet Shipley Santaris Pharma A/s The Institute of Cancer Research Horsholm, Denmark Royal Cancer Hospital London, United Kingdom

46 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Lymphangiogenesis | angiogenesis | gene therapy | infl ammatory diseases | lymphedema | tissue ischemia |

Lymphangiogenomics Genome-wide Discovery and Functional Analysis of Novel Genes in Lymphangiogenesis

Summary

Lymphangiogenomics is an Integrated Project with 14 par- ticipating consortium members. Its aim is to dissect the processes of lymphangiogenesis thoroughly and to com- pare them with angiogenesis at the genetic, molecular, cellular and functional levels.

Aim

The aim of this project is to discover novel genes important for lymphatic vascular versus blood vascular development and function, and to study the functional role and therapeu- tic potential of their gene products in lymphangiogenesis using state-of-the-art technologies.

Expected results

These studies will provide a new and fundamental understand- ing of the molecular and cellular basis of lymphangiogenesis and therefore enable scientists to develop therapies to sup- press the growth of lymphatic vessels (for example for cancer and infl ammatory diseases) or to stimulate their growth (for example for tissue ischemia and lymphedema). Lymphatic vessels in a whole mount preparation of the mouse ear skin are visualised with Lymphangiogenomics puts forward ambitious and competi- antibodies to LYVE-1 (green). Blood vessels are stained with PECAM-1 antibodies (red). tive research objectives addressing biological processes of high medical importance using a multidisciplinary analysis and validation approach.

Potential applications

Novel therapies for cancer, infl ammatory diseases, lymphe- dema and tissue ischemia.

BIOLOGY 47 Coordinator Project number LSHG-CT-2004-503573 Kari Alitalo Hellmut Augustin Markku Jalkanen Centre of Excellence in Molecular/Cancer Biology KTB Tumorforschungsgesellschaft mbH Lymphatix Oy (Lymphatix Ltd) EC contribution Biomedicum Helsinki Dept. of Vascular Biology Helsinki, Finland € 9 000 000 University of Helsinki and Angiogenesis Research [email protected] Helsinki, Finland Freiburg, Germany Duration [email protected] [email protected] Christer Betsholtz 60 months Karolinska Institutet Lena Claesson-Welsh Laboratory of Vascular Biology Starting date Partners Dept. of Genetics and Pathology Division of Matrix Biology 01/05/2004 Uppsala University Dept. of Medical Biochemistry Anne Eichmann Vascular Biology Unit and Biophysics Instrument Institut National de la Santé Uppsala, Sweden Stockholm, Sweden IP et de la Recherche Médicale [email protected] [email protected] Paris, France Project website [email protected] Miikka Vikkula www.lymphomic.org BCHM/Christian de Duve Institute Per Lindahl of Cellular Pathology Göteborg University Laboratory of Human Molecular Genetics Göteborg, Sweden Brussels, Belgium [email protected] [email protected]

Dontscho Kerjaschki Peter Carmeliet Medical University Vienna Centre for Transgene Technology Klinisches Institut fuer Klinische Pathologie and Gene Therapy Vienna, Austria Flanders Interuniversity Institute [email protected] for Biotechnology University of Leuven Elisabetta Dejana Leuven, Belgium IFOM Fondazione Istituto FIRC [email protected] di Oncologia Molecolare Milan, Italy Seppo Ylä-Herttuala [email protected] A.I. Virtanen Instituutti University of Kuopio Gerhard Christofori Kuopio, Finland Institute of Biochemistry and Genetics [email protected] Dept. of Clinical-Biological Sciences University of Basel Mattias Kalén Basel, Switzerland AngioGenetics AB Medicinaregatan [email protected] Gothenburg, Sweden [email protected]

48 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Breast cancer | metastasis | gene profi ling | organ-specifi c metastasis |

MetaBre Metastasis in breast cancer is a complex multi-step process. Genetic changes in tumour cells give rise to aggressive met- Molecular mechanisms involved in astatic cells, and their subsequent development in specifi c sites depends on a web of cellular and matrix interactions organ-specifi c metastatic growth within each organ microenvironment. Understanding the key molecular mechanisms of these metastatic processes processes in breast cancer can lead to improvements in the prognosis and treatment of breast cancer patients.

Summary Aim

Breast cancer is often accompanied by the development of MetaBre aims to discover new gene and protein markers, metastases, particularly in bone, liver, lung, brain or lymph which can be used for diagnosis as a signature of metastasis node tissues. The metastases cause a range of symptoms to specifi c organs, and also be targeted for therapy. To ultimately leading to increased morbidity and mortality. achieve this, the partners will analyse samples of breast pri- Metastasis is a complex multi-step process and little is known mary tumours and metastases, with due care of the ethical about the molecular mechanisms that direct metastases to aspects, as well as established breast cancer cell lines. MetaBre form in certain organs in diff erent patients. MetaBre will ana- will also study genes and molecules that are already sus- lyse diff erential gene and protein expression in primary pected of involvement in metastasis. This builds on previous breast cancers and metastases in order to identify the mole- work of the partners and will enhance understanding of cules involved in organ-specifi city. These will be investigated the role of these molecules in metastasis, as well as iden- as potential novel therapeutic targets and biomarkers for tifying new opportunities for development of therapies prognosis of organ-specifi c metastasis in breast cancer and diagnostic methods. patients. MetaBre has research activities aimed at: • gene profi ling and proteomic analysis to identify new molecular targets; Expected results • functional analysis of new targets in in vitro and in vivo models; MetaBre aims to generate the following results: • mechanisms of angiogenesis and invasion; • identifi cation and characterisation of molecular signatures • organ-cancer cell interactions; including serum biomarkers for diagnosis of organ-specifi c • development of new pharmacological therapies and diag- metastatic potential in breast cancer; nostic techniques; • identifi cation of new molecular targets for inhibition of • preliminary clinical trials. angiogenesis, invasion of metastatic cells, and growth of metastases in specifi c organs; MetaBre will develop in vivo models for validation of molecular • development of a catalogued collection of primary tumours, targets and screening of therapeutic molecules. Metastases metastases and related samples; will be detected in vivo with optical imaging of cancer • development of new clinically relevant in vitro and in vivo cells transfected with optical reporter genes, and magnetic models for study of metastatic disease in breast cancer; resonance techniques. • development of diagnostic techniques and identifi cation of at least one novel pharmacological therapy. Problem Potential applications More than 200 000 women are diagnosed in Europe every year with breast cancer. The lifetime risk of developing The project will identify novel molecular mechanisms that breast cancer is currently one in ten and the disease is the may be targeted for therapy of metastatic disease in breast leading cause of death in women between the ages of 35 cancer. The genes related to organ-specifi c metastasis may and 55. There has been considerable success in the treat- be used as biomarkers for stratifi cation of breast cancer ment of breast cancer in recent years, if detected in its early patients according to the risk of developing metastases, stages. However, breast cancers are prone to metastasise either through gene expression microarray analysis of pri- and cause secondary lesions in bone, liver, lung, brain and mary tumours, or through measurement of those markers lymph nodes. Once solid metastatic tumours are established, present in serum. the likelihood of complete remission reduces and, depending on the site of metastases, they can cause considerable pain and increased mortality.

BIOLOGY 49 Project number LSHC-CT-2004-503049

EC contribution € 4 005 295

Duration 48 months

Starting date 01/01/2004

Instrument STREP

Project website www.metabre.org

Image of a bone metastasis obtained by 3 dimensional computerised micro-tomodensitometry.

Coordinator

Anna Maria Teti Philippe Clement-Lacroix Angels Sierra Dept. of Experimental Medicine ProSkelia SAS Fundació Privada Institut d’Investigació University of L’Aquila Romainville, France Biomèdica de Bellvitge L’Aquila, Italy Barcelona, Spain [email protected] Gabri van der Pluijm Leiden University Medical Center Marc Bracke Leiden, The Netherlands Ghent University Partners Ghent, Belgium Ben-Tsion Williger Roberto Buccione CancerTek Pharmaceuticals Ltd Vincent Castronovo Consorzio Mario Negri Sud Kiriat-Oro, Israel University of Liège Italy Liège, Belgium Maciej Ugorski Rosette Lidereau Wroclaw University of Environmental Centre René Huguenin and Life Sciences Saint-Cloud, France Wroclaw, Poland

Philippe Clezardin Suzanne Eccles INSERM U664 Institute of Cancer Research Paris, France United Kingdom

50 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Mitosis | phosphorylation | RNAi | mass spectrometry | chemical inhibitors |

MitoCheck Problem

Regulation of Mitosis by Better understanding of mitotic process in mammalian cells. Phosphorylation – A Combined Functional Genomics, Proteomics Aim The objectives of this project are: and Chemical Biology Approach • to identify all human protein complexes required for mitosis; • to analyse how these complexes are regulated through phosphorylation by mitotic kinases; Summary • to evaluate the potential of mitotic kinases as diagnostic or prognostic markers in clinical oncology. The proliferation of cells depends on the duplication and segregation of their genomes. The latter is an immensely complex process that remains poorly understood at Expected results a molecular level. Mistakes during mitosis contribute to can- cer, whereas mistakes during meiosis that cause aneuploidy • A list of mammalian proteins that have important roles are the leading cause of infertility and mental retardation. during mitosis. During mitosis, sister DNA molecules are dragged towards • Subunit composition of the mitotic protein complexes opposite poles of the cell due to their prior attachment and their mitosis-specifi c phosphorylation sites. to microtubules with opposite orientations (bi-orientation). • Expression profi les of mitotic kinases in tumour samples Bi-orientation involves dissolution of the nuclear membrane, and the potential of the mitotic kinases as diagnostic or changes in chromosome organisation, and re-organisation of prognostic markers in clinical oncology. the spindle apparatus. How mitotic cells coordinate these • A web-based database. disparate but inter-locking processes is poorly understood. One thing, however, is certain – protein kinases like Cdk1 have fundamental roles. Nevertheless, Cdk1’s actual function Potential applications remains mysterious, despite recognition of its importance by a Nobel Prize. The same is true for other mitotic kinases, such Our basic understanding of the cell division process at as Plk1 and Aurora A and B. We need to know what set of a molecular level will be advanced. proteins are phosphorylated, what their functions are, or how phosphorylation changes their activity. The project will generate knowledge relevant for diagnos- tics and biomarker research as well as for target identifi cation Identifi cation of kinase substrates has been hampered by for new antiproliferative pharmaceuticals. diffi culties in mapping phosphorylation sites, in experimen- tally controlling protein kinase activity, and in evaluating We will develop genomics and proteomics technology, the physiological consequences of defi ned phosphorylation applicable not only to mitosis research but also to other sites. The premise behind this proposal is that all three hur- research areas, and we will contribute to the integration and dles can be overcome by new technologies, namely the use international visibility of the European research area. of RNA interference to identify, in a systematic (functional genomics) manner, potential substrates, iTAP-tagging to purify protein complexes, small molecules to inhibit specifi c kinases in a controlled fashion, and mass spectrometry to identify phosphorylation sites on complex subunits. Because the concept behind this project could be applied to other areas, it will have an impact on European cell biology far beyond the cell cycle community.

BIOLOGY 51 Coordinator Project number LSHG-CT-2004-503464 Jan-Michael Peters Gary Stevens Forschungsinstitut für Molekulare Gene Bridges GmbH EC contribution Pathologie Gesellschaft m.b.H. Heidelberg, Germany € 8 578 177 Vienna, Austria [email protected] [email protected] Duration Andrea Musacchio 48 months European Institute of Oncology Partners Milan, Italy Starting date [email protected] 01/04/2004 Jan Ellenberg European Molecular Biology Laboratory Ariane Abrieu Instrument Heidelberg, Germany Centre National IP [email protected] de la Recherche Scientifique Montpellier, France Project website Roland Eils [email protected] www.mitocheck.org Deutsches Krebsforschungszentrum Heidelberg, Germany Tim Hunt [email protected] Clare Hall Laboratories, Cancer Research UK South Mimms, United Kingdom Frank Sieckmann [email protected] Leica Microsystems CMS GmbH Mannheim, Germany Kai Stoeber [email protected] University College London London, United Kingdom Tony Hyman [email protected] Max-Plank-lnstitut für Molekulare Zellbiologie und Genetik Richard Durbin Dresden, Germany Genome Research Limited [email protected] Wellcome Trust Sanger Institute Cambridge, United Kingdom [email protected]

52 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Therapy | genome | telomerase | diagnosis | drugs |

MOL CANCER MED and telomere maintenance. Repression of telomerase in the somatic tissues of humans, and probably other long-lived Developing molecular medicines mammals, appears to have evolved as a powerful protective barrier against cancer. Immortalisation in vitro of normal for cancer in the post-genome era human cells that lack telomerase involves the reactivation of telomerase or, rarely, an alternative (ALT) mechanism for maintaining telomeres. It is clear that telomerase is obligatory for continuous tumour cell proliferation, clonal evolution and Summary malignant progression. Because telomerase is found in around 90% of human cancers and is essential for the continued pro- The cellular immortality enzyme telomerase (one of the most liferation (and clonal evolution) of cancer cells, it represents promising universal cancer markers) and associated telomere one of the most exciting anti-cancer targets thus far discov- maintenance mechanisms represent novel anti-cancer tar- ered. Results with a variety of telomerase inhibitory strategies gets of enormous therapeutic and diagnostic potential. In in human cancer cells have confi rmed that its functional inac- MOL CANCER MED, a multinational EU translational cancer tivation results in progressive telomere shortening, leading to research consortium has been established, in which expert growth arrest and/or cell death through apoptosis. Promising cancer geneticists and molecular biologists will interact with candidate small molecule inhibitors are beginning to emerge prominent pharmacologists, clinicians and pathologists to that will form the basis for anti-telomerase drug develop- develop these exciting new cellular targets into measurable ment. MOL CANCER MED is based on successful Framework pre-clinical advances, within a four-year time-frame. 5 research concerned with establishing the value of the cellu- The project has been structured into three, highly interactive lar immortality enzyme telomerase as an anti-cancer target areas of activity, involving the fundamental evaluation and (Project: QLG-1999-01341; TACIT) and represents an expan- pre-clinical validation of: sion and elaboration of this. TACIT yielded results that have • telomerase as a target for cancer treatment and diagnosis triggered new translational research with clearly defi ned clini- based on new molecular knowledge about its expression cal applications. To this set of activities have been added and function; carefully selected new EU research teams, notably in the area • associated downstream telomere maintenance mecha- of drug development. nisms as additional targets for novel drug design; • new anti-cancer drugs based on these targets. The con- sortium will bring to bear diverse and complementary Aim technological know-how of considerable power to deliver the above primary objectives. Eff ective management will The principal aim of MOL CANCER MED is to fully exploit the maximise synergies across MOL CANCER MED in order results of recent fundamental advances in understanding the to produce genuine improvements in the design of new role of telomerase and telomere maintenance mechanisms in treatments that promise to be active against a broad human cancer development, in order to achieve genuine clini- spectrum of common human malignancies. cal benefi t (i.e. in developing both improved diagnostics and anti-cancer therapies). The principal measurable objectives of the project, over the complete 48 months period, are: Problem • to validate further the potential of telomerase and telomere maintenance systems in cancer therapy and diagnosis; Cancer is a leading cause of death in the western world, • to identify novel molecular targets based on telomere second only to cardiovascular disease, and is therefore structure, function & stability, that may be of value in treat- a European public health problem of overwhelming human ment and diagnosis of the common human cancers; and economic signifi cance. The incidence of cancer is set to • to create a programme of novel small molecule drug increase substantially with demographic and possibly envi- development based initially on recently identifi ed (but ronmental infl uences playing a part. However, there is now an thus far poorly exploited) targets and, later (from month improved molecular understanding of the key genetic, bio- 12 onwards) exploiting completely new targets identifi ed chemical and cellular changes leading to cancer, in signifi cant during the project. part due to the eff orts of diverse groups of world-class EU- based scientists. With the completion of the human genome sequence imminent, it is now timely to initiate a major Euro- Expected results pean coordinated eff ort to translate fundamental scientifi c knowledge about cancer into safer, more eff ective, therapies • Novel anti-cancer drug targets and diagnostic methodol- and improved early diagnostic procedures. ogies derived from advances in: • the understanding and defi nition of biochemical MOL CANCER MED is focused on a single group of highly response pathways underpinning the telomere check- promising anti-cancer targets associated with telomerase point for somatic cell proliferation;

BIOLOGY 53 • the identifi cation and molecular/functional charac- Project number terisation of natural mechanisms of telomerase LSHC-CT-2004-502943 repression and cell self-renewal (including hTERT repressor genes and chromatin remodelling factors) EC contribution in normal human cells and their dysregulation in € 4 000 000 human cancers; • understanding the mechanisms of action and pharma- Duration cological activity of existing small molecule telomerase 48 months inhibitors (eg BIBR1532); • establishment of the precise roles of telomere aggre- Starting date gates and telomere-length-independent functions of 01/10/2004 telomerase in human cancer. • An advanced molecular understanding of telomerase Instrument regulation at chromosome ends (eg involving the key IP telomere-binding proteins POT1 and hEST1A) and a com- prehensive evaluation of such proteins as anti-telomerase Project website drug targets. www.brunel.ac.uk/ • New and eff ective molecular inhibitors (eg siRNAs, research/molcancermed/ ribozymes and peptide nucleic acids) of telomerase and telomere maintenance (targeting hTERT transcription and telomere-related proteins discovered within the MOL CANCER MED consortium) for the purpose of vasli. • Panels of new molecular markers of telomerase repres- sion, telomere maintenance and associated signalling Coordinator pathways, that can be developed into precise, rapid assays for use in novel ‘kits’ for early cancer diagnosis and Robert Newbold Uwe Martens prognostic evaluation. Brunel University Medical University Center Freiburg • An understanding of the diff erential eff ects of telomer- Uxbridge, United Kingdom Freiburg, Germany ase/telomere maintenance inhibition on normal human [email protected] tissues and in cancers using organotypic in vitro human Petra Boukamp cell models. DKFZ • Rational design of libraries of novel small molecule com- Partners Heidelberg, Germany pounds for screening against new targets, and selection of small molecule antitelomerase/telomere maintenance Stephen Neidle Maria Blasco drug leads active against individual new targets discov- London School of Pharmacy CNIO ered during the course of MOL CANCER MED. London, United Kingdom Madrid, Spain • Identifi cation of potential anti-cancer drugs from the above, following biochemical, pharmacological and func- Jean-Louis Mergny Keith Nicol tional (in vitro and in vivo) anti-tumour assays. INSERM University of Glasgow • Preclinical exploitation of potential novel cancer drugs Paris, France Glasgow, United Kingdom through interface with clinical oncology centres and SMEs. John Mann Nadia Zaffaroni Queens University Belfast National Cancer Institute Potential applications Belfast, United Kingdom Milan, Italy

The emphasis of the LIFESCIHEALTH Priority is very fi rmly Maurizio D’Incalci Nedime Serakinci placed upon multidisciplinary translational research, in which Istituto de Richerche Mario Negri University of Southern Denmark fundamental scientifi c knowledge is harnessed for the spe- Milan, Italy Vejle, Denmark cifi c purpose of generating, within the timeframe of FP6, reagents, treatments and diagnostics that are of clinical value. Joachim Lingner Goran Roos In MOL CANCER MED, a highly focused strategy will be EPFL Umeå University adopted towards applying molecular genetic knowledge Lausanne, Switzerland Umeå, Sweden about the mechanisms underlying the cancer process to the development of completely new approaches to cancer Kenneth Parkinson treatment, eg in bringing molecular biology, cell biology, QMUL genomics and target evaluation together with small molecule London, United Kingdom drug discovery.

54 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Multiple myeloma | cancer stem cell | clonal disease progression |

MSCNET Aim

Myeloma Stem Cell Network: Based on the above hypothesis, the aims will be: • to study whether the putative myeloma stem cell (MSC) a translational programme identifying exists as a less diff erentiated clonally related memory B-cell or as a more mature plasma blast/plasma clono- and targeting the myeloma stem cell genic cell; • to identify genes of potential impact on stem cell function; • to propose new therapeutic strategies.

Summary Expected results Multiple myeloma (MM) is a disease where malignant plas- ma cells accumulate in the bone marrow. Normal plasma The results of the scientifi c programme are expected to cell development at this site is thought to refl ect a synchro- redefi ne stem cell characteristics and especially to charac- nous terminal diff erentiation of B cells that have followed terize the myeloma stem cell compartment and its progeny, sequential stages of maturation. In MM, however, disease as well as its relationship to the tumour micro-environment. characterisation has revealed a number of phenotypic and This insight will allow us to examine whether there are any molecular features that suggest the existence of a clonally MSC-related features that can be targeted by future specifi c related ‘less mature’ cell, and the question arises whether therapies to ablate malignant disease. this may be a stem cell critical to propagating disease.

To address this, the MSCNET has formulated a strategy Potential applications which includes genomic and proteomic approaches, in order to examine the nature of the cell underlying MM dis- Identifying the nature of the MSC will have a profound ease origins and progression. This will utilise both in vitro impact on our understanding of pathogenesis, not only for and in vivo models of the disease, and examine MM at pres- MM but for all malignant B-cell diseases. Importantly, the entation and during its advance, in order to track factors MSCNET is well placed to identify potential drug-based governing disease behaviour in this regard. approaches to attack MSC and disease progression.

Problem

MM is at present an incurable disease, for which eff ective new therapies are being actively sought. It is by no means clear, however, what the nature of clonal propagation is in MM. To progress work in this area, the MSCNET has set out to identify the nature of the cell underlying disease survival and persistence.

One of the most striking concepts emerging in cancer biology is a role for cancer stem cells (CSCs) in feeding malignant cell growth and tumour maintenance. By defi nition, these CSCs have an indefi nite self-renewal potential, and are able to populate both their own pool and the growth of the tumour. Although the fi rst indication that such a cell might exist came from studies in leukaemia, evidence for CSCs in solid tumours lends further support for the concept of a myeloma stem cell. The question for the MSCNET is whether such a stem cell exists in MM.

BIOLOGY 55 Coordinator Project number LSHC-Ct-2006-037602 Hans E. Johnsen Surinder S. Sahota Aalborg Hospital, Aarhus School of Medicine EC contribution University Hospital Southampton, United Kingdom € 2 734 000 Dept. of Haematology Aalborg, Denmark Nico A. Bos Duration [email protected] University Medical Center 36 months Groningen, The Netherlands [email protected] Starting date Partners 01/11/2006 Bernhard Klein Karin Vanderkerken University of Montpellier Instrument Vrije Universiteit Brussel Montpellier, France STREP Brussels, Belgium [email protected] [email protected] Project website Dirk Hose www.myeloma- Pieter Sonneveld University of Heidelberg europe.org Erasmus University Medical Center Heidelberg, Germany Rotterdam, The Netherlands [email protected] [email protected] Zojer Niklas Alberto Orfao Wilheminenhospital University of Salamanca Wien, Austria Salamanca, Spain [email protected] [email protected]

56 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | p53 tumour suppressor | mutations | gain-of-function | p53 status | clinical outcome | mutant p53-reactivating drugs | novel cancer therapy |

Mutp53 Problem

Mutant p53 as a target for improved Cancer is a major cause for human suff ering in Europe as well as elsewhere in the world. It causes immense eff ects on cancer treatment the cancer patients themselves, on their families, as well as on society at large. In addition to the severe human suff ering and their immediate societal impact, cancer treatment and management is also a major economic burden. The impor- Summary tance of this problem and the urgency of the need for novel approaches to cancer management and treatment have Mutations in the p53 tumour suppressor gene are the most been recognised by the EC, as refl ected by the establish- frequent genetic alteration in human cancer, occurring in ment of a specifi c call in the area of ‘Combating Cancer’. over 40% of all cases of cancer. One well-studied outcome of these mutations is the loss of the tumour suppressor Mutations in the p53 tumour suppressor gene are the most activity of the wild type (wt) p53. However, there is growing frequent genetic alteration in human cancer, occurring in evidence that many of the mutations that occur in the p53 over 40% of all cases of cancer. We propose to explore protein generate mutant p53 proteins (mutp53) have mutp53 as a target for novel anticancer therapies. Such acquired new biochemical and biological properties. therapies should aim to either abrogate the gain of function Through this gain of function (GOF), mutp53 is believed to (GOF) eff ects of mutp53, or restore wt-like properties to contribute actively to the cancer process. mutp53, so that it can now regain its tumour suppressor capabilities. A multi-disciplinary approach will be under- We propose to explore mutp53 as a target for novel anti- taken to explore and exploit the contribution of mutp53 cancer therapies. Such therapies should aim to either to cancer. abrogate the GOF eff ects of mutp53, or restore wt-like properties to mutp53, so that it can now regain its tumour suppressor capabilities. A multi-disciplinary approach will Aim be undertaken to explore and exploit the contribution of mutp53 to cancer. In our proposed project, we introduce a multidisciplinary approach to explore mutp53 as a new target for innovative One component of this project will investigate in depth the treatment. molecular properties of mutp53: structural studies will pin- point the changes that particular mutations infl ict on the A primary objective of the ‘Combating Cancer’ initiative is structure of p53, and allow the classifi cation of mutp53 into ‘to combat cancer by developing improved patient-oriented distinct subclasses. In parallel, biochemical studies will strategies… to better treatment with minimal side-eff ects’ explore the mode of action of mutp53 within cells, includ- with a focus on ‘encouraging the development of evidence- ing its impact on patterns of gene expression, identifi cation based guidelines for good clinical practice’. of specifi c DNA sequences targeted by mutp53, and dis- covery of mutp53-interacting cellular proteins. Preclinical Our project meets these requirements in at least two dis- models for mutp53-driven cancer will also be developed, as tinct ways: a critical instrument for pre-clinical studies. • We aim to improve the use of contemporary chemother- apy through providing better guidelines based on The other component will aim at translating this wealth of correlations between p53 genotype of the tumour and information into better cancer therapy. One avenue will its response to particular types of anti-cancer drugs. address the clinical relevance of particular p53 mutations in It is important to keep in mind that, although novel ther- human cancer, particularly its impact on the patient’s apeutic approaches are very exciting and promising, response to chemotherapy. This should lead to guidelines millions of cancer patients all over Europe are being for more eff ective use of conventional therapy. The other treated every day with standard chemotherapy. Beyond avenue will explore novel therapies targeted at mutp53 and its limited effi cacy, this is also associated with signifi cant mutp53-expressing tumour cells. A major eff ort will focus toxicity and therefore often unjustifi ed patient suff ering. on the discovery of small compounds that can restore The ability to make better predictions as to which par- wtp53-like activity to mutp53. An innovative approach to ticular chemotherapeutic regimen is most likely to work immunotherapy directed against mutp53-overexpressing for a particular patient thus has far-reaching implica- cancer cells will also be explored. Owing to the extremely tions, both in ensuring better and more eff ective high frequency of p53 mutations, the success of this project treatment and, not less importantly, in preventing unnec- will impact on a very large number of cancer patients in essary suff ering from severe side-eff ects in cases where Europe and worldwide. it is clear that a particular treatment is not going to work.

BIOLOGY 57 Providing new recommendations to oncologists, allowing Potential applications them to ‘individualise’ the chemotherapy course chosen for a given patient, will therefore meet the objective of Cancer represents one of the most severe health problems in better treatment with minimal side-eff ects, and will the European community. Cases are growing with the age of the provide evidence-based guidelines for good clinical population. The economic and emotional burden is enormous. practice. Mutp53 protein is expressed in about 50% of all human tumours. In some categories with growing incidence, e.g. lung • A major component of this project is aimed at develop- cancer, colon carcinoma and skin tumours, more than 60-70% ing novel therapies, based on mutp53 knowledge to be of the tumours are associated with mutated p53. This may be gained by the consortium. The increased selectivity and due to the induction of p53 mutations by dietary and envi- specifi city of such drugs is most likely to reduce side- ronmental carcinogenic insults, which are encouraged by eff ects on normal patient tissue, because such tissue modern western society’s lifestyle (exposure to sun, very does not express any mutp53, unlike the targeted tumour heavy smoking in most parts of Europe, high-fat diet). cells. Thus, any successful drug that comes out of this project is highly likely to lead to improved clinical prac- In some types of cancer, expression of mutp53 appears to tice and to better treatment, with reduced side-eff ects be particularly highly correlated with the more aggressive as compared to the presently available options. Moreo- tumour stages. Yet, in many cancers, mutation of p53 ver, the fact that close to half of all human tumours appears to occur during the very early steps of carcinogen- possess mutp53 in abundant amounts makes any new esis. This is particularly true for cancers of the lung, drug emanating from this endeavour potentially valua- head-and-neck, bladder, skin and oesophagus. In these ble to a very large number of cancer patients. Such drug, pathologies, mutp53 is amongst the earliest tumourigenic if successful, may thus have far-reaching impacts, not changes that can be detected in the patient, sometimes only on individual cancer patients, but also on European ahead of the clinical diagnosis of a cancer lesion. The expres- society as a whole. sion of mutp53 is relatively easy to diagnose, employing immunohistochemical assays that are already available as commercial kits and are in use in many pathology laborato- Expected results ries throughout Europe. However, there is still a lack of rapid, low-cost and sensitive assays for mutation detection, and The proposed project will address the following main this is the key to the systematic implementation of mutp53- objectives: based strategies for cancer diagnosis, prognosis, and • elucidate the biochemical basis for mutp53 GOF (GOF), treatment. This is why one of the activities of our consorti- with special emphasis on genomics and proteomics um will be to support the validation and the transfer into approaches; production of a new type of micro-array developed by • evaluate the contribution of mutp53 to the malignant Asperbio, an SME partner of our consortium. Improved properties of cancer cells; detection of p53 mutations may enable earlier cancer diag- • explore in depth the structural properties of selected nosis, increased curability and reduction in the societal mutp53 proteins, in order to provide leads for structure- impact of cancer morbidity and mortality. based rational drug design; • evaluate the impact of mutp53 status on the response of An eff ective novel treatment of cancers expressing mutp53 selected types of human tumours to chemotherapy, and could help to prolong life expectancy and quality of life. Such use this information to formulate guidelines for more a treatment may be applicable for eradicating small lesions in eff ective use of currently available anti-cancer therapies; pathologies where mutation is an early event, thus providing • search for molecules and compounds that can selectively low-cost, low-stress approaches for lesions that are currently interfere with mutp53 GOF or restore wtp53 activity to managed through surgery and/or chemotherapy. On the other mutp53, and explore them as potential anti-cancer drugs; hand, mutp53-based therapies can be applied synergistically • initiate clinical trials (Phase I) with one mutp53-selective with conventional therapy regimens in patients with advanced drug that has already gone successfully through pre- cancers. The mutp53-based approach thus opens a whole clinical studies; range of possibilities that can be implemented in current • generate leads and new tools towards the development medical practice without costly equipment, infrastructures or of mutp53- based immunotherapy. extensive training programmes.

58 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Development of eff ective anti-cancer therapy for mutp53- Project number expressing tumours would lower direct and indirect costs by LSHC-CT-2004-502983 reduction of surgery and intensive care, reduction of dura- tion of medical survey, reduction of emotional burden for EC contribution patients and their family and faster reintegration of patients € 8 000 000 as part of the working economy. In addition, one should keep in mind that although novel anti-cancer therapies are a Duration very exciting avenue, millions of cancer patients in Europe 60 months are presently being treated with conventional chemotherapy. Current chemotherapy has severe adverse eff ects on the Starting date quality of life of the treated patient. The combination of data 01/02/2004 from experimental model systems and the cancer patient mutp53 database might potentially identify groups of Instrument patients who are not suitable for particular types of contem- IP porary chemotherapy. Better tools to decide which patients should be treated and which to be left untreated are Project website extremely important in reducing the suff ering of those www.mutp53.com patients who will not benefi t from the currently available cancer therapy modalities.

Coordinator

Klas Wiman Giovanni Blandino Pierre Hainaut Karolinska Institutet Ada Sacchi International Agency for Research Dept. of Oncology-Pathology Regina Elena Cancer Centre on Cancer – IARC Cancer Centre Karolinska Molecular Oncogenesis Laboratory Lyon, France Karolinska Hospital Rome, Italy [email protected] Stockholm, Sweden [email protected] Anne-Lise Börresen-Dale Christoph Huber Institute for Cancer Research Matthias Theobald Dept. of Genetics Dept. of Hematology and Oncology Partners Oslo, Norway Johannes-Gutenberg-University Medical School Mainz, Germany Galina Selivanova Gianni Del Sal Sten Nilsson Laboratorio Nazionale CIB Emil Palecek Karolinska Institutet Trieste, Italy Institute of Biophysics Dept. of Oncology-Pathology Academy of Sciences of the Czech Republic Cancer Center Karolinska Wolfgang Deppert Brno, Czech Republic Stockholm, Sweden Heinrich-Pette Institute Hamburg, Germany Neeme Tönisson Reuven Agami Asper Biotech Hein Te Riele Moshe Oren Tartu, Estonia Division of Tumour Biology Varda Rotter The Netherlands Cancer Institute Eytan Domany Thomas Stanislawski Amsterdam, The Netherlands Zippora Shacked GanyMed Pharmaceuticals AG Weizmann Institute of Science Mainz, Germany Jiri Bartèk Rehovot, Israel Institute of Cancer Biology Claes Post Dept. of Cell Cycle and Cancer Alan Fersht Aprea AB Copenhagen, Denmark MRC Centre for Protein Engineering Stockholm, Sweden University of Cambridge Cambridge, United Kingdom

BIOLOGY 59 Keywords | Vector | nano-sciences | protein-based drugs |

Nano4Drugs Problem

An Innovative Protein-Based Drug A series of barriers limits the targeted delivery of newly developed protein-based drugs, of which three are of critical Delivery Device using Fluorescent importance: • transport of protein-based drugs across the cell membrane; Diamond Nano-Particles • understanding the inter and intra-cellular routes taken by protein-based drugs; • exploitation of the 3D structure of the target, to narrow the protein-based drug specifi city, a condition to develop Summary new, safer and more eff ective drugs by reducing undesir- able side eff ects. Advances in genomics have resulted in the development of new protein-based drugs and this trend will increase in the next decade. However, delivery technologies for these Aim drugs must be designed to surmount biochemical and ana- tomical barriers to safely permit their passage to an Nano4Drugs intends to exploit the exceptional properties intended site. of diamond nano-particles to develop a novel delivery tech- nology that should overcome these barriers. The targeted delivery of protein-based drugs is limited by a series of barriers and advances made to overcome these barriers will lead to the development of new, safer and more Expected results eff ective drugs by reducing undesirable side eff ects. To this end, the Nano4drugs consortium has integrated top-level The cargo will be made of a stable, biocompatible traceable teams across Europe to develop an innovative, challenging, diamond nano-particle of a small size (< 25 nm) with selected frontier biotechnology device ideally suited for the targeted surface functional groups able to form an oriented covalent delivery of protein-based drugs. or reversible complex with the protein-based drugs.

The device consists of biocompatible non-bleachable fl uo- As a proof of concept, we will use this new vector to target rescent diamond nano-particles that can be grafted with microtubules which are main critical intra-cellular compo- both cell-penetrating peptides and protein-based drugs. nents involved in major biological processes, such as cell proliferation or neuronal axonal transport. As a proof of concept, Nano4drugs will target microtubules in two diff erent biological contexts, neuron and cancer. The protein-based drugs will consist of anti-microtubules pep- Potential applications tides recently discovered by one team in Nano4Drug, and of new ones that will be tested during the project with the Protein-based drug delivery in the context of cancer therapy help of a post-genomic computer-based system of choices (microtubules are key components for chromosome segre- designed to guide and improve the development of protein- gation at the end of mitosis) and neurodegenerative diseases based drugs. that imply microtubules (for example Alzheimer and spastic paralysis). At the end of this STREP, Nano4Drugs will provide Europe with a better understanding of ways to overcome protein- based drug delivery barriers. In achieving its objectives, Nano4Drugs will also deliver new potential treatments for societal health diseases such as neurological degenerative diseases and cancer.

60 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHC-CT-2005-019102 Patrick A. Curmi Diane Braguer INSERM Université d’Aix-Marseille 2 EC contribution Paris, France Marseille, France € 2 453 000 [email protected] [email protected] Duration Anke Krueger 36 months Partners Christian-Albrechts-University of Kiel Kiel, Germany Starting date Solange Lavielle [email protected] 01/01/2006 JP Boudou Université Pierre et Marie Curie Fedor Jelezko Instrument Laboratoire Synthèse Structure et University of Stuttgart STREP Fonctionnement de Molécules Bioactives Stuttgart, Germany Paris, France [email protected] Project website [email protected] www.nano4drugs.com [email protected] Marco Fragai Consorzio Interuniversitario François Treussart Risonanze Magnetiche di École Normale Supérieure de Cachan Metalloproteine paramagnetiche Laboratoire de Photonique Quantique et Florence, Italy Moléculaire [email protected] Cachan, France [email protected] Stéphane Legastellois Indicia Biotechnology Alain Thorel Oullins, France École Nationale Supérieure des Mines de Paris [email protected] Centre des matériaux Evry, France Rebecca del Conte [email protected] ProtEra s.r.l. Florence, Italy Isabelle Geahel [email protected] Inserm Transfert Laboratoire – Projets Européens Paris, France [email protected]

BIOLOGY 61 Keywords | Drosophila | breast cancer | colorectal cancer | mammospheres | crypt | tissue array | larval neuroblast | sensory organ precursor |

ONCASYM targeted at destroying rapidly proliferating cells. Stem cells often proliferate slowly and might not be eliminated by such Cancer stem cells and therapies, which might explain the high relapse rate observed for some cancers. Alternative therapies that target stem asymmetric cell division cells are not available. This is partly due to our limited under- standing of proliferation control in stem cells and the lack of appropriate cancer models which mimic the development of tumours from defi ned stem cell populations. Summary

An intense line of current investigation into cancer is based Aim on the connection between tumourigenesis and stem cell biology. Some tumours may originate from the transforma- The goal of this project is to develop new therapeutic tion of normal stem cells, at least in the case of blood, breast, strategies that target tumour stem cells. Stem cells are skin, brain, spino-cerebellar and colon cancers. In addition, characterised by their ability to divide asymmetrically and tumours may contain ‘cancer stem cells’, rare cells with indef- thereby form self-renewing and diff erentiating daughter inite potential for self-renewal that drive tumourigenesis. cells at the same time. Even a slight change in the balance Interestingly, the same signalling pathways (TGF-beta/BMP, between these two cell types could dramatically increase Wnt and Notch pathways) appear to regulate self-renewal in the number of daughter cells created by a stem cell and stem cells and cancer cells. thereby contribute to tumour formation. Self-renewal occurs through the asymmetric cell division of stem cells, which thereby generate a daughter stem cell and another daughter cell that contributes to populate the devel- Expected results oping organ or the growing tumour. In one of the best understood asymmetric cell division models, the Drosophila In our project we plan: nervous system, asymmetry is mediated by a biased Notch- • to discover the genes involved in asymmetric cell divi- dependent signalling event between the two daughter cells. sion and tumour suppression in normal and malignant ONCASYM partners have recently shown: stem cells, using Drosophila as a model system, and to • that the process of biased signalling during asymmetric fi nd their human and mouse homologues; cell division is controlled by endocytosis; • to use this candidate gene list to fi nd markers for the • that tumours can be induced in mutants with altered identifi cation of normal and cancer stem cells in the stem-cell asymmetric division. In human normal and mammary gland and the intestinal crypts and use these cancer stem cells, asymmetric cell division is supposed markers to image the asymmetric cell division event. to take place, but it has not directly been proven yet. Furthermore, the role of biased signalling by endocytosis in these stem cells has not been addressed to date. Potential applications The aim of this project is threefold: • to screen for genes involved in asymmetric cell division We will directly translate the acquired knowledge into the of human cancer stem cells; clinical practice. • to characterise the asymmetric cell division of these • We plan to validate the newly identifi ed ‘stemness’ sig- stem cells by using these candidate genes as markers; nature as a clinical tool for genomic grading and • to study functionally the role of the identifi ed candidate prognostic evaluation. This task will be initially accom- genes during asymmetric cell division of cancer stem plished by retrospectively performing meta-analysis, cells. Our ultimate goal is to untangle the molecular using the currently available public databases as well as machinery of cancer stem cell asymmetric division, the wide collection of cases from our tumour registry. thereby providing druggable targets for cancer therapy. • Tissue microarrays will be used to further validate the relevance of candidate ‘stemness’ genes to the diagnos- tic routine, by establishing their predictive strength in Problem relation to the common clinical-prognostic parameters. • Prospectively, the identifi ed ‘stemness’ genes will be Cell types within a tumour vary in their ability to form the introduced as ‘biomarkers’ for the clinical and prognostic whole tumour mass. In fact, only very few cells can give rise evaluation of cancer patients enrolled in ad hoc clinical to all cells present in the tumour. These so-called tumour trials at the European Institute of Oncology, even stem cells have been characterised in a variety of tumours, including their use in the procedure of the sentinel node including leukaemia, breast cancer and brain tumours. Their in order to identify the presence of stem cells in existence challenges conventional tumour therapy, which is metastasis.

62 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2006-037398

EC contribution € 2 823 800

Duration 36 months

Starting date 01/10/2006

Instrument STREP

Project website www.Oncasym.unige.ch

Drosophila as a model system for tumourigenesis. Transplanted tissue into Drosophila abdomen (black scars) do not cause tumours (labelled in green) unless the transplanted tissue is mutant for factors involved in asymmetric cell division (right fl y). ONCASYM uses this assay as a gene discovery tool for the genes involved in tumourigenesis.

Coordinator

Marcos Gonzalez-Gaitan Umberto Veronesi Dept. of Biochemistry European Institute of Oncology University of Geneva Milan, Italy Geneva, Switzerland [email protected] Jürgen Knoblich Institute of Molecular Biotechnology of the Austrian Partners Academy of Sciences Vienna, Austria Hans Clevers The Netherlands Institute Cayetano Gonzalez for Developmental Biology Institut de Reçerca Hubrecht Laboratory Biomédica Royal Netherlands Barcelona, Spain Academy of Sciences Utrecht, The Netherlands Andre Hoekema Galapagos NV Pier Paolo de Fiore Mechelen, Belgium Istituto FIRC di Oncologia Molecolare Milan, Italy

BIOLOGY 63 Keywords | TRAIL | Ras | CRC-colorectal cancer | PI3K | DISC | choline kinase | aurora inhibitors | caspase-2 | mitochondria | mouse models |

ONCODEATH Expected results

Sensitisation of solid tumour cells We believe that the principal objective of our project is reachable, for the following reasons. The novelty and inno- to death receptor-related therapies vative potential of the ONCODEATH project is based on the strength of its partners, a highly effi cient management and organisation plan, and a novel technology develop- ment strategy: all of these address R&D possibilities for Summary cancer therapy, which derive from very recent fi ndings for the role of additional mutations in colorectal cancer forma- TNF-related apoptosis-inducing ligand (TRAIL) is currently tion, as well as that the fact that tumours have intrinsic a promising anti-tumour agent with proven activity on sev- defective apoptotic pathways, like ‘Achilles’ heal’, that can eral cell and animal cancer models. A unique feature of TRAIL be exploited per case. is its specifi city towards malignant cells while sparing normal cells. At present, preclinical studies with recombinant TRAIL ONCODEATH can off er possibilities to test novel signalling are in progress as well as with an anti-TRAIL-R2 monoclonal drugs alone and in combination with a very potent apoptotic antibody with no hepatotoxicity. In order to identify specifi c ligand TRAIL, in order to enhance potency and overcome cell death determinants induced by KRAS, BRAF and PIK3CA resistance/non-responsiveness of tumours and fi nally induce oncogenes, examination of specifi c pathways like B-RAF, tumour-selective death. MEK, PI3K, Rho, and BCL-2 will be performed. Studies will be further extended to animal models of tissue-specifi c K-ras-induced carcinogenesis. Potential applications

Combined action of TRAIL with other therapeutic mole- We will investigate resistance of pathways to apoptosis cules will be utilised, in order to succeed optimum eff ects present in tumour cells and we will aim to sensitise these to with minimum concentrations and toxicity. The potential cell death by treatment with a combination of agents. These fi ndings of our study will be determined by the present pathways will be studied by genomic technologies, imaging research project and will provide mechanistic basis for technologies, biochemistry, tumour biology and novel thera- a pharmacogenomic approach which could be further ther- peutic agents which are prepared on specifi c target and apeutically exploited, in order to provide cancer patients pathway inhibition. The analysis will be performed on repre- with novel personalised therapies in the near future. sentative cell as well as mouse models for colorectal carcinogenesis. Specifi c oncogenic mutations will be ana- lysed according to the research plan described. If successful, Problem the eff orts should provide landmark discoveries in the fi eld, which would greatly advance our current knowledge and In the last decade, an encouraging decline of the death rate exploitation of defective apoptotic pathways in tumour cells. from cancer has been observed, as a result of recent advances in prevention, early diagnosis and therapy. Eff orts are made towards the generation of ‘smart’ anti-cancer drugs that will target specifi c molecules, depending on the molecular phenotyping of the patient’s tumour.

Aim

• Panel on new cell lines with up- and down-regulated colon cancer-related oncogenes. • Map of TRAIL-induced proximal signalling pathways per system. • Determinants of caspase-2 activation and Bax in TRAIL- induced apoptosis of tumour cells. • Assessment of a role of mitochondrial fi ssion and fusion in TRAIL-mediated apoptosis. • Selection of PI3 kinase and Aurora inhibitors that cooperate with TRAIL in inducing apoptosis of colon cancer cells. • Assessment of sensitivity of tumours induced by activated Incorporation of various inhibitors to help overcome possible kinase resistance to TRAIL oncogenes in transgenic mice and in mouse xenografts. induced apoptosis.

64 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHG-CT-2006-037278

EC contribution € 2 344 900

Duration 36 months

Starting date 01/11/2006

Instrument STREP

Normal cell growth and epithelial like morphology are severely altered once cells enter apoptosis. Project website www.eie.gr/nhrf/ institutes/ibrb/ eu-projects/oncodeath/ index-en.html Coordinator

Alexander Pintzas Spiros Linardopoulos National Hellenic Cancer Research UK Research Foundation Institute of Cancer Research Institute of Biological Research Breakthrough Breast and Biotechnology Cancer Research Centre Laboratory of Signal London, United Kingdom Mediated Gene Expression [email protected] Athens, Greece [email protected] Jean-Claude Martinou University of Geneva Geneva, Switzerland Partners [email protected]

Ladislav Andera Juan Carlos Lacal Czech Academy of Sciences Instituto de Investigaciones Institute of Molecular Genetics Biomédicas Laboratory of Cell Signaling Madrid, Spain and Apoptosis [email protected] Prague, Czech Republic [email protected] Sylvie Robine Institut Curie Boris Zhivotovsky UMR 144 CNRS/Institut Curie Karolinska Institutet Paris, France Institute of Environmental Medicine [email protected] Stockholm, Sweden [email protected] Georgios Nasioulas Genekor S.A. Paul Workman Athens, Greece Cancer Research UK Centre [email protected] for Cancer Therapeutics The Institute of Cancer Research Sutton, United Kingdom [email protected]

BIOLOGY 65 Keywords | Prostate cancer | androgen receptor | bone metastasis | high-throughput target identifi cation and validation | high-throughput low molecular weight compound screening |

PRIMA metastatic prostate cancer. In the PRIMA project, a multi- disciplinary eff ort is proposed to explore pathways that lead Prostate Cancer to the most lethal aspect of prostate cancer, i.e. hormone- therapy-unresponsive bone metastatic lesions. It has become Integral Management Approach clear that in the majority of advanced prostate cancers, the androgen receptor-signalling pathway is active even in the absence of androgens. European research teams with a lead- ing role in androgen receptor research will integrate their Summary eff orts to exploit androgen receptor-mediated signalling as a therapeutic target. Prostate cancer is one of the most common malignancies in the western male population. In Europe, approximately This should be achieved by: 40 000 men die of prostate cancer each year and, due to • targeting the androgen receptor itself; the ageing population, that number is likely to increase to • interfering with androgen receptor-activation by non- around 60 000 men in 2020. Therefore prostate cancer is steroids; a signifi cant medical problem with which the European • studying non-transcriptional functions of the androgen Community will be confronted increasingly in the oncoming receptor; decades. For localised prostate cancer, radical therapies, • targeting essential androgen-receptor co-factors over- aiming at eradicating all malignant processes in the pros- expressed in prostate cancer; tate gland, are available, which can cure the patient. • inhibiting those androgen receptor target genes that However, if the malignant process has locally or distantly regulate prostate cancer cell growth, survival and spread, no curative medical intervention is currently in diff erentiation. existence. Since the early 1940s, androgen ablation therapy has been the mainstay in an attempt to control prostate The androgen receptor teams will join forces with European neoplasms, but unfortunately this is only of a palliative investigators that study interactions between prostate can- nature and tumour progression is inevitable, due to the cer cells and the bone microenvironment. expansive growth of cancer cells that are unresponsive to currently available hormone therapies. Furthermore, pros- Expression profi ling of members of the transforming growth tate cancer cells have a strong tendency to spread to factor superfamily and signal transduction molecules in the bone, a site where metastases cause great morbidity, cell lines, animal models and clinical specimens should pro- ultimately leading to a painful death. vide more insight into the role of these molecules in the development of bone metastatic lesions. Furthermore, epithe- lium-mesenchymal transition will be extensively studied. The Problem exploration of pathways leading to hormone therapy-unre- sponsive bone metastatic disease will use functional genomics There has been little progress in the management of meta- and expression profi ling as technology platforms. These tech- static prostate cancer since Huggins and Hodges proposed nology platforms will also be used to identify novel candidate endocrine treatment of the disease. It has become clear that targets for treatment and a specifi c bioinformatics platform the treatment is palliative and not curative. Therefore, new will be developed to analyse all collected data. In the targeted targets for therapy need to be identifi ed, and methods to discovery phase, candidate target genes will be identifi ed interfere with these to change the course of the disease that, in addition to already available targets from earlier col- have to be developed and tested pre-clinically in (animal) laborative programmes, need to be phenotypically and/or model systems. functionally validated. Phenotypical validation will be per- formed in archival material of patients with a well-documented follow-up in all stages of the disease process. In addition, high- Aim throughput functional, cell-based analysis and molecular target validation will be performed by knocking down genes The main aim is the identifi cation of appropriate targets for that are over-expressed in hormone refractory or metastatic therapy for advanced prostate cancer. Two hypothesis-driven prostate cancers using RNA interference. The knowledge approaches are combined with target discovery eff orts obtained from the targeted discovery phase and validation using state-of-the-art, highthroughput, molecular profi ling phase will be used to establish assays, which will, in turn, be technologies. The identifi ed targets are validated at two levels, used for highthroughput screening of low molecular weight i.e. phenotypically and functionally (high-throughput small compounds (i.e. more than 25 000 compounds). The assays interfering RNA screens). Once identifi ed, validated targets will use easy-to-upscale formats and reporters that can be are used to screen for low molecular weight compounds, easily read out. The fi nal phase of the project will be the test- which are subsequently tested in animal models for bone ing of interesting compounds for their ability to interfere

66 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME effi ciently with cancer cell proliferation and/or survival in Project number a bone environment in the absence of androgens. The lead LSH-CT-2004-504587 compounds will be tested for their effi cacy in models for bone metastatic prostate cancer. Hence, the translation of EC contribution the obtained knowledge into therapeutic strategies is an € 6 000 000 integrated part of the project. Duration 60 months Expected results Starting date We expect to identify 3-5 novel targets that will be pursued 01/07/2004 for the utility in high-throughput screens of low molecular weight compounds. We expect to identify 2-3 molecules Instrument that can be tested in an animal model for bone metastatic IP prostate cancer. Project website www.primaproject.org Potential applications

Treatment of metastatic prostate cancer. Based on the animal models a decision will be made for animal toxicological test- ing (beyond the scope of this IP) and phase 1 clinical trials. The consortium will start a joint venture with a pharmaceutical company.

Coordinator

J. A. Schalken Johan Tijhuis Gabri van der Pluijm Radboud University Nijmegen COMPOUND Handling BV Leiden University Medical Center Medical Center Nijmegen, The Netherlands Leiden, The Netherlands Dept. of Urology Nijmegen, The Netherlands Zoran Culig Tapio Visakorpi [email protected] Medizinische Universität Innsbruck University of Tampere Innsbruck, Austria Tampere, Finland

Partners Craig Robson Varda Rotter University of Newcastle upon Tyne Weizmann Institute of Science Jan Trapman Newcastle upon Tyne, United Kingdom Rehovot, Israel Erasmus Medical Center Rotterdam, The Netherlands Andrew Cato David Neal Forschungszentrum Karlsruhe GMBH The Chancellor, Master and Scholars Bohdan Wasylyk Karlsruhe, Germany of the University of Cambridge Centre Européen de Recherche Cambridge, United Kingdom en Biologie et Médecine George Thalmann Strasbourg, France Universität Bern Bern, Switzerland Freddie Hamdy University of Sheffield Norman James Maitland Sheffield, United Kingdom University of York York, United Kingdom Olli Kallioniemi University of Turku Olivier Cussenot VTT Technical Research Centre Centre de Recherche pour Turku, Finland les pathologies prostatiques Paris, France

BIOLOGY 67 Keywords | Genomics | molecular genetics | transcription factors |

Regulatory Genomics The specifi c aims are: • to develop novel high throughput multiwell-plate and Advanced Genomics Instruments, DNA-chipbased methods for determination of TF bind- ing specifi city; Technology and Methods for • to determine experimentally the binding specifi cities of known cancer- associated TFs; Determination of Transcription Factor • to predict computationally, and to verify experimentally, elements that are regulated by these TFs in genes that Binding Specialities; Applications are essential for cell proliferation; • to develop a SNP genotyping chip composed of SNPs for Identifi cation of Genes Predisposing that aff ect the function of TF-binding sites conserved in mammalian species; to Colorectal Cancer • to use this chip for the genotyping of patients with hereditary cancer predisposition as well as controls in three European populations, for identifi cation of regulatory SNPs associated with cancer. Summary

Determination of the sequence of the human genome, and Expected results knowledge of the genetic code through which mRNA is translated, have allowed rapid progress in the identifi cation This project aims to understand the basic principles involved of mammalian proteins. However, less is known about the in growth regulation by oncogenic TFs, and is expected to molecular mechanisms that control the expression of genes. have a major impact in the understanding of cancer. Identifi - This project sets out to address this problem by developing cation of SNPs associated with low penetrance cancer novel tools and methods for analysing the specifi city of tran- predisposition would be a major breakthrough in the eff ort scription factors to bind to particular sequences of DNA. to understand inheritance of quantitative trait loci, and will have implications on the population’s healthcare.

Problem The methods developed within the project(1) have already allowed genome-scale prediction of regulatory elements in Not enough is known about the molecular mechanisms that the human genome, and the methods developed should control expression of human genes, and about the varia- make feasible the analysis of DNAbinding specifi cities of tions in gene expression that underlie many pathological all TFs, and consequently signifi cantly improve our under- states, including cancer. This is caused in part by a lack of standing regulation of gene expression. information about the second genetic code – binding spe- cifi cities of transcription factors (TFs). Deciphering this regulatory code is critical for cancer research, as little is Potential applications known about the mechanisms by which the known genetic defects induce the transcriptional programs that control cell We expect that the project will lead to the identifi cation of proliferation, survival and angiogenesis. In addition, changes genes that associate with colorectal cancer. This will have in binding of transcription factors caused by single nucleotide direct implications on diagnosis and treatment of a cancer polymorphisms (SNPs) are likely to be a major factor in many type that aff ects more than 200 000 Europeans every year. quantitative trait conditions, including familial predisposition to cancer. Methods, tools and instrumentation for advanced genomics developed within this project will improve EU scientifi c com- petitiveness in the rapidly developing fi eld of regulatory Aim genomics, and will allow EU scientists to be in a very good starting position to decipher the genetic code controlling The objective is to develop novel genomics tools and methods regulation of gene expression. for the determination of transcription factor binding spe- cifi city. These tools will be used for the identifi cation of regulatory SNPs that predispose to colorectal cancer, and (1) Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E, Taipale J, for characterisation of downstream target genes that are Genomewide Prediction of Mammalian Enhancers Based on Analysis of Transcription- common to multiple oncogenic TFs. Factor Binding Affi nity. Cell. 124:47-59, 2006.

68 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHG-CT-2004-512142

EC contribution € 2 200 000

Duration 48 months

Starting date 01/09/2004

Instrument STREP

Project website research.med.helsinki.fi / regulatorygenomics/

A high-throughput assay of transcription factor binding specifi city developed within the Regulatory genomics project (Hallikas et al., Cell 124:47-59, 2006).

Coordinator

Jussi Taipale Torben Ørntoft University of Helsinki Aarhus University Hospital Molecular/Cancer Biology Programme Dept. of Clinical Biochemistry Helsinki, Finland Aarhus N, Denmark [email protected] [email protected]

Jan Lubinski Partners Pomeranian Medical University Szczecin, Poland Jörg Hoheisel [email protected] Deutsches Krebsforschungszentrum Admin. contact: [email protected] Functional Genome Analysis Heidelberg, Germany [email protected]

Markus Beier Febit biotech gmbh Heidelberg, Germany [email protected]

BIOLOGY 69 Keywords | Cancer | ageing | cellular senescence | cell death | DNA damage | telomerase | immunosurveillance |

SENECA prevention and therapy. Presently the research fi elds of biological ageing and cancer in Europe remain largely From Cellular Senescence and Cell Death fragmented, without structured links or widespread inter- to Cancer and Ageing disciplinary approaches. Aim

Summary The main goal of the project is to improve the awareness of ageing research among cancer researchers, stimulating The main objective of the SENECA project is to improve the cooperative research between the two disciplines. The awareness of ageing research among cancer researchers, enhanced cooperation should aim at redefi ning molecular stimulating cooperation between the two disciplines. To targets and improving cancer prevention and therapeutics achieve this objective a conference will be organized to in the ageing population. This goal will be achieved by provide a forum for scientifi c exchange among leading sci- organizing an international conference for approximately entists working in the fi elds of ageing and cancer, as well as 300 participants October 4-6, 2007. to stimulate cooperation aimed at redefi ning molecular tar- gets and improving cancer prevention and therapeutics in the ageing population. The discussion will focus on such Expected results issues as DNA damage, telomeres and telomerase in cancer and ageing, eff ects of tissue environment in tumour forma- The conference will provide a forum for scientifi c exchange tion, impact of the ageing immune system on cancer among outstanding European scientists working in the fi elds immunosurveillance and immunotherapy, links between of ageing and cancer. The discussion will focus around such stem cells and cancer and ageing, links between tumour issues as: DNA damage, telomeres and telomerase in cancer suppression and cellular senescence, and cellular senes- and ageing, eff ects of tissue environment in tumour forma- cence as a new target in anticancer therapy. Attendance of tion, impact of the ageing immune system on cancer approx. 300 scientists and representatives of other key immunosurveillance and immunotherapy, links between stakeholder groups from around the world is anticipated. stem cells and cancer and ageing, links between tumour suppression and cellular senescence, and cellular senes- cence as a new target in anticancer therapy. The conference Problem will also bring together other key stakeholder groups such as policy makers, clinicians and industry. Age is the most important demographic risk factor for many life-threatening human cancers. Over two-thirds of all diag- The proposed event will contribute to attracting scientists nosed cancers occur in people over the age of 65. According from cancer research and other disciplines to ageing to IARC, worldwide cancer rates increase sharply with age: research. It will help to establish sustainable organizational for the age group 65 years and older incidents of cancer are links between these two closely related scientifi c fi elds, 2-3 times higher than in the 45-64 age group and 12-36 times structuring European research in oncogerontology. higher than in the 25-44 age group. The increased incidence of cancer in elderly people has been related to age-associat- ed changes occurring with time in the whole system. The Potential applications elderly are more vulnerable than younger individuals to envi- ronmental carcinogens not only because of potentially The planned conference is expected to: greater exposure time, but for other reasons, including • stimulate cancer specialists to use the insights, results impaired macromolecular repair and defense against reac- and methodologies stemming from ageing research in tive oxygen species, age-dependent changes in tissue studying aetiology, prevention and therapy of cancer, environment facilitating increased pro-infl ammatory status, especially in the elderly; possibly diminished immuno-surveillance of malignant trans- • design strategies as to how basic research results in can- formation and pro-cancerogenic activity of senescent cells. cer and ageing can be best transferred into industrial exploitation and clinical practice. This may be an impor- Since tumours include cancer cells with an extensive prolif- tant starting point for the development of new preventive erative history, subject to senescence and senescence- and therapeutic measures. It may give a whole new avoidance mechanisms, cancer researchers commonly study dimension to geriatric medicine, as it will shift the various aspects of biological ageing. However, many cancer emphasis from care – which is extremely expensive – to specialists, clinicians, and industry representatives remain maintenance of function and prevention of disease as unaware of what ageing research can offer for cancer long as possible.

70 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Partners Project number LSSM-CT-2006-037312 Ewa Sikora Graham Pawelec Nencki Institute of Experimental Biology University of Tübingen, Germany (TU) EC contribution Polish Academy of Sciences (NENCKI) € 142 800 Warsaw, Poland Vladimir Anisimov [email protected] N.N. Petrov Research Institute Duration of Oncology (PRIO) 24 months St. Petersburg, Russian Federation Starting date 01/10/2006

Instrument SSA

BIOLOGY 71 Keywords | RNA silencing | microRNA | RNA interference | short interfering RNA | developmental biology | molecular biology | gene expression |

SIROCCO correct Argonaute protein is necessary for cleavage of the target messenger RNA. siRNAs and miRNAs have Silencing RNAs: organisers been found in a variety of organisms including plants, fruit fl ies, zebrafi sh, mice, and humans. sRNAs are also and coordinators of complexity a useful tool in the laboratory, where they can be used to in eukaryotic organisms silence gene expression (RNA interference). Aim

The overall objectives of the SIROCCO project are: Summary • create catalogues of sRNAs from healthy and diseased cells. Novel sRNAs will be identifi ed through using a combi- RNA silencing is the natural ability of a cell to turn off genes. nation of bioinformatics and high throughput sequencing; Only a few years ago it was unknown, but now RNA silencing • determine the tissue- and cell-type pattern of miRNA is one of the most powerful tools available to researchers. expression using microarray, RNA blot and in situ hybridisa- Recent discoveries have revealed a previously unknown role tion methods; for RNA (ribonucleic acid). They have shown how, in addition • fully refi ne methods for sRNA detection. These detection to the previously understood role as a cellular messenger methods will be enhanced using locked nucleic acid- that directs protein synthesis, RNA can also silence expres- containing and other oligonucleotide probes, and by sion of genes. By introducing specifi c silencing RNAs into an modifi ed PCR methods; organism, the expression of genes can be turned down in • characterise proteins and subcellular compartments required a controlled way. The phenomenon of RNA silencing is for sRNA processing and activity. At present, there is a foun- thought to have evolved as a defence mechanism against dation of knowledge about miRNAs, but very little is known viruses. In primitive cells it was a type of immune system that about siRNAs. Genetic, biochemical and imaging approaches could recognize and then silence viral genes. Later in evolu- will be used to fully characterise the molecular machines tion the silencing mechanism was recruited for switching off responsible for both miRNA and siRNA biogenesis; genes involved in normal growth of cells and responses to • dissect sRNA regulatory networks. It is known that miRNAs stress. Small regulatory RNAs (sRNAs) are the mediators of may aff ect particular target mRNAs but how their activity RNA silencing and are important integrators of genetic, epi- fi ts into more complex regulatory networks is poorly under- genetic and other regulatory systems. They are the focus of stood. Developing this understanding is one of the major the SIROCCO programme. sRNAs have been referred to as objectives of the SIROCCO programme; the dark matter of genetics: a recently discovered mass of • identify rules for sRNA effi ciency and specifi city. The RNA- molecules that crucially aff ect the behaviour of the genetic silencing effi ciency of sRNAs will be determined by assay universe through interactions at the RNA level. of sRNAs, their precursors or their DNA in transgenic organ- isms, in cell cultures or in vitro; • explore delivery methods for sRNAs or sRNA precursors. Problem Effi cient use of sRNAs as pharmaceuticals will depend on The exploitation of sRNAs off ers many opportunities for the development of methods for their effi cient delivery into improving the diagnosis and therapy of human disease and cells and animals. Current technology uses modifi ed viruses for advances in biotechnology. sRNAs fall into two major to introduce siRNAs into cells to reduce expression of a tar- classes: get gene. In the later stages of the project, the SIROCCO • short interfering RNAs (siRNAs) which are 21-24 nucle- consortium will initiate research into the suppression of otide RNAs derived from long double-stranded RNA; genes implicated in various diseases. • microRNAs (miRNAs) which are derived from transcripts containing partially double-stranded stem-loop ‘hairpin’ The mechanism of RNA silencing must be thoroughly under- structures about 70 nucleotides long. Both are cleaved stood in order to use RNA as a drug without side eff ects. It is from their precursor RNA by double stranded RNA-spe- also necessary to understand more about the role of silencing cifi c endonucleases. One strand of the resulting small RNA RNAs in normal growth and development. That information is loaded into RNA-induced silencing complex (RISC) that will then allow us to use the presence of silencing RNAs to also contains Argonaute (AGO) proteins. Binding to the diagnose disease states in a cell.

72 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Somite-specifi c expression of miR-206. Mouse embryo (E10.5) was hybridized to an LNA oligonucleotides complementary to miR-206. The blue staining indicates the very specifi c accumulation of miR-206 in the somites. (Wheeler G, Valoczi A, Havelda Z, Dalmay T. In situ detection of animal and plant microRNAs. DNA Cell Biol. 2007 Apr; 26(4):251-5.)

Expected results Potential Application

The SIROCCO consortium will investigate the stages in RNA silencing technology has enormous potential for use as growth, development and disease that are infl uenced by a therapeutic agent in the treatment of infectious diseases sRNAs. The project can be considered to have three over- and for any condition involving the mis-regulation of gene lapping phases. The fi rst is descriptive and will continue expression. It is known that diff erent microRNAs can func- throughout the programme. This phase aims to describe the tion as tumour suppressors or oncogenes and that their full complement of sRNAs in a range of organisms and cell expression levels have diagnostic and prognostic signifi - types and correspondingly to develop a complete under- cance. The role of small RNAs in complex neuropathological standing of the proteins that act as enzymes, co-factors and disorders such as schizophrenia and in neurodegenerative structural components of the sRNA machinery. conditions such as Alzheimer’s Disease is being investigated by members of the SIROCCO consortium. Diagnostic or The second phase involves testing the function of sRNAs therapeutic advances in these areas would have powerful and sRNA-related proteins in the basic sRNA mechanisms, public health implications. and eventually establishing their role in regulatory networks through experimental intervention. Genetic and molecular The SIROCCO consortium aims to understand and exploit methods will be used to manipulate the expression of these the diversity of sRNA mechanisms. The elucidation of the components, while biological assays and molecular profi ling genomics of sRNA and of sRNA-based regulation will lead of RNA will be used to assess the role of the targeting to novel and fundamental insights into the composite genetic components. networks that underlie normal and diseased growth and development. Achieving these aims will reinforce European In the third, predictive phase of the programme, the aim will competitiveness in fundamental research and innovation be to develop rules to describe the behaviour of sRNA sys- and will solve important societal problems relating to public tems as isolated regulatory modules and as part of complex health by improving diagnosis and treatment of diseases. regulatory networks. Component activities in this phase will involve the computation of rules and their validation by experimentation. It will be possible from this phase to design sRNA mimics of natural sRNAs, and to predict their eff ects in cells and organisms. It will also be possible to predict the behaviour of cells or organisms in which the sRNA machinery is regulated by developmental or external stimuli.

BIOLOGY 73 Coordinator Project number LSHG-CT-2006-037900 David Baulcombe Detlef Weigel Prof Giuseppe Macino University of Cambridge Max Planck Institute for University of Rome ‘La Sapienza’ EC contribution Cambridge, United Kingdom Developmental Biology Rome, Italy € 11 781 445 [email protected] Tübingen, Germany [email protected] [email protected] Duration Roberto Di Lauro 48 months Partners Gunter Meister BIOGEM Biotecnologie Avanzate s.c.a r.l. Max Planck Institute for Biochemistry Naples, Italy Starting date Eric Miska Martinsried, Germany [email protected] 01/01/2007 University of Cambridge [email protected] Cambridge, United Kingdom Jørgen Kjems Instrument [email protected] Thomas Meyer University of Aarhus IP Max Planck Institute for Infection Biology Aarhus, Denmark József Burgyán Berlin, Germany [email protected] Project website Agricultural Biotechnology Centre [email protected] www.sirocco-project.eu/ Godollo, Hungary Xavier Estivill [email protected] Elisa Izaurralde Center for Genomic Regulation Max Planck Institute for Barcelona, Spain Annick Harel-Bellan Developmental Biology [email protected] Centre National de la Recherche Tübingen, Germany Scientifique [email protected] Caroline Dean Villejuif, France John Innes Centre [email protected] Gyorgy Hutvagner Norwich, United Kingdom The University of Dundee [email protected] Olivier Voinnet Dundee, United Kingdom Centre National de la Recherche [email protected] Michael Wassenegger Scientifique AlPlanta-Institute for Plant Research Strasbourg, France Simon Arthur Neustadt, Germany [email protected] The University of Dundee [email protected] Dundee, United Kingdom Witold Filipowicz [email protected] Peter Mouritzen Friedrich Miescher Institute Exiqon A/S for Biomedical Research Tamas Dalmay Vedbaek, Denmark Basel, Switzerland University of East Anglia [email protected] [email protected] Norwich, United Kingdom [email protected] Stephen Cohen René Ketting Temasek Life Sciences Laboratory Hubrecht Laboratory Irene Bozzoni Singapore Utrecht, The Netherlands University of Rome ‘La Sapienza’ [email protected] [email protected] Rome, Italy [email protected]

74 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Epigenetics | gene regulation | histone modifi cation | small molecule inhibitors | cancer therapy |

SMARTER its epigenetic control systems and its dynamic structure in Development of small modulators relation to gene expression must be integrated. of gene activation and repression Aim by targeting epigenetic regulators The SMARTER project aims at the development and improvement of compounds targeting epigenetic regula- tors. These compounds will be tested in various assays making it possible to collect data sets of several parameters Summary as histone modifi cations, chromatin states, gene expression patterns and physiological characteristics in an integrative The identity of a given cell within a metazoan organism is manner for the fi rst time. primarily defi ned by the expression pattern of its genes. The activation and repression of particular genes is tightly regu- Therefore major objectives are: lated by the concerted action of transcription factors that • identifi cation of small molecule inhibitors that target recognize and bind specifi c DNA sequences within regula- various histone-modifying enzymes; tory regions. Work done over the last 20 years revealed this • validation of these inhibitors through in vivo analytics of basic mechanism of gene activation and repression, while histone modifi cations states; recent experiments exposed an additional layer of regula- • establishment of histone modifi cation states as standard tion involving modifi cations of DNA and bound histones. readouts for drugs that target epigenetic modifi ers; These modifi cations are involved in cellular inheritance of • improvement of known epigenetic modulators through transcriptional states through cell division and development medicinal chemistry; and as they are not coupled to DNA sequence are referred • identifi cation of target genes that are regulated by the to as epigenetic. Many factors that impact on epigenetic SMARTER molecules; phenomena are clearly distinct from basic transcription fac- • application of the SMARTER molecules in standard tors and are involved in regulating chromatin structure. animal model systems to verify their activity in living Modulation of chromatin structure is frequently achieved by organisms. intrinsic enzymatic activities that either mark particular regions within the genome for activity or repression or use the hydrolysis of ATP to remodel nucleosomal arrays. This Expected results variation of gene expression patterns in response to external and internal signals has a major infl uence on stem cell dif- Our proposal will thereby promote the development and ferentiation, the maintenance of tissue integrity and the improvement of a new branch of cancer drugs and as well adaptation of organisms to environmental dynamics. support validation of new potential drug target enzymes. Recently, small molecule inhibitors that target chromatin- Additionally, tools will be generated which allow new insights modifying enzymes have been used for cancer treatment, in fundamental mechanisms of gene regulation by epigenetic which has opened new avenues in therapeutical research. modifi cation. The SMARTER project aims at the development and im provement of such compounds, which is the primary mission of Chroma, the SME participating in the consortium. Potential applications

In the context of human health, an understanding of gene Problem regulation is central to our understanding of many medical complaints and conditions. Fundamental aspects of chro- The epigenetic level of gene regulation is being analysed matin function are increasingly recognized as important intensively worldwide. However, the knowledge gained factor in the development of many severe and often untreat- from these studies has not been transferred to drugs or able diseases. Therefore many proteins that are involved in drug candidates for the treatment of major diseases. the regulation of chromatin structure are potential drug tar- Equally, development of small molecules targeting epige- gets and small molecules directed against these factors will netic regulators have so far not been the major focus of play an increasingly important role in treating patients that drug discovery eff orts. are aff ected by one of these maladies.

To pursue this promising approach it is obviously important The cooperation between leading European chromatin labs to further improve understanding how the eukaryotic and Chroma is expected to greatly strengthen the SMEs genome in general, and the human genome in particular, knowledge base and thereby having a strong impact on its operates. Therefore knowledge about its DNA sequence, ability to enter drug candidates in clinical trials.

BIOLOGY 75 Project number LSHG-CT-2006-037415

EC contribution € 2 500 000

Duration 48 months

Starting date 01/12/2006

Instrument STREP

Project website www.smarter- chromatin.eu

Coordinator Partners

Axel Imhof Scott Cuthill Adolf-Butenandt-Institut Chroma Therapeutics LMU Oxford, United Kingdom Munich, Germany [email protected] Dirk Schuebeler Friedrich-Miescher-Institut Basel, Switzerland Project Management Manel Esteller Julia Hochstatter CNIO Adolf-Butenandt-Institut Madrid, Spain LMU Munich, Germany Tony Kouzarides [email protected] Gurdon Institute Cambridge, United Kingdom

76 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Hereditary | tricarboxylic acid cycle | fumarase | succinate dehydrogenase | renal | paraganglioma | leiomyoma |

TCAC in Cancer Aim

Defects in the Tricarboxylic The two key tasks to achieve this project’s objective are: • characterising the natural history and prevalence of Acid (Krebs) Cycle TCAC-defi cient cancers; • unravelling the molecular mechanisms driving TCAC- associated tumourigenesis. Summary Expected results For this project, top European cancer research groups working on the association between defects in the tricar- The impact of the proposed research is two-fold. First, it pro- boxylic acid cycle (TCAC) and cancer form a consortium vides a basis for cancer detection, prevention and treatment to profoundly characterise the human phenotypes to ena- in high-risk individuals with TCAC defects. The discoveries by ble identifi cation and effi cient cancer prevention, and to us and others linking TCAC defects to a high risk of tumours unravel the underlying molecular mechanisms. Recent are so recent that even the very basic data on the natural his- breakthrough fi ndings by the consortium participants and tory of the respective syndromes is missing and, without this others have shown that defects in at least four TCAC genes knowledge, evidence-based measures to fi ght this novel – fumarate hydratase (FH, fumarase), and succinate dehy- tumour type cannot be developed. Second, the proposed drogenase (SDH) B, C, and D – can confer susceptibility research will create data on the frequency of TCAC-defi cient to cancer. We shall take these studies forward by charac- hereditary and sporadic cancers, and will characterise the terising the natural history of the syndromes in large molecular mechanisms underlying their genesis. This will be European materials. a major advancement for cancer research in general.

Simultaneously, we shall perform functional studies to elu- cidate the cellular events induced by these defects by Potential applications systematic biology approaches including functional studies in cell lines, model organisms, and transcription profi ling of This project will create data for management of TCAC- TCAC defi cient and profi cient tumours and models. defi cient tumours.

TCAC defect-associated expression patterns will be utilised Diagnosis to examine other cancer types for such defects. We have • Improved molecular diagnosis of hereditary susceptibility. evidence that modifying genes play a key role in TCAC • Classifi cation of tumours. defect-associated tumourigenesis and candidate regions Also, it will create an expression profi le-based classifi er for have been identifi ed. Following gene identifi cation, the TCAC defi cient cancers. possible role of these modifi ers in low penetrance cancer predisposition in the general population will be examined. Management The rationale to form this consortium is simple and strong. • Hereditary susceptibility: it goes without saying that an The consortium brings together the key European cancer exact diagnosis of the syndromes involved is a very sig- researchers studying TCAC-associated tumourigenesis. nifi cant factor in improving the management of the Studying the tumourigenic eff ects of FH and the diff erent patient, and the relatives. Appropriate follow-up strate- units of SDH separately would be ineff ective, and formation gies and much more accurate genetic counselling on of the consortium will ensure that Europe will maintain the cancer risk will become available. initiative in this new and exciting fi eld of research. The deliv- • TCAC-defi cient tumours: whether hereditary or sporadic, erables arising from the work packages will contribute to TCAC-defi cient tumours are likely to display special the common goals; prevention of TCAC-associated cancers biological properties which are relevant for clinical man- and learning the lessons these lesions can teach to cancer agement, including response to drug treatment. We research. anticipate that the more detailed molecular classifi ca- tion of tumours provided by eff orts of this proposal will considerably improve the standard care of such lesions.

BIOLOGY 77 Project number LSHC-CT-2005-518200

EC contribution € 2 751 000

Duration 48 months

Starting date 01/01/2006

Instrument STREP

Immunofl uorescence staining of FH in HeLa cells shows strong mitochondrial (and weak cytoplasmic) protein expression.

Coordinator

Lauri A. Aaltonen Ian Tomlinson University of Helsinki Molecular and Population Dept. of Medical Genetics Genetics Laboratory Biomedicum Helsinki London Research Institute Helsinki, Finland Cancer Research UK [email protected] London, United Kingdom

Andrzej Januszewicz Partners National Institute of Cardiology Warsaw, Poland Peter Devilee Leiden University Richard Houlston Medical Center Institute of Cancer Research Human Genetics, Pathology University of London Leiden, The Netherlands London, United Kingdom

Hartmut P.H. Neumann Medizinische Universitätsklinik Freiburg Freiburg, Germany

78 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | HSV-1 | hepatocellular carcinomas | oncolytic vectors | targeting |

THOVLEN Problem Data from epidemiological studies indicate that HCC accounts Targeted Herpesvirus-derived for 80% of all primary liver cancers and is one of most preva- lent malignant diseases worldwide. It is the fi fth most common Oncolytic Vectors for Liver Cancer cancer, with an estimated average of about 0.45 million new cases diagnosed each year, and it ranks fourth in mortality European Network rate. Furthermore, the incidence of HCC has increased notice- ably over the past two decades and has become progressively associated with younger age groups. Despite development of novel therapeutic methods in recent years, prognosis of Summary advanced HCC remains very poor, with a life expectancy of about six months from time of diagnosis and a less than 3% The overall objective of THOVLEN is to develop safe and survival rate for untreated cancer over fi ve years. This disease effi cient herpes simplex virus type 1 (HSV-1)-derived onco- therefore represents a major challenge for public health in lytic vectors, designed to strictly target and eradicate human Europe and in the world. It decreases human longevity, hepatocellular carcinomas (HCC), the most common liver impairs citizens’ quality of life and represents an immense cancer of adults. HSV-1 is certainly one of the most promising burden to Europe’s healthcare services. New therapeutic viral platforms for the development of improved oncolytic strategies are clearly needed to improve this situation. The vectors, as anticipated by the unique biological properties of possibility of developing an anti-cancer therapy whose activity this virus and confi rmed by the encouraging results coming increases with time, while retaining tumour specifi city and from clinical trials in gliomas. However, the fi rst generations expressing multiple anti-tumour activities is a new and still of oncolytic HSV-1 vectors have also shown limitations uncharted area of cancer therapy and, in this context, the regarding effi cacy and safety. New generations of innovative administration of HSV-1 oncolytic vectors shows a considera- HSV-1 vectors with improved potency and safety are required ble promise. Therefore, by developing our project, THOVLEN before the oncolytic strategy using HSV-1 becomes a stand- will ultimately serve to accelerate the development of new, ard therapeutic reality against cancer, and this is the goal of safer and more eff ective treatments. THOVLEN. One of the most important innovative contribu- tions of our project concerns the overall approach towards the improvement of HSV-1-based oncolytic viruses. Instead Aim of focusing on the development of vectors carrying dele- tions in particular virus genes, we will engineer competent, The central goal of THOVLEN is to design HCC-targeted virus but replication-restricted, HSV-1 vectors, strictly targeted to vectors that will simultaneously display multiple targeting HCC. These vectors will combine multiple HCC-targeting elements acting at diff erent steps of the virus life cycle, in approaches, both at the level of entry and at the level of order to ensure maximum aggressiveness for HCC cells with gene expression and replication, and will be able to multiply minimum or no virulence for healthy tissues. In addition, the and spread only in HCC, while displaying no virulence in nor- unique advantage of the HSV genome to carry about 40 kbs mal healthy tissues. Additionally an important innovation is of foreign DNA will be exploited in the context of designing related to the ability of the HSV-1 vectors to permit a sophis- a multimodal approach for cancer therapy, required for ticated and fl exible combined approach against HCC. That is, improvement of the inherent anti-tumour activity of the virus. in addition to optimising the oncolytic properties of HSV-1 The availability and the expertise in using several well-defi ned vectors, THOVLEN will exploit the very large transgenic capa- animal models for liver cancer will allow us to evaluate safety bility of HSV-1 to generate vectors that will simultaneously and effi cacy of our vectors in relevant systems. Through fun- display multiple and multimodal anti-tumour activities acting damental research, we will generate novel genomic and either locally or systemically, including combined expression of proteomic information on the interactions between the onco- anti-angiogenic, immune-modulatory and oncolytic proteins. lytic vectors and the normal and cancer cells, which will guide the rational design of vectors targeted to HCC cells, therefore resulting in the improvement of the vector oncolytic potency, and the improvement of safety.

BIOLOGY 79 Expected results Project number We will investigate diff erent ways of producing HSV-1 vec- LSHB-CT-2005-018649 tors conceived to penetrate specifi cally, express genes and replicate into HCC, therefore killing these cells and allowing EC contribution the spread of the virus to infect other tumour cells. In addi- € 2 494 460 tion to their inherent targeted oncolytic potential, these vectors will express enhancing transgenic sequences, encod- Duration ing immune-modulators, anti-angiogenic molecules, fusion 36 months proteins, or toxic proteins, which are expected to have an additive negative action on tumour growth. Our expectation Starting date is to produce, by the end of the project, a number of such 01/01/2006 vectors, combining targeting and enhancing functions, which will be fully evaluated for effi cacy and toxicity on dif- Instrument ferent HCC animal models, including standard and transgenic STREP mice, and woodchucks. Project website www.tholven.eu Potential applications

Treatment of primary liver cancers (hepatocellular carcinomas).

Coordinator

Alberto L. Epstein Penelope Mavromara Centre de Génétique Moléculaire Hellenic Pasteur Institute et Cellulaire Athens, Greece CGMC – UMR 5534 – CNRS [email protected] Université Claude Bernard Lyon 1 Villeurbanne, France Ruben Hernandez Alcoceba [email protected] Fernando Corrales Fundacion para la investigacion medica aplicada Partners Pamplona, Spain [email protected] Thomas Brocker [email protected] Ludwig-Maximilians-Universität München Institute for Immunology Andres Crespo Munich, Germany Genopoietic [email protected] Miribel, France [email protected] Roberto Manservigi Università degli Studi di Ferrara Jean-Jacques Diaz Dipartimento di Medicina Sperimentale Centre de Génétique Moléculaire e Diagnostica et Cellulaire Sezione di Microbiologia Université Claude Bernard Lyon 1 Ferrara, Italy Villeurbanne, France [email protected] [email protected]

80 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Apoptosis | autophagy | necrosis | programmed | cell death |

TransDeath Project number Programmed Cell Death across LSHG-CT-2004-511983 EC contribution the Eukaryotic Kingdom € 2 500 000

Duration 36 months Summary Starting date The project aims to broaden the experimental net to catch 01/12/2005 regulators of programmed cell death (PCD) by comparative research on diverse organisms that each may be uniquely Instrument suited to unravel a type of conserved PCD process. The major STREP approach will be across the eukaryotic kingdom and the main objective will be to understand these types of cell death Project website in humans. TransDeath thereby aims to produce knowledge www.transdeath.org on genes and biochemical processes that regulate PCD in diff erent organisms, and to apply that knowledge to develop strategies and targets for human disease therapy. Potential applications

Test genes and biochemicals on PCD related to normal human Problem function and disease.

Programmed cell death (PCD) is normally invoked during development and immunity, but inappropriate PCD is asso- ciated with pathologies, including cancer and degenerative Coordinator diseases. Conserved genes controlling apoptosis, a type of PCD dependent upon caspase proteinases, were fi rst identi- John Mundy Nektarios Tavernarakis fi ed in the model organism C. elegans. This work received University of Copenhagen Foundation for Research and Technology a Nobel Prize in 2003, and biomedical research has established Copenhagen, Denmark Heraklion, Greece related mammalian PCD pathways. However, phylogenetically [email protected] [email protected] conserved PCD types other than apoptosis exist in animal and non-animal cells. This TransDeath project will focus on Adi Kimchi cellular and molecular events in these less well-known cell Partners Weizmann Institute of Science death types. Rehovot, Israel Kai-Uwe Fröhlich [email protected] University of Graz, Aim Graz, Austria Roberto Testi [email protected] University of Rome ‘Tor Vergata’ The specifi c TransDeath objectives include: Rome, Italy • characterising the diversity of genes and biochemicals Corinne Clavé [email protected] controlling PCD of diverse types; CNRS – UMR 5095 • functionally comparing these genes and biochemicals Bordeaux, France Jonathan Jones between organisms; [email protected] The Sainsbury Laboratory • deriving genetic and functional models of PCD evolution. Norwich, United Kingdom Pierre Goldstein dimitrios.tsitsigiannis@sainsbury- CNRS – CIML laboratory.ac.uk Expected results Marseille, France [email protected] Angelika Bonin-Debs The results of this project should be of value to the European Xantos Biomedicine AG and international scientifi c communities. Our eff orts will Guido Kroemer Munich, Germany strengthen European research in the strategic area of func- CNRS – UMR 8125 [email protected] tional genomics and yield information on gene function in Villejuif, France PCD immediately relevant to pharmaceutical R&D. [email protected]

BIOLOGY 81 Keywords | Metastase | xenografts | tyrosine kinases | biomarkers | tumour profi ling | siRNA | animal models | drug design |

TRKCancer Project number The anoikis suppressor TrkB as a target LSHC-CT-2006-037758 EC contribution for novel anti-cancer agents € 2 368 715

Duration 36 months Summary Starting date The failure of anti-cancer therapies generally results from 01/01/2007 locally intractable invasive growth or from the presence of metastases refractory to treatment with curative intent. Instrument A novel therapeutic strategy is to develop new anti-cancer STREP drugs specifi cally targeting the invasive or metastatic phe- notype of tumour cells. Expected results We propose to validate at the pre-clinical level a strategy that targets the critical mechanism allowing apoptosis eva- • Novel animal models. sion and survival of invasive or metastatic tumour cells. • Novel TrkB inhibitors as potential anti-cancer drugs. Anoikis is a process by which a cell detached from its resi- • Novel biomarkers of metastasis. dent tissue undergoes apoptosis as a result of loss of normal cell-matrix interactions. Loss of anoikis allows survival of cancer cells in abnormal micro-environments, such as tissue Potential applications compartments invaded by the primary tumour, and the intravascular compartment, during the metastatic process. • Novel anti-cancer agents. The BDNF receptor TrkB is a potent suppressor of anoikis • New diagnostic tools and indices of therapeutic effi cacy. and is responsible for apoptosis evasion that occurs in aggressive human tumours overexpressing TrkB.

The aim of the present proposal is to validate TrkB as a tar- get for new anti-cancer drugs, aiming to restore anoikis and thereby destroy the invasive and metastatic cancer cells.

Problem

• Metastasis is a cause of cancer relapse. • TrkB, as an anoikis suppressor, may favour metastasis, Coordinator Partners but the relevance of this target has not been assessed in relevant cancer models. Pierre Sokoloff Daniel Peeper • There are no TrkB inhibitors ready for clinical trials. Institut De Recherche Pierre Fabre Nederlands Kanker Instituut • Biomarkers of metastasis are lacking. Castres Cedex, France Amsterdam, The Netherlands [email protected] [email protected]

Aim Julia Schueler Institute for Experimental • To validate TrkB as a target for anti-metastasis agents by Oncology (Oncotest) using human tissue-derived animal models. Freiburg, Germany • To identify novel TrkB inhibitors. [email protected] • To explore mechanisms of action of TrkB inhibitors and to identify biomarkers of metastasis. Wolter Mooï Vrije Universiteit Medical Center Amsterdam, The Netherlands [email protected]

82 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Tumour | host | signalling | stem cell | angiogenesis | lentivirus |

Tumour-Host Genomics Problem

Genome-wide Analysis of Signalling Tumour cell growth depends on interactions with its micro- environment. The development of cancer therapies targeting Pathways in Regulation of the these interactions is hampered by the fact that the molecular mechanisms behind tumourhost interactions are often poorly Interactions between Tumour and Host understood. Cells: Applications of Cancer Therapy Aim

• To identify endothelial/BM cell-specifi c cis-regulatory Summary elements for use in lentiviral in vivo targeting vectors. • To develop a targeted lentiviral library for the inhibition of selected major cell signalling pathways. In addition to oncogenic mutations that act cellautono- • To identify tumour-derived factors that lead to increased mously, tumour cell growth depends on interactions with its angiogenesis and recruitment of stromal cells contributing microenvironment. The tumour microenvironment consists to a microenvironment permissible for tumour growth. of cells of haematopoietic and mesenchymal origin, includ- • To identify host-derived factors that induce tumour cell ing infl ammatory cells, stem and progenitor cells, fi broblasts, growth and tumour stem cell self-renewal. endothelial cells and vascular mural cells. Tumour cell • To te st in vivo the eff ect of targeted lentiviruses in inhibi- growth is known to depend on the interaction of tumour tion of tumour growth and metastasis. cells with such stromal cells. For example, a growing tumour needs to recruit normal endothelial and vascular mural cells to form its blood vessels. In addition, tumour cells induce Expected results stromal cells to secrete factors that contribute to tumour cell growth and invasion. Stromal cell-dependent interac- The project aims to develop novel tools and methods to tions represent an attractive target for cancer therapy, study tumourhos interactions in cancer, and to apply these because normal cells are genetically stable, and would not techniques to the identifi cation of molecules and processes be expected to develop resistance to therapeutic agents. in normal cells, which could be targeted by novel anti- The development of such therapies is hampered by the fact cancer therapeutic agents. In addition, we also propose to that the molecular mechanisms behind tumour-stroma develop targeted lentiviruses that specifi cally express genes interactions are often poorly understood. in bone marrow-derived cells and/or in endothelial cells, which would allow in vivo delivery of therapeutic agents into In summary, the work plan entails development of novel tumours. advanced functional genomic instruments, technologies and methods to study tumour-host interactions in cancer, and to apply these techniques to the identifi cation of mole- Potential applications cules and processes in normal cells, which could be targeted by novel anti-cancer therapeutic agents. In addition, we will Potential target genes for the treatment of cancer will allow develop targeted lentiviruses which would allow in vivo the search, and preclinical and clinical validation of respective delivery of therapeutic agents into tumours. Functional val- lead compounds. idation of the discovered targets and developed delivery systems will be performed in in vivo models of murine Tumour-host interactions are universally essential for the tumour growth and dissemination. For purely technical rea- growth and dissemination of any malignant disease, and sons, melanoma and prostate cancer models are planned to the results of this project could in principle ultimately be be utilised fi rst. However, tumour-host interactions are applicable for any kind of human cancer. universally.

Essential for the growth and dissemination of any malignant disease, and the results of the experiments will be applica- ble for any kind of human cancer. The work has signifi cant exploitation potential and relevance for health in the under- standing of the molecular mechanisms of tumourhost interactions, and in the treatment of cancer.

BIOLOGY 83 WP5: Angionic factors, Factors recruiting stromal Project number and BM derived cells LSHC-CT-2005-518198

EC contribution Lentiviral targering (WP7,8) € 2 700 000

Selected (WP2) Duration and RNAi screen identifi ed (WP3,6) Tumor Host 36 months signaling pathway inhibitors Starting date Validited host-cell specifi c Selected (WP2) and RNAi screen 01/11/2005 regulatory elements (WP4) identifi ed (WP3) signalising pathway inhibitors Instrument

WP6: Tumor growth factors STREP

Summary of the science and technology objectives of the project, and the work package structure. Project website The project aims to develop novel tools and methods to study tumour-host interactions in cancer, research.med.helsinki. and to apply these techniques to the identifi cation of molecules and processes in normal cells, which fi /tumorhostgenomics/ could be targeted by novel anti-cancer therapeutic agents. In addition, we will also develop targeted default.htm lentiviruses that specifi cally express genes in bone marrow-derived cells and/or in endothelial cells, which would allow in vivo delivery of therapeutic agents into tumours. Abbreviations: BM, bone marrow; RNAi, RNA interference; WP, work package.

Coordinator

Petri Salven University of Helsinki Helsinki, Finland [email protected]

Partners

Peter ten Dijke Leiden University Medical Center Leiden, The Netherlands

Luigi Naldini San Raffaele Telethon Institute for Gene Therapy Milan, Italy

Kari Alitalo Jussi Taipale University of Helsinki Helsinki, Finland

84 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Aetiology

The uncontrolled cell growth characterising cancer can be initiated by the interaction of human cells with specifi c agents, on the basis of an individual genetic predisposition. Despite great advances in the understanding of these interactions, our ability to treat tumours remains very low: this is a clear sign that much remains to be learnt. Human carcinogenesis related knowledge has shown a dramatic increase in its width and complexity over the last few years. In fact, the availability of enhanced and more powerful tools along with a more functional translational approach including valuable proof-of-principle feedback from the clinical per- spective have created the opportunity to look more closely into the regulatory processes of the cell growth and, once initiated, cancer behaviour (including tissue invasion and metastatic potential). Not only it is now clear that diff erent regulatory pathways are to be altered in order to create a predis- position for cancer initiation: environmental external factors (biological, chemical and physical agents) seem to have diff erent activities when they act on the cell alone or in combination. The striking evi- dence that diff erent patterns of gene-to-environment interactions can develop when a population with certain genetic characteristics move from an area of the world to another (as like as the incidence of breast cancer of Japanese people levelling the one of Northern Americans when the former move from Japan to US) add as well a further degree of complexity to the overall. A quick and reliable identifi cation of agents capable to induce carcinogenesis, along with a better under- standing of the genetic substrate on which these environmental factors express their action is ideally coupled with epidemiological and molecular pathology state of the art validated information and prelimi- nary results from clinical experiences. These processes of gathering multidisciplinary enhanced knowledge benefi t from a look forward perspective towards cancer prevention and treatment strategies. EU funded projects aimed to better understand cancer aetiology clearly shift towards a pragmatic applica- tion of the basic knowledge generated so far and do exploit the whole range of foreseen funding instruments: from the Specifi c Support Action –SSA- ‘AIDIT’ aimed at extending the clinical platform of another EU fund- ed initiative (IMPACT) to the Framework Programme Associated and Candidate Countries for the targeted screening of prostate cancer in men with genetic predisposition; to the Specifi c Targeted Research Project (STREP) ‘POLYGENE’ aimed at identifying novel key determinants underlying breast and prostate cancer and fi nally to the large Integrated Project ‘CARCINOGENOMICS’ aimed at creating a validated high-through- put genomic based test for assessing genotoxic and carcinogenic properties of chemical compounds in vitro; the Network of Excellence ‘GENOMEL’ aimed at understanding the genetic causes (susceptibility) of melanoma and the gene-to-environment interaction, predominantly with the exposition to the sun light and the ‘Integrated Project INCA’ focused on the role of biological agents capable of inducing chronic infections in the pathogenesis of infection-associated cancers.

Alfredo Cesario Keywords | Prostate cancer | BRCA1 | BRCA2 | targeted screening | associate candidate countries |

AIDIT Problem

Advancing International Prostate cancer is a common cancer in men but the cause of the disease remains a mystery. There is a potential for Co-operation and Developing improving patient management and for reducing early mortality by targeting screening for prostate cancer. Studies Infrastructure for Targeted Screening have indicated that BRCA1 and BRCA2 genes signifi cantly increase the risk of prostate cancer but further work is of Prostate Cancer in Men with needed in the area to determine the exact risks of this patient population. International collaboration has been established Genetic Predisposition in 23 countries worldwide but out of the Associate Candidate Countries only one centre in Turkey is involved.

Summary Aim

In the EU, approximately 200 000 men are diagnosed annu- To expand the IMPACT study collaboration into the Asso- ally with prostate cancer, and this fi gure is likely to increase ciate Candidate Countries through advertising the study due to the ageing population, which will cause a consid- both to the general population and to researchers using erable healthcare problem. Inherited genetic factors are media, establishing a website and holding an international important in this disease, for example the breast cancer conference. predisposition genes BRCA1 and BRCA2 have been report- ed to increase the risk of prostate cancer signifi cantly. The European IMPACT study (scheduled to begin in 2005) aims Expected results to put in place networks and infrastructures in 23 countries (18 of them in Europe) to identify a male population har- • To host an international conference to bring all collabo- bouring germ line mutations in the BRCA1 and BRCA2 rators together and meet and share knowledge. genes, and recruit them into targeted screening pro- • To identify and recruit new centres in ACCs. grammes for prostate cancer. IMPACT also aims to support • To recruit ACC members onto the IMPACT study, and future research into the targeted screening and clinical specialist and steering committees. management of prostate cancer in high-risk individuals. • To increase awareness of the BRCA1/2 link to prostate The main goal of this proposal (AIDIT) is to stimulate co- cancer and encourage genetic testing in individuals at risk. operation with Associated Candidate Countries (ACCs) in • Development of a centralised website. relation to the IMPACT study. It is intended that a Specifi c • To raise the profi le of the need for increased detection of Support Action (SSA) could provide the means to identify mutations in BRCA1 and BRCA2 in men, and for improved and recruit appropriate centres in the ACCs; stimulate the clinical management of prostate cancer in the ACCs. participation of research teams in ACCs and connect exper- • To educate the relevant stakeholders through the crea- tise in all collaborating countries in this area. Networking tion of reliable, informative, and fast communication and dissemination of the latest results from ongoing pros- hardware and software systems. tate cancer screening studies are crucial elements of this proposal, which has the long-term aim of enabling centres in the ACCs to join the IMPACT study, thus establishing Potential applications a larger consortium and research base. AIDIT is also aimed at raising the profi le of the need to improve clinical man- • Promote future research collaborations between teams agement of prostate cancer, educating the relevant in these countries and the current IMPACT consortium. stakeholders, improving quality of life, reducing early mor- • To assist in guiding future clinical management of men tality and reducing the fi nancial burden of healthcare. It will with BRCA1 and BRCA2 mutations. consider relevant gender, ethical and societal issues, sup- porting the implementation of the Sixth Framework Programme and, in particular, the Combating Cancer topic of Thematic Priority 1. AIDIT can only occur under the auspices of an EU SSA.

86 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME INDICENCE OF PROSTATE CANCER: ASR (WORLD) (ALL AGES) Project number LSSM-CT-2005-018686

EC contribution € 330 057

Duration 18 months

Starting date 01/12/2005

Instrument SSA

Project website Under construction

‹5.9 ‹14.1 ‹22.1 ‹31.0 ‹95.1 GLOBOCAN (IARC 1998)

Coordinator Partners

Rosalind Eeles Jan Lubinski Reader in Clinical Cancer Genetics International Hereditary Cancer Centre and Honorary Consultant Pomeranian Medical University in Cancer Genetics and Clinical Oncology Szczecin, Poland Cancer Genetics Unit [email protected] Institute of Cancer Research/ Royal Marsden NHS Trust Guven Luleci Sutton, United Kingdom Akdeniz University [email protected] Faculty of Medicine Departments of Medical Biology and Genetics Antalya, Turkey [email protected]

AETIOLOGY 87 Keywords | Life Sciences, Genomics and Biotechnology for Health |

CARCINOGENOMICS either genotoxic or non-genotoxic. For the important class of non-genotoxic carcinogens, no suitable test model is Development of a high throughput available at all. The available mechanistic information is relatively more clear-cut for genotoxic carcinogens, and genomics-based test for assessing genotoxicity testing of chemicals is mandated by regula- tory agencies worldwide. A four-test battery is required genotoxic and carcinogenic properties comprising bacterial mutagenesis, in vitro mammalian mutagenesis, in vitro chromosome aberration analysis and of chemical compounds in vitro in vivo chromosome stability analysis. However, for phar- maceuticals, it has been assessed that these assays in combination predict rodent carcinogenicity correctly by not more than 38% while simultaneously producing high Summary percentages of false positives; the correctness of predic- tion by the in vivo assay appears only 11,5% while the The major aim of CARCINOGENOMICS is to develop in vitro percentage of false positives is 15%. A survey of over methods for assessing the carcinogenic potential of com- 700 chemicals demonstrates that even 75–95% of non- pounds, as an alternative to current rodent bioassays for carcinogens gave positive (i.e. false positive) results in at genotoxicity and carcinogenicity. The major goal is to devel- least one test in the in vitro test battery. False positive op a battery of mechanism-based in vitro tests accounting results in in vitro/in vivo assays for genotoxicity obviously for various modes of carcinogenic action. These tests will be overrate the necessity of rodent carcinogenicity studies. designed to cover major target organs for carcinogenic But also rodent cancer bioassays provide inadequate data action e.g. the liver, the lung, and the kidney. The novel assays to estimate human cancer risk: this creates a signifi cant will be based on the application of ‘omics’ technologies problem for interpreting the results of animal experiments (i.e. genome-wide transcriptomics as well as metabonomics) with carcinogens in relation to humans. to robust in vitro systems (rat/human), thereby also explor- ing stem cell technology, to generate ‘omic’ responses from a well-defi ned set of model compounds causing genotoxicity Aim and carcinogenicity. Phenotypic markers for genotoxic and carcinogenic events will be assessed for the purpose of This project concedes to a crucial area within the LifeSci- anchoring gene expression modulations, metabolic profi les Health Priority, namely “the Development of new in vitro tests and mechanism pathways. Through extensive biostatistics, to replace animal experimentation”. With reference to the literature mining, and analysis of molecular-expression data- Three R Principle (Replace, Reduce, Refi ne) as highlighted in sets, diff erential genetic pathways will be identifi ed capable the LifeSciHealth Priority, the CARCINOGENOMICS project is of predicting mechanisms of chemical carcinogenesis in vivo. directed towards replacing chronic rodent bioassays for Furthermore, generated transcriptomic and metabonomic assessing chemical genotoxicity and carcinogenicity. data will be integrated into a holistic understanding of sys- tems biology, and applied to build an iterative in silico model For this purpose, CARCINOGENOMICS will produce inno- of chemical carcinogenesis. Subsequently, predictive genetic vative genomics-based in vitro screens for assessing pathways will be used as the scientifi c basis to develop high carcinogenic properties of chemicals, with high through- throughput technology for accelerating analysis of genomics put features which upon proper validation by ECVAM will responses in vitro, indicative for human carcinogenic risk, by bring technology applicable to REACH Combining path- a factor of 100. It is expected that the outcome of this project way-associated gene expression with metabolic profi les will generate a platform enabling the investigation of large generated in vitro, as is foreseen in the CARCINOGENOM- numbers of compounds for their genotoxic and carcino- ICS represents a highly innovative approach possibly genic potential, as envisaged under the REACH initiative. leading to in silico models that may be used to predict the This will contribute to speeding the identifi cation of poten- carcinogenic potential of a compound in vivo. tial harmful substances to man, while lowering costs and reducing animal tests. With the aim to develop in vitro methods for testing the car- cinogenic properties of compounds as an alternative to the chronic rodent bioassays for assessing chemical genotoxici- Problem ty and carcinogenicity, the CARCINOGENOMICS project will address the following S&T objectives to: The evaluation of the carcinogenic potential of a com- • develop predictive mechanistic models based on tran- pound is currently completely depending on chronic scriptome and metabonome profi ling in rat and human rodent bioassays administering chemicals at maximally primary cells from prioritized target organs, in order to tolerated doses. Chemical carcinogens are classifi ed as discriminate genotoxic from non-genotoxic carcinogens;

88 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME The parallelogram approach in CARCINOGENOMICS for developing predictive screens

Animal Human in vivo in vivo

Animal cells Human cells in vitro in vitro

• optimise cell systems into more robust cellular systems Expected results with an extended life span, stable phenotype, and xeno- biotic metabolic competence; The project will deliver a battery of mechanism-based in vitro • explore the suitability of embryonic stem cells as an tests accounting for various modes of carcinogenic action. alternative source of robust, human-derived cells for Based on ‘omics’ technologies, these tests will be designed assessing target organ-specifi c carcinogenic actions; to cover major target organs for carcinogenic action e.g. the • discern the biological pathways which in the predictive liver, the lung, and the kidney. models are essential for class discrimination, and to test the pathway models for predicting carcinogenicity; • build an in silico model for chemical carcinogenesis of Potential applications the liver; • describe inter-individual diff erences in the response to In developing these toxicogenomics-based tests as alter- carcinogenic challenges; natives to current chronic animal models for evaluating • develop a specialized chip with high throughput fea- genotoxic and carcinogenic properties of chemicals, this tures, in order to facilitate testing of large numbers of project will signifi cantly contribute to better hazard and risk chemicals at high speed and low costs; evaluation studies. In order to study the impact of such know- • pre-validate of the developed models according the ledge including the availability of toxicogenomics-based ECVAM guidelines; predictive screens on existing legislation and recent regu- • investigate how the novel genomics-based in vitro tests latory initiatives, CARCINOGENOMICS features a separate for genotoxicity and carcinogenicity may fi t within the sub-Workpackage on associated legal and regulatory issues. EU regulatory and legal frameworks; • establish a European public infrastructure giving an inte- The CARCINOGENOMICS consortium involves various SMEs grated view of the genomics data but also the associated in the areas of robust in vitro cellular systems, genomics phenotypical information; analysis and bioinformatics, as well as with regard to high • disseminate the outcome of the study to potential users. throughput technologies enabling accelerated and more effi cient testing.

AETIOLOGY 89 Coordinator Project number LSHB-CT-2006-037712 Jos Kleinjans Hector Keun Paul Carmichael Maastricht University (UM) Imperial College, London Unilever EC contribution Dept. Health Risk Analysis & Toxicology London, United Kingdom London, United Kingdom € 10 440 000 Maastricht, The Netherlands [email protected] [email protected] [email protected] Duration Myriam Fabre Paul Jennings 60 months ADVANCELL Innsbruck Medical University Partners Barcelona, Spain Innsbruck, Austria Starting date [email protected] [email protected] 01/11/2006 Jose Castell University Hospital Susanna-Assunta Sansone Jochen Koenig Instrument La Fe, Valencia European Molecular Biology Laboratory Genedata IP Valencia, Spain European Bioinformatics Institute Basel, Switzerland [email protected] Heidelberg, United Kingdom [email protected] Project website [email protected] www.carcinogenomics.eu/ Vera Rogiers Christophe Chesne Vrije Universiteit Brussel Rob Stierum Biopredic International Brussels, Belgium TNO Quality of Life Rennes, France [email protected] Delft, The Netherlands [email protected] [email protected] Petter Bjorquist Edward Lock Cellartis Ralf Herwig John Moores University Gothenburg, Sweden Max Planck Institute Liverpool, United Kingdom [email protected] for Molecular Genetics [email protected] München, Germany Leon Mullenders [email protected] Leiden University Medical Centre Leiden, The Netherlands Raffaella Corvi [email protected] European Commission DG JRC – IHCP – ECVAM (Centre for Michael P. Ryan the Validation of Alternative Methods) University College Dublin Brussels, Belgium Dublin, Ireland [email protected] [email protected] Bernward Garthoff Erwin Roggen European Consensus Platform Novozymes for Alternatives Bagsvaerd, Denmark Brussels, Belgium [email protected] [email protected]

90 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Melanoma | genetics | naevi | sun exposure |

GenoMEL Aim

Genetic and environmental The objective of GenoMEL is to understand the genetic causes of melanoma and how the identifi ed susceptibility determinants of melanoma: genes interact with the environment, predominantly with sun exposure. The intent is then to use the information translation into behavioural change obtained to improve on the ranking of risk factors for melanoma and to understand the phenotypic markers of those susceptibility genes. These fi ndings will then be con- verted into a web based tool, called a content management Summary system (CMS), for use by the general public, in order to cal- culate individual risks of melanoma. The CMS will be assessed GenoMEL, formerly known as the Melanoma Genetics and correlated with reported behaviour in the sun. We will Consortium, has focused on the identifi cation of familial then ‘close the loop’ by designing materials for use primarily high-penetrance melanoma genes. To date, the consortium on the web but also as written materials to educate Euro- has been very successful in identifying susceptibility genes pean people about the primary and secondary prevention and developing joint data collection for gene/environment of melanoma. interaction studies. In order to continue its proactive role, GenoMEL is developing a multidisciplinary European plat- form with relevant input from international participants. This platform will also enable the investigation of attitudes to risk of melanoma in Europe, and translate that risk perception into behavioural change.

Problem

Melanoma is an important health issue within Europe because it continues to increase in incidence in many Member States and because it has a relatively fl at-age incidence curve, so that the tumour is disproportionately frequent in young per- sons. Furthermore, in the new European Member States, there are concerns that as affl uence increases incidence levels will rise precipitously if action is not taken to discourage risky behaviours in the sun. There are already, unfortunately, data suggesting that survival from melanoma is poorer in these European countries than in western European countries. A GenoMEL researcher at work.

AETIOLOGY 91 Project number LSHC-CT-2005-018702

EC contribution € 10 452 723

Duration 60 months

Starting date 01/12/2005

The CDKN2A locus – the fi rst high penetrance melanoma susceptibility gene to be identifi ed. Instrument NoE

Project website www.genomel.org

Coordinator

Julia A. Newton Bishop Florence Demenais David Elder Brigitte Bressac-de Paillerets Leeds Institute of Molecular Medicine INSERM, Institut National University of Pennsylvania Institut Gustave Roussy University of Leeds de la Santé et de Philadelphia, USA Villejuif, France Leeds, United Kingdom la Recherche Médicale [email protected] Paris, France Sancy Leachman Marko Hocevar University of Utah Institute of Oncology Giovanna Libera Bianchi-Scarrà Salt Lake City, USA Ljubljana, Slovenia Partners Universita degli Studi di Genova Genova, Italy Dirk Schadendorf Jan Lubinski Nelkele Gruis Deutsches Krebsforschungszentrum Pomeranian Medical University Leiden University Medical Centre Johan Hansson Heidelberg, Germany Szczecin, Poland Leiden, The Netherlands Karolinska Institutet Stockholm, Sweden Esther Azizi Nicholas Kim Hayward Tel Aviv University Queensland Institute of Medical Research Andre Wijfjes Tel Aviv, Israel Brisbane, Australia ServiceXS B.V. Leiden, The Netherlands Martyn Rainford Graham Mann New Knowledge Directorate University of Sydney Antony Young Leeds, United Kingdom Westmead Institute of Cancer Research King’s College London Sydney, Australia London, United Kingdom Olita Heisele Biomedical Research Susana Puig Sarda Håkan Olsson and Study Centre Hospital Clinic i Provincial University Hospital University of Latvia de Barcelona Lund, Sweden Riga, Latvia Barcelona, Spain

92 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Virus | bacteria | HPV | HTLV | HCV | EBV | KSHV | HHV8 | helicobacter pylori |

INCA Aim

The role of chronic infections The INCA project will investigate the role of six of these infectious agents – EBV, KSHV/HHV8, HPV, HTLV-I, HCV, in the development of cancer and HP – in the pathogenesis of infection-associated cancer. In addition, the co-factor role of enterohepatic HP will also be investigated.

Summary The INCA Integrated Project aims towards a better under- standing of the molecular and cellular circuits involved in the Approximately 17% of the human cancer cases occurring development of cancers caused by these infectious agents, worldwide are caused by infectious agents, in particular by of the mechanisms of long-term persistence of these infec- viruses, bacteria and some parasites. Using a multidiscipli- tious agents in apparently healthy hosts, and of genetic nary approach, the INCA project will investigate the role of factors contributing to the development of these types of six of these infectious agents in the pathogenesis of infection- cancer. associated cancers. Expected results Problem Based on this knowledge, INCA will develop and validate ani- To date, nine infectious agents have been recognised as mal models to study chronic infl ammation and cancer human carcinogens by the International Agency for the progression, and new diagnostic procedures for the identifi ca- Research on Cancer: Epstein-Barr virus (EBV), Kaposi sar- tion of infected individuals likely to develop infection-associated coma herpes virus (KSHV), Human papillomavirus (HPV), malignancies. This will ultimately lead to the identifi cation of Human T-cell lymphotropic virus (HTLV-I), Hepatitis B virus new drugs and procedures to interfere with processes that are (HBV), Hepatitis C virus (HCV), Helicobacter pylori (HP), central to the development of infection-associated cancer. Schistosoma haemotobium and liver fl ukes (Opisthorchis The results of this joint eff ort will contribute to the under- viverrini, Clonorchis sinensis). These nine infectious agents standing of malignant transformation and provide new tools are responsible for about 17% of cancer cases worldwide, i.e. to address an urgent socio-economic and human need. approximately 1.6 million newly diagnosed cases of cancer annually. In addition, more recent epidemiological evidence suggests that Chlamydiae could play a co-factor role in the Potential applications development of cervical and lung cancer, and an involvement of enterohepatic Helicobacter in hepatobiliary tumours has Diagnostics and therapy. been suggested. Moreover, infection-associated cancer is also of increasing importance in immunosuppressed individuals, i.e. transplant recipients and AIDS patients.

AETIOLOGY 93 Coordinator Project number LSHC-CT-2005-018704 Thomas F. Schulz Jose Machado Paivi Ojala Hanover Medical School Institute of Molecular University of Helsinki EC contribution Dept. of Virology Pathology and Immunology Biomedicum Helsinki € 12 400 000 Hanover, Germany University of Porto & Haartman Institute [email protected] Porto, Portugal Helsinki, Finland Duration 48 months Susanne Kruger-Kjaer Mario Luppi Partners Danish Cancer Society Università degli Studi Starting date Institute of Cancer di Modena e Reggio Emilia 01/01/2006 Sebastian Suerbaum Epidemiology Experimental Haematology Laboratory Hanover Medical School Copenhagen, Denmark Modena, Italy Instrument Institute of Medical Microbiology IP Hanover, Germany Massimo Tommasino Bruno Cucinelli Silvia Franceschi Annette Ringwald Project website Charles Bangham International Agency for Carole Amroune www.inca-project.org Paul Farrell Research on Cancer – IARC ARTTIC SA Imperial College of Science Lyon, France Paris, France Technology and Medicine Wright Fleming Wing Werner Zwerschke Harald Mischak London, United Kingdom Austrian Academy of Sciences Mosaiques Diagnostics Institute for Biomedical & Therapeutics AG Maria Masucci Ageing Research Hanover, Germany Karolinska Institutet Innsbruck, Austria Stockholm, Sweden Michael Pawlita Luc Willems Deutsches Krebsforschungszentrum Thomas F. Meyer National Fund for Scientific Research Heidelberg, Germany Max Planck Society for Faculté Universitaire des the Advancement of Science Sciences Agronomiques György Kéri MPI für Infektionsbiologie Gembloux, Belgium Vichem Chemie Research Ltd Berlin, Germany Budapest, Hungary Vincenzo Ciminale Thomas Iftner Università degli Studi di Padova Jochen Koenig Frank Stubenrauch Padua, Italy Translating 135 Eberhard-Karls-Universität Tübingen Genedata AG Institut für Med. Virologie Ralph Grassmann Basel, Switzerland Tübingen, Germany Friedrich-Alexander Universität Erlangen-Nürnberg Staffan Normark Agnès Labigne Institute of Clinical and Birgitta Henriques-Normark Institut Pasteur Molecular Virology Swedish Institute for Infectious Paris, France Erlangen, Germany Disease Control Solna, Sweden Francis Megraud Lawrence Young Université Victor Segalen University of Birmingham Matthias Dürst Bordeaux 2 Medical School Jena University C.H.U. Bordeaux Institute of Cancer Studies Jena, Germany Bordeaux, France Birmingham, United Kingdom

Jean Crabtree George Mosialos University of Leeds Aristotle University of Thessaloniki St James’ University Hospital Thessaloniki, Greece Leeds, United Kingdom

94 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Breast | prostate | gene | association studies |

POLYGENE Problem

Inherited risk of breast Although several important genes have been shown to con- tribute to cancer susceptibility, multiple studies suggest that and prostate cancer a major portion of such genes remain to be found. This is par- ticularly true for prostate cancer. The major obstacles to fi nding those genes are the limited size of most studies and the inade- quacy of the statistical methods available. Here we will address Summary these problems by studying samples from two large popula- tions of breast and prostate cancer patients and developing Studies of cancer families have identifi ed high-penetrance novel methods for the analysis of the resulting data. cancer genes such as BRCA1 and BRCA2. However, although these genes have resulted in novel insights into Aim cancer genes and pathways, it is clear that a large compo- nent of inherited cancer risk remains unaccounted for. It This project has two major aims: to determine the contribu- has been proposed that common low penetrance cancer tion of polymorphic variants in a large number of candidate susceptibility genes contribute signifi cantly to the genetic genes to the risk of breast and prostate cancer, and to predisposition of cancer in a polygenic model of inherit- develop effi cient statistical and computational methods for ance. Association studies have been suggested as the the analysis of genetic and association data. method of choice for fi nding susceptibility alleles of high frequency but low penetrance. Here we propose to take advantage of accumulating genomic data and two Euro- Expected results pean populations of diff erent history and structure to determine the contribution of candidate cancer suscep- We expect to confi rm or exclude the association of multi- tibility genes to diff erent clinical forms of breast and ple candidate cancer genes with breast and prostate cancer prostate cancer. We will use a population-based associa- in the Icelandic and Dutch populations. Also, the study may tion study in Iceland and Holland to map the risk profi les identify novel candidate cancer genes, which can translate associated with common polymorphic variants in and near into novel diagnostic markers for breast or prostate cancer candidate cancer susceptibility genes in breast and pros- and possible targets for therapy. In addition, we expect to tate cancer patients. We will also develop methods for develop novel statistical algorithms and software for analysis statistical analysis of the resulting data. The proposed of genetic association data. study has the potential to cast light on how genetic vari- ants aff ect the risk of cancer initiation, and how it aff ects progression and response to treatment. Finally, the results Potential applications may serve as a starting point for building models of genetic risk of these cancers. Potential applications include a commercial software pack- age for the analysis of complex genetic data and novel cancer genes to be used as predictive markers for breast or prostate cancer risk, or for developing drugs.

AETIOLOGY 95 Project number LSHC-CT-2005-018827

EC contribution € 2 962 908

Duration 36 months

Starting date 01/11/2005

Instrument STREP

Project website www.polygene.eu An IGC researcher examines cells in tissue culture under the microscope.

Coordinator Partners

Thorunn Rafnar Leif Schauser deCODE genetics Bioinformatics ApS Reykjavík, Iceland Århus C, Denmark [email protected] Jotun Hein University of Oxford Oxford, United Kingdom

L.A.L.M. Kiemeney Radboud University Nijmegen Medical Center Epidemiology and Biostatistics Nijmegen, The Netherlands

96 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Prevention

The fact that preventing the onset of a cancer is among the best treatment options is a well estab- lished and shared fundamental concept within the oncology community. Moreover it is widely accepted that the majority of cancers could be preventable. The understanding of the extremely complex cancer aetiology is clearly the base for any prevention and treatment strategy to be eff ective. Regrettably, despite all the information available, still the rate of cure of tumours remains generally very low. When prevention is considered it is not only a matter of deepening the scientifi c knowledge. This information has to be given a pragmatic value via a synergy with public health, education and sup- port initiatives. The general population and the stakeholders in the capacity of taking such potentially eff ective actions have to be thoroughly and extensively educated. Furthermore, when a cause is identifi ed as potentially capable to have a strong correlation with the induction of a cancer, any action aimed at removing that cause should be carefully monitored to assess its real effi cacy. This process has already brought in the past to the achievement of impressive and positive results connected with the measures taken in order to tackle the negative eff ects of smoking, alcohol and dietary intake. Three EU funded projects foster the integration of the aetiology of cancer with preventive measures. These are: the Coordination Action (CA) ‘EPIC’ aimed at the production of a large mass of data poten- tially relevant for the identifi cation of nutritional and environmental causes of cancer with the clear objective of establishing enhanced public health strategies for the prevention of cancer and other chronic diseases; the CA ‘EUROCADET’ aimed at underpinning and promote the implementation of European and national policies to prevent cancer and the Specifi c Targeted Project (STREP) ‘MAMMI’ aimed at enhancing early detection methodologies for breast cancer based on beyond-state-of-the–art Positron Emission Tomography (PET) imaging methodologies.

Alfredo Cesario Keywords | Diet | lifestyle | physical activity | coronary heart disease (CHD) | stroke | chronic disease |

EPIC Expected results

European Prospective Investigation New scientifi c knowledge will be gained on the roles that diet, obesity, physical activity, alcohol, tobacco and socioe- into Cancer, Chronic Diseases, conomic factors play in the risk of developing cancer, coronary heart disease and stroke in the ten European coun- Nutrition and Lifestyle tries studied. This will include: • a greater understanding of the complex relationships between these health outcomes, and diet and alcoholic beverage intake; Problem • updated results on the health-damaging eff ects of tobacco and the benefi ts of quitting tobacco; There are a series of complex relationships between a) the • the identifi cation of long-term disease risk prediction of consumption of major foods and alcoholic beverages by dif- biomarkers of diet, aiming to identify new biomarkers ferent European populations, and b) the anthropometric for the identifi cation of subjects at increased cancer characteristics and physical activity (PA) levels of diff erent risk due to nutritional imbalances; European populations and the causation/prevention of • methodological guidelines on quality/standardised meth- diff erent cancers, coronary heart disease (CHD) and stroke. ods for measuring diet and PA.

Scientifi c reports and papers will be published. Aim

The objective of this action is to reinforce and expand the Potential applications collaboration between 27 European institutions so as to ensure that there is a major European resource containing: Recommendations for public health policies on strategies • a very large database of 521 000 European subjects for the prevention of cancer, CHD and stroke in Europe, from ten European countries who provided detailed through the improvement of dietary habits and the promotion information on diet, lifestyle and health status between of a healthy lifestyle. 1992 and 1999; • a bio-repository of blood samples collected at baseline and stores in liquid nitrogen; • follow-up data on over 28 000 cancer cases diagnosed after baseline, and over 15 500 deaths from all causes.

This will produce a large mass of data relevant for the iden- tifi cation of nutritional and environmental causes of cancer and other chronic diseases, and this knowledge will contrib- ute to the development of eff ective public health strategies for the prevention of cancer, CHD and stroke.

This will also enhance the development of statistical meth- ods for multicentre, Europe-wide studies on diet and chronic disease.

98 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number SP23-CT-2005-006438 Elio Riboli Carmen Martinez Petra Peeters Imperial College of Science, Andalusian School of Public Health University Medical Center Utrecht EC contribution Technology and Medicine Granada, Spain Julius Centre for Health Sciences € 999 745 London, United Kingdom and Primary Care [email protected] Françoise Clavel-Chapelon Utrecht, The Netherlands Duration Institut Gustave Roussy 48 months Villejuif, France Goran Hallmans Partners University of Umeå Starting date Heiner Boeing Umeå, Sweden 01/01/2006 H.B. Bueno-de-Mesquita Deutsches Institut für Ernährungsforschung National Institute of Public Health Potsdam, Germany Rosario Tumino Instrument and the Environment Associazione Iblea CA Bilthoven, The Netherlands Goran Berglund per la Ricerca Epidemiologica Lund University Ragusa, Italy Project website Nicholas Day Dept. of Medicine www.epic.iarc.fr University of Cambridge Malmo, Sweden Franco Berrino Cambridge, United Kingdom Istituto Nazionale per lo Studio Domenico Palli e la Cura dei Tumori Anne Tjonneland Centro per lo Studio Milan, Italy Danish Cancer Society e la Prevenzione Oncologica, Copenhagen, Denmark Florence, Italy Paolo Vineis Servizio Universitario Timothy Key Carlos Gonzalez de Epidemiologia dei Tumori Cancer Research UK – Epidemiology Unit Catalan Institute of Oncology Università di Torino Oxford, United Kingdom Barcelona, Spain Turin, Italy

Eiliv Lund Jakob Linseisen Miren Dorronsoro University of Tromso Deutsches Krebsforschungszentrum Fundación Vasca de Innovación Tromso, Norway (German Cancer Research Centre) e Investigación Sanitarias Heidelberg, Germany San Sebastian, Spain Nick Wareham Medical Research Council Carmen Navarro Aurelio Barricarte Epidemiology Unit Consejeria de Sanidad y Politica Social Instituto de Salud Publica de Navarra Cambridge, United Kingdom de la Region de Murcia Pamplona, Spain Murcia, Spain Salvatore Panico Rudolf Kaaks Universtita degli Studi di Napoli Federico II Kim Overvad International Agency for Research Naples, Italy Aalborg Hospital on Cancer – IARC Aalborg, Denmark Lyon, France Antonia Trichopoulou National and Kapodistrian University of Athens Athens, Greece

PREVENTION 99 Keywords | Cancer incidence | prevention | risk factors | smoking | alcohol | overweight | fruit and vegetables | physical activity |

EUROCADET Problem

Key determinants of the future Extensive research in the fi eld of cancer aetiology and pre- vention has been performed in the last decades and is still incidence of cancer across Europe: going on. However, a systematic over view and integration of (in)eff ective strategies, their prerequisites, effi cacy and impact of prevention possible impact is lacking. This project aims to integrate and synthesise the current knowledge of and experience with eff ective preventive activities, and project their expected eff ects on the future burden of cancer in Europe. Summary

Up to 40% of Europeans will suff er from cancer at some Aim time in their life and, in middle age, 40% of all deaths are due to this disease. Since up to 40% of cancers may also be The aim is to underpin and promote implementation of preventable, primary prevention remains essential, as the European and national policies to prevent cancer by provid- European Cancer Code also emphasises. Entry-points for ing estimates of the potential impact that interventions preventive interventions were identifi ed based on known directed at key determinants of the incidence of this disease risk factors for cancer, partly overlapping with other chronic may have on the future burden of cancer in the various parts diseases. Yet, with the exception of hygienic and occupational of Europe up to 2040. measures and discouraging smoking, primary prevention was not very successful, especially in lower socio-economic status (SES) groups; avoidable exposure to risk factors Expected impact demands more attention. The impact of this project will be that a perspective for can- This project aims to underpin national and European poli- cer prevention is shown, which makes maximal use of existing cies to prevent cancer by providing estimates of the knowledge in such a way that policy-makers are persuaded potential impact of interventions on determinants of cancer to invest more in eff ective long-term prevention eff orts. Fur- incidence on the future burden of cancer in Europe. Specifi - thermore, the project will help in formulating realistic targets cally, we aim to: at realistic terms (often over decades) to be reached by pre- • estimate the prevalence and quantitative impact of major ventive measures designed to reduce the exposure to risk lifestyle (smoking, excessive alcohol use, fruit and vegeta- factors and/or the incidence of cancer, but also make recom- ble consumption, overweight and physical activity) and mendations for the further studies needed to improve primary socio-economic determinants on cancer incidence, con- prevention eff orts to reduce the burden of cancer. cerning cancers of the oral cavity, larynx, lung, oesophagus, stomach, pancreas, colo-rectum, bladder, kidney, breast, endometrium and prostate, comprising 60% of the Potential applications incidence; • assess the potential to reduce exposure to these determi- Benefi ting from preventive actions directed at chronic dis- nants by reviewing evidence of eff ectiveness of interventions eases such as cancer, diabetes and cardio-vascular disease, and policies as well as barriers to implementation; this coordination action for cancer prevention prepares • estimate the future burden of cancer across Europe based a solid basis for fur ther active evidence–based preventive on autonomous trends and various scenarios of imple- policies that can aff ect many generations of Europeans born mentation of eff ective interventions. since the 1940s, but especially since the 1980s and 90s, by combining evidence with incentives to change unhealthy This coordination action will generate intensive interaction habits or not star t them, which is more relevant for the with national and international researchers, and policy-mak- younger generations. European variation can provide an irre- ers who will provide input to scenario development and sistibly strong example of the potential eff ects that changes refl ect on its outcome so that ambitious policies can be in lifestyle can have. In this respect, the systematic attention rolled out. Regional workshops will serve to implement sce- for the role of socio-economic status (SES) is impor tant. The nario development for prevention, based on the Prevent approach to estimate the long-term impact of prevention by model developed at Erasmus MC in Rotterdam. A special means of scenario development opens the way for involving web portal will be designed allowing for interactive commu- a broad array of stakeholders who are robbed of excuses not nication among participants, archiving of relevant data and to act. The scenarios will be made available at a special web development of scenarios, and enabling Member States to por tal, allowing the Member States and regions to adapt the adapt to their needs (‘do-it-yourself’) and circumstances, input to their specifi c needs and circumstances, and creating possibly also beyond the project. an oppor tunity for interaction with policy-makers at European, national and international levels.

100 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number SP23-CT-2005-006528 Jan Willem Coebergh Hermann Brenner Johan Mackenbach Deutsches Krebsforschungszentrum EC contribution Dept. of Public Health Heidelberg, Germany € 987 963 Erasmus MC [email protected] Rotterdam, The Netherlands Duration [email protected] Giuseppe Costa 48 months [email protected] Azienda Sanitaria Locale 5 Servizio di epidemiologia Starting date Grugliasco (Torino), Italy 01/04/2005 Partners [email protected] Instrument J. Brug Andrea Micheli CA A. Kunst Instituto Nazionale per lo Studio Dept. of Public Health e la Cura dei Tumori Project web-site Erasmus MC Milano, Italy www.eurocadet.org Rotterdam, The Netherlands [email protected] [email protected] [email protected] Eero Pukkala Finnish Cancer Registry Knut-Inge Klepp Helsinki, Finland University of Oslo [email protected] Dept. of Nutrition Faculty of Medicine Hans Storm Oslo, Norway Anne Tjonneland [email protected] Danish Cancer Society Copenhagen, Denmark Josép Borras [email protected], Institut Català d’Oncologia [email protected] L’Hospitalet de Llobregat, Spain [email protected] Antonia Trichopoulou University of Athens Philippe Autier School of Medicine Paolo Boffetta Dept. of Hygiene and Epidemiology Paola Pisani Athens, Greece International Agency for [email protected] Research on Cancer – IARC Lyon, France Witold Zatonski [email protected] The Maria-Slodowska-Curie Cancer Center [email protected] and Institute of Oncology [email protected] Dept. of Epidemiology and Cancer Prevention Warsaw, Poland [email protected]

PREVENTION 101 Keywords | PEMT | PET mammography | molecular imaging | breast cancer diagnosis | chemotherapy |

MAMMI Aim

Mammography with molecular imaging • Design and development of a dedicated low cost PET camera prototype for breast examination with an intrinsic resolution of less than 1 mm, high sensitivity, and tomo- graphic 3D reconstruction. Summary • Study of new and more specifi c radio-pharmaceuticals for breast cancer detection and therapy monitoring (FLT, FAS, The proposed project focuses on the development of a PET etc.). Perform phase I clinical trials of the radio-tracers. prototype dedicated to the examination of breast cancer, • Clinical multi-centric validation of the new PEMT prototype. using a gamma ray sensor based on an innovative design and the new generation of photo-detectors and scintillat- ing crystals. The innovative features of the PEMT (Positron Expected results Emission MammoTomography) system we propose will imply a high resolution (pushed to the physical limit), higher MAMMI proposes a new PET device specifi cally designed for sensitivity and lower cost. It includes integrated analogue breast cancer diagnosis and evaluation of therapy response. and digital electronics through the design of an ASIC chip. The dedicated breast cancer PET camera will improve the The main application will be early breast cancer diagnosis position resolution of current whole-body PET cameras and evaluation of chemotherapy response. New radio-tracer (about 5 mm) and will push it to the physical limit (slightly molecules will be searched for the detection and visualisa- below 1 mm). tion of the pharmacokinetics of breast tumours, more specifi c than glucose (FDG) for breast cancer, and based on human The new detector design will also have the ability to detect amino and fatty acids. Phase I Clinical trials will be performed the depth of interaction of the gamma ray interactions with- with the new radio-tracers. A clinical multi-centric validation in the crystal with a resolution better than 3 mm. This is an will be performed for the PEMT prototypes. essential feature since it allows for an improvement of the fi nal image resolution by almost eliminating the parallax error present in current PET detectors. This is essential in Problem the case of breast examination since the detector cameras are placed close to the body, to increase the sensitivity. Breast cancer is the most common non-skin cancer and the leading cause of cancer death in women. The best condition The advantages of the new generation of photo-detectors for successful breast cancer treatment is early detection. (silicon photo-multipliers), such as their compactness, will Some studies indicate that early breast cancer detection has be explored. The design of the electronics, including an reduced the disease mortality by about 29%. The ability to ASIC, will allow an acquisition rate capability of the order of defi ne the extent of disease, to monitor response, and to 1 MHz, with minimum dead time, to cope with the higher predict tumour behaviour in patients with breast cancer are sensitivity. therefore important public health problems. Moreover MAMMI will develop and study more specifi c than Conventional methods for breast cancer imaging like X-ray FDG radio-tracers for breast cancer diagnostic and therapy mammography, ultra-sound and Magnetic Resonance Imag- monitoring, based on human amino acids (such as FLT) and ing (MRI) produce morphologic and structural images, show fatty acids (such as FAS). lesions (like micro-calcifi cations), but not cancers. On the contrary, imaging methods based on Molecular Imaging show functional images, metabolism. This implies that they Potential applications are much more sensitive and hence can be used to detect and locate malign tumours at an early stage. For instance, The main application will be early breast cancer diagnosis PET (Positron Emission Tomography) is a powerful tool for and evaluation of chemotherapy response. New radio-tracer non-invasive molecular imaging diagnostic based on gam- molecules will be searched for the detection and visualisa- ma ray (emitted by an isotope compound, previously tion of the pharmacokinetics of breast tumours, more administered to the patient) detection. specifi c than glucose (FDG) for breast cancer, and based on human amino and fatty acids.

102 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2006-037555

EC contribution € 2 500 000

Duration 48 months

Starting date 01/01/2007

Instrument STREP – SME

Project website ifi c.uv.es/mammi

Coordinator

Jose Ma Benlloch Johann Hauer Consejo Superior Fraunhofer-Institut für de Investigaciones científicas Integrierte Schaltungen IFIC – Instituto de Física Corpuscular Erlangen, Germany Valencia, Spain [email protected] Pedro Branco DIGI-UTOPIKA LTD Lourinhã, Portugal Partners Norberg Gunnar Sibylle Ziegler C-Rad Imaging AB Klinikum Rechts der Isar der Technischen Frösön, Sweden Universität München München, Germany Anders Brahme Karolinska Institutet Angels Bernabeu Stockholm, Sweden General equipment for Medical Imaging, S.L. Renato A. Valdes Olmos Paterna, Spain Netherlands Cancer Institute Amsterdam, The Netherlands

PREVENTION 103

Early Detection, Diagnosis and Prognosis

Cancer is one of the leading causes of death in Europe and the western world, second only to cardio- vascular diseases, a trend that is exacerbated by an aging population and increasing the economic burden of this disease. At present, diagnosis of cancer very often happens late in the course of the disease, when cancer cells have already invaded surrounding tissues and metastasised throughout the body, because current diagnostic methods are not suffi ciently sensitive and specifi c. An early diagnosis of cancer would improve prognosis and treatment and could save thousands of lives a year with obvious advantages for public health care costs and quality of life. Although advances in EU-wide breast cancer (mammography), prostate cancer (prostate-specifi c antigen testing) and cervical cancer screening (PAP smear and the likely introduction of PCR-based detection of human papilloma virus DNA) have provided important progress in the early detection and diagnosis of the disease, current diagnostic and prognostic biomarkers and methods still do not reach the sensitivity and specifi city that is needed to reliably detect early-stage disease in the majority of can- cers in for example non-invasive blood, urine, saliva, breath or stool assays. As a result, most therapeutic strategies are limited in their success or even doomed to failure. The 25 projects in this section focus on the molecular characterisation of a series of cancers with the aim to translate this knowledge into novel early detection and diagnostic markers and tools, ranging from cancer (stem) cells in peripheral blood, lymph nodes and tumour tissues, breath-gas analysis, genetic tests to imaging probes and devices and endoscope technology.

Jan van de Loo Keywords | Exhaled breath analysis | lung cancer | oesophageal cancer | medical diagnosis | therapeutic monitoring | gas chromatography | mass spectrometry | PTR-MS | SIFT-MS | laser spectrometry | ion mobility spectrometry |

BAMOD Problem

Cancer is one of the leading causes of death in the western Breath-Gas Analysis for Molecular- world. More than 940 000 people died of lung cancer in Europe in the year 2000. These diseases have a tremendous Oriented Detection of Minimal Diseases impact on healthcare systems and economics. At present, the diagnosis of cancer often happens late in the course of the disease; early diagnosis would improve prognosis and treatment and could save thousands of lives. Summary

Cancer is one of the leading causes of death in Europe and Aim the western world. At present, diagnosis of cancer occurs late in the course of the disease since available diagnostic The objectives of the project are: methods are not sufficiently sensitive and specific. An early • the identification of sensitive and specific molecular diagnosis of cancer would improve prognosis and treatment, marker sets in human breath for the detection of early and could save thousands of lives a year. cancer stages; • the development of reliable analytical methods to detect There is strong evidence to suggest that particulate cancers these markers in the clinical environment; can be detected by a molecular analysis of exhaled air. • the production of easy-to-use and non-expensive equip- Breath analysis represents a new diagnostic technique that ment to facilitate breath analysis as a novel cancer is without risk for the patient, even if repeated frequently, screening tool. and can provide information beyond conventional analysis of blood and urine. Recent results suggest that detection of The proposal is centred on five studies: in vivo lung cancer diff erent kinds of cancer is possible by means of breath and oesophageal cancer studies, a study of cancer cell lines analysis in the very early stages of the disease. in vitro, a study of immune-system related cells and a study of bacterial cell lines. This project is focused on the diagnosis of minimal dis- ease and early stages of lung and oesophageal cancer. The SMEs in our consortium will develop analytical method- The analytical techniques will be gas chromatography ology for subsequent use in clinical applications. with mass spectrometric detection (GC-MS), proton trans- fer reaction mass spectrometry (PTR-MS), selected ion flow tube mass spectrometry (SIFT-MS), laser spectrometry Expected results and ion mobility spectrometry (IMS). The major objective is the establishment of a non-invasive, In order to establish a reliable clinical method for the diag- breathbased test for early detection of lung and oesophageal nosis of minimal residual cancer diseases, clinical expertise, cancer. The development of sensitive detection technology, basic research and technical development is necessary. a database of molecular markers related to cancer, and The European consortium set up to pursue this research the development of specific sensors for such markers is work involves specialists with skills in the fields of basic anticipated. and clinical research, and analytical instrument develop- ment. Thus, the consortium has the expertise to investigate and screen exhaled breath for many molecular species, to Potential applications identify specific cancer markers and the statistical tools to treat the data. The developed breath-based tests for the detection of lung and oesophageal cancer should be introduced to assist clinical diagnosis and therapeutic monitoring.

106 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2005-019031

EC contribution € 2 998 228

Duration 36 months

Starting date 01/02/2006

Instrument STREP

Detection of lung and oesophageal cancer based on exhaled breath. Project website eu-proposal. voc-research.at

Coordinator

Anton Amann Manfred Mürtz Innsbruck Medical University Universtitätsklinikum Düsseldorf Dept. of Anaesthesia and Düsseldorf, Germany General Intensive Care Innsbruck, Austria Boguslaw Buszewski [email protected] Nicolaus Copernicus University Torun, Poland

Partners Ireneusz Sliwka Polish Academy of Sciences Jochen Schubert Krakow, Poland Universität Rostock Rostock, Germany Viktor Witkovsky Slovak Academy of Sciences Rosa Margesin Bratislava, Slovakia Leopold-Franzens-Universtität Innsbruck Innsbruck, Austria Kerstin Wex IT Dr. Gambert GmbH Karl Unterkofler Wismar, Germany Vorarlberg University of Applied Sciences Armin Hansel Dornbirn, Austria IONIMED Analytik GmbH Innsbruck, Austria Nandor Marczin Imperial College London Patrick Spanel London, United Kingdom Trans Spectra Limited Keele, United Kingdom

Jörg Ingo Baumbach Institute for Analytical Sciences Dortmund, Germany

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 107 Keywords | Molecular tumour imaging | cancer therapy | PET-based treatment planning | PET-CT simulation | apoptosis | tumour hypoxia | aptamers | PET-CT-RT | diagnostic treatment unit |

BioCare the delineation of the tumour on a background of normal Molecular Imaging for Biologically tissue anatomy is achieved. Obviously, fl uorodeoxyglucose (FDG) is not tumour-specifi c, Optimised Cancer Therapy as all regions with an increased metabolic rate will show an elevated uptake. However, in the new era of molecular imag- ing it is likely to be followed by more specifi c tumour markers, allowing an even more accurate imaging of the Summary tumour clonogen density. Methionine and other amino acids are already available as tracers and, although they may be Early tumour detection and response monitoring require better than FDG, they may still not be suffi ciently specifi c, maximum sensitivity and specifi city of the imaging method. since they are incorporated in all tissues that are being This project focuses on the clinical evaluation and develop- renewed. For some tumours, there are more specifi c mark- ment of new, more specifi c molecular tracers for the early ers such as 11C-Choline, and FHBC or FDHT (fl uorodihydro- detection of tumour cells. A large number of new and testosterone) for imaging androgen receptors in prostate potentially more specifi c tracers than fl uorodeoxy-glucose cancer. Vasculature could be visualisable by known tracers 11 15 (FDG) will be tested, including amino acid analogues, small such as ammonia ( CH3) or water (H2 O). tumour-binding peptides, aptamers, peptides binding to mutant p53 proteins and nanoparticles. The more tumour specifi c the tracer, the more accurately it will be possible to Aim image the true tumour cell density and, more importantly, the true response of the tumour to therapy. Molecular imaging of radiation-induced alteration of tumour cell proliferation and functional receptor expression. In There is also a need to consolidate experience in the use of recent years, radiotracer-based molecular imaging with recently developed molecular tracers to assess radiothera- positron emission tomography in oncology has evolved as a py and chemotherapy response in order to improve on valuable tool for staging of disease and evaluation of thera- state-of-the-art treatments. To maximise the sensitivity and py response. This success is mainly based on the application tumour image quality, a high-resolution, wide fi eld-of-view, of the glucose analogue 18Fluorodeoxyglucose, which traces ultra-sensitive fully integrated PET-CT camera, capable of tumour tissue by the fact that most tumours exhibit imaging half the human body in a few minutes, will be enhanced glucose consumption. But the tumour microenvi- designed. Furthermore new adaptive therapy planning and ronment is not depending only on glucose metabolism. biological optimisation codes and a dedicated PET-CT Perfusion, hypoxia, amino acid uptake and receptor status detector for incorporation in treatment units will be designed are important parameters which have high impact on the in close corporation with university researchers and SMEs. treatment success. Additionally to ‘the classics’, FDG and This will allow an effi cient clinical integration and high methionine, new PET-tracers to monitor these parameters patient throughput. The associated increase in accuracy of are under development. With the advent of high-resolution tumour imaging and the three-dimensional in vivo tumour animal PET scanners there is now the opportunity to inves- responsiveness data will hopefully allow the clinical intro- tigate in vivo the tumour microenvironment of transplanted duction of accurate biologically based adaptive treatment tumours in small animals under therapy conditions, espe- optimisation methods. cially for radiation therapy – for example the knowledge on the course of oxic or hypoxic conditions has the potential to develop strategies to overcome treatment failure due to Problem hypoxia-related radiation resistance. PET off ers the oppor- tunity to investigate the radiation response of tumours Cancer imaging is at the dawn of a third revolution of accu- longitudinal during the treatment time, to evaluate the pre- rate tumour diagnostics. During the 1970s and early 1980s, dictive strength of diff erent parameters or their combination, computed tomography (CT) with diagnostic X-rays made and to test the effi cacy of newly developed tracers in com- a revolution in accurate delineation of normal tissue anato- parison to ‘standard tracers’. The functional PET data will be my as well as gross tumour growth. In the mid 1980s and supplemented by tumour histology, immunohisto-chemistry 1990s, magnetic resonance imaging and spectroscopy (1.2) and autoradiography to complement the tumour-patho- allowed even more accurate diff erential diagnostics of soft physiologic data. tissue malignancies with the possibility of distinguishing between tumour tissues, oedema and normal tissues. The inte- In the future we thus need improved tracers to the image gration of positron emission and X-ray computed tomography tumour spread before treatment. This will enable accurate in one unit and MRSI – MR spectroscopic imaging – is bringing delineation of the clinical target volume based on visualised a third diagnostic revolution to tumour imaging. By combining uptake by the tumour, for example along well-known path- these two imaging modalities, an unprecedented accuracy in ways of microscopic lymphatic invasion.

108 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Aptamers. Molecular imaging, the science that combines Our research project is subdivided into four major activities non-invasive in vivo imaging and molecular biology, has addressed through nine work packages. begun to use labelled oligonucleotides as radiotracers. The aptamers, single-stranded oligonucleotides have a complex Activity Work packages three-dimensional structure and can interact with suitably PET-Camera Developments 1 conformed proteins with an affi nity and specifi city compa- Development of New Tracers 2, 3, 4, 5, 8 rable to that of receptor–ligand binding. Systematic evolution Experimental and Clinical Validation 3, 6, 7 of ligands by exponential enrichment (SELEX) is an empiri- Implementation in Medical Oncology 6, 7, 9 cal technique for selecting oligonucleotides that will bind to a given target, using a repetitive process of selective bind- ing and amplifi cation by polymerase chain reaction. Like Expected results phage display, SELEX off ers the potential of rapidly design- ing radiolabelled ligands for almost any target. The labelling of single-stranded oligonucleotides with a positron or sin- WP1 Proof of principle of 1 mm resolution PET and fully gle-photon emitter can result in valuable radiopharmaceuticals integrated PET-CT detection for diagnostic and ther- with promising applications for: apeutic applications. • imaging of specifi c mRNAs, i.e. visualisation of the WP2 Development of assay allowing distinction between expression of specifi c genes in vivo; apoptotic versus necrotic cell kill. Study of possibili- • monitoring of antisense chemotherapy, i.e. measuring ties to image the mutant p53 protein in vivo. the effi ciency of eff orts to block the expression of spe- WP3 Development and workshop on human tumour mod- cifi c genes; el assessment by small animal PET. • gene radiotherapy, i.e. the targeting of radiation damage WP4 Development of aptamers for tumour-associated to specifi c DNA sequences in order to destroy tumours; target structures. • imaging of protein targets by the use of aptamer oligonu- WP5 Development and clinical testing of new hypoxic cleotides, i.e. oligonucleotide ligands obtained by in vitro tumour markers. evolution of selection-amplifi cation steps, or selected for WP6 Development and validation of high quality FDG, FLT their interaction with nucleic acid-binding proteins; and FRT methodologies for PET-CT imaging in Euro- • pre-targeting strategies based on the specifi city of pean centres. complementary sequence hybridisation. Nevertheless, WP7 Development of accurate methods for PET-CT-based oligonucleotides are intrinsically poor pharmaceuticals treatment simulation and therapy verifi cation for because of their large size, low stability, poor membrane biologically optimised intensity modulated radiation passage and a number of undesirable and sometimes therapy. unpredictable side eff ects. As an alternative to the inher- WP8 Development, testing and pharmacogenetic charac- ently unstable phosphodiester DNAs, chemically modifi ed terisation of radiolabelled angiogenesis inhibitors. oligonucleotides, such as phosphorothioate, methyl- WP9 Development of biologically optimised predictive phosphonate and peptide nucleic acid oligomers, have assay and adaptive treatment planning techniques been developed, and some are in clinical trials for the based on PET-CT tumour and dose delivery imaging. chemotherapy of several types of tumours. Imaging techniques could be useful in the development of such therapies. In addition, the potential of targeting virtually Potential applications any disease or physiological process, by changing only the sequence of the oligomer, could provide a means of Beside the signifi cant improvement in sensitivity and specifi - identifying serious diseases in a very early stage, and be city for early tumour detection and response monitoring with a highly specifi c modality to diagnose and diff erentiate the new tracers, detection systems and algorithms devel- various cancers. This has stimulated eff orts to develop oped in the project, a large number of SMEs will be involved such radiopharmaceuticals in many laboratories, and in developing products of general interest to the entire can- encouraging results have been reported using techne- cer community. The SMEs are an integral part in the project tium-99m, indium-111, carbon-11, fl uorine-18, bromine-76 in making the new tools available, not only for Europe but and iodine-125 labelled oligonucleotides. also for the world market. The close integration between clinical and research activities at numerous university hospi- The overall goals are two-fold namely: tals with the SMEs will form new centres of excellence where • to improve and speed up the implementation of European SMEs will benefi t from close clinical and research PET-CT imaging in cancer management; collaboration at the same time as new products will be • to develop new European intellectual property to developed to the benefi t of cancer patients. improve tumour imaging by more specifi c tumour trac- ers. They will result in considerably increased resolution, sensitivity and specifi city in tumour detection.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 109 These centres of excellence will integrate the fi ve corner- Project number stones of European societies: LSHC-CT-2004-505785 • basic and clinical research; • innovation and advanced product development; EC contribution • clinical practice and experience; € 6 000 000 • entrepreneurs or SMEs; • the marketplace in medical applications represented by Duration hospital care systems. Sometimes it is relevant to include 55 months venture- and research-capital investors as a sixth entry in this listing. The centres of excellence formed by the Starting date collaboration in the present project will be a unique 01/03/2004 engine for European development in cancer care for the new millennium. Instrument IP

Project website www.biocare-eu.com

Coordinator

Anders Brahme Albert van der Kogel Harry Bartelink Roger Svensson Karolinska Institutet Radiation Oncology UMC St. Radboud The Netherlands Cancer Institute RayClinic AB (RayEducation) Stockholm, Sweden Nijmegen, The Netherlands Amsterdam, The Netherlands Stockholm, Sweden [email protected] [email protected] [email protected] [email protected]

Susanne Keidiing Marek Moszynski Christine Verfaille Partners Aarhus University Hospital Soltan Institute for Nuclear Studies European Society for Therapeutic Aarhus, Denmark Otwock, Poland Radiology and Oncology Bettina Beuthien-Baumann [email protected] [email protected] Brussels, Belgium University of Technology Dresden [email protected] Dresden, Germany Jean Bourhis Heikki Minn [email protected] Radiation Oncology Department University of Turku Hans Falk Hoffmann Institut Gustave-Roussy Turku, Finland European Organisation for Nuclear Research Patricia Price Villejuif, France [email protected] Geneva, Switzerland University of Manchester [email protected] [email protected] Manchester, United Kingdom Gunnar Norberg [email protected] Ulrich Hahn C-RAD Imaging AB Erik Hedlund University of Hamburg Östersund, Sweden C-RAD Innovation AB Bernd Johannsen Hamburg, Germany [email protected] Uppsala, Sweden Forschungszentrum Rossendorf e.V. [email protected] [email protected] Dresden, Germany Peter Björklund [email protected] Vincent Gregoire PEVIVA AB Université Catholique de Louvain Stockholm, Sweden Phillippe Lambin Louvain la Neuve, Belgium [email protected] University of Maastricht (GROW) [email protected] Maastricht, The Netherlands Johan Löf [email protected] Karin Haustermans RaySearch Medical AB Universitair Ziekenhuis Gasthuisberg Stockholm, Sweden Leuven, Belgium [email protected] [email protected]

110 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Monoclonal antibodies | bispecifi c | bifunctional | nanoparticles | genetic engineering | leukaemia and lymphoma | cancer therapy |

BMC Problem

Bispecifi c Monoclonal Antibody Monoclonal antibodies given as a single modality treatment induce tumour remissions in less than 50% of patients with Technology Concept well-selected type of cancer; complete tumour remissions are scarce. Thus, while the rapid introduction of mAbs for cancer therapy is very encouraging in favour of the use of this type of biological molecule, much progress is still Summary necessary to understand the mechanism of the action of therapeutic mAbs in order to make them more specifi c and Monoclonal antibodies (mAbs) represent a new form of effi cient in a broader range of cancer types. Indeed, it is protein-based drug having demonstrated a signifi cant a paradox that despite the great success of some well- impact on the treatment of several types of cancers. Their selected mAbs in the treatment of some cancer types, the specifi city towards cell surface receptors makes them able principal mechanism by which mAbs are inducing the to target and destroy tumour cells. However, much progress destruction of cancer cells has not yet been completely elu- is still necessary to understand the mechanism of the bind- cidated. Furthermore, the reasons why some patients ing and activity of antibodies in order to improve their respond to mAbs therapy, while others with almost the same targeting capabilities and their effi ciency. To reach these tumour do not, is not yet understood. The possible causes objectives, the BMC project will: for a poor response to mAbs therapy include a low density • develop a recombinant bispecifi c mAb with tetrameric of target antigen on the surface of tumour cells, which limits binding sites, directed against two diff erent antigens the activity of complement mediated cytotoxicity (CDC), expressed on the same target tumour cell; and of antibody dependent cell-mediated immunity (ADCC), • develop new bispecifi c or bifunctional molecules with a low sensitivity of tumour cells to an apoptosis signal or a the property of cross-linking two diff erent receptors on poor accessibility of the injected mAbs to the tumour cells. the surface of the cell; • modify the carbohydrate moiety of bispecifi c antibodies and the tumour targeting of the complement regulator Aim molecule, properdin, to trigger the activation of the complement enzymatic cascade at the tumour site. The global aim of the project is to improve the monoclonal antibody therapy with special emphasis on B-Chronic Lym- The recombinant molecules are directed against a selected phocytic Leukaemia and Mantle zone B-cell lymphoma, target antigen for mAb therapy, CD5, as well as a B-cell which will be achieved by: marker to be selected, in order to treat a specifi c type of • a link between targeting and activity: increase of under- leukaemia, the B-CLL. However, the described innovative standing of apoptosis signalling; cancer immunotherapy strategy will also be extended to • exploitation of the complement activity on tumoural cells the treatment of many other types of cancers, especially all as it is known to function on bacteria, overcoming the carcinomas. known inhibitory molecules present in eukaryotic cells; • development of novel approaches to optimise the tar- The consortium is made up of nine partners: geting and destruction of tumoural cells by: • six RTDs specialising in genetic engineering (CNRS), inno- • engineering new constructs of recombinant bispecifi c or vative molecule design (UNIL), antibody vectorisation with bifunctional antibodies reacting with two diff erent anti- nanoparticles (HUJI), CDC activity improvement and cell gens on the same tumour cells; line and animal model development (UBO), mechanisms • developing new strategies for the induction of complement- of therapeutic antibodies on patients’ cells (OORRBG), dependant cytotoxicity (CDC), either through modifi cations toxicology studies and standardisation (ITEM); of the glycosylation of bispecifi c monoclonal antibodies, or • two biotechnology SMEs specialising in therapeutic by genetically fusing properdin to recombinant monoclonal antibody development (MAT) and antibodies in vitro antibodies; production (MABGENE); • chemical conjugation of antibodies of diff erent specifi ci- • one company dedicated to the project management ties on emulsion nanoparticles; – ALMA. • evaluation and validation of the novel tumour targeting strategies proposed in the BMC project on tumour cells from patients with CD5+ B-cell lymphoproliferative dis- eases, as well as in an experimental model of SCID mice grafted with CD5+ B-cell lines.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 111 Expected results Project number LSHB-CT-2005-518185 Optimise the benefi t/risk ratio in B CD5+ B-cell leukaemias and lymphomas. EC contribution € 2 450 000

Potential applications Duration 36 months This could be applied to other types of cancer. Starting date 01/11/2005

Instrument STREP

Coordinator

Jean Kadouche Josée Golay MAT BioPharma Azienda Ospedaliera – Ospedali Evry, France Riuniti di Bergamo [email protected] Bergamo, Italy [email protected]

Partners Jürgen Borlak Fraunhofer Gesellschaft zur Christian Berthou Förderung der angewandten Université de Bretagne Occidentale Forschung e.V. Brest, France Institut für Toxikologie und [email protected] Experimentelle Medizin München, Germany Jean-Pierre Mach [email protected] Université de Lausanne Lausanne, Switzerland Patrick Henno [email protected] MABGENE SA Ales, France Martine Cerutti [email protected] Centre National de la Recherche Scientifique Benjamin Questier Paris, France ALMA Consulting Group [email protected] Lyon, France [email protected] Simon Benita Hebrew University of Jerusalem Jerusalem, Israel [email protected]

112 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Metalloproteinase | protease | metastasis | diagnostics | tumour imaging |

CANCERDEGRADOME In the battle against cancer, the Degradome is important in three principal areas. Extracellular proteases and • Cellular proteases and their inhibitors are components of the molecular machinery of malignancy, and thus are the cancer degradome: attractive as therapeutic targets. • Degradome genes are valuable as prognostic and diag- innovative diagnostic markers, nostic markers of disease that can improve the accuracy of conventional clinical and histopathological assessment. therapeutic targets and tumour • Cellular proteases are target molecules for improving imaging agents tumour detection and imaging. The goals in molecular diagnostics are to develop molecular profi ling technologies and markers of disease status that are broadly applicable to the selection of patients for therapy, Summary or to screening of disease-free individuals who may benefi t from prophylactic interventions. Extracellular proteases have complex roles with distinct functions at diff erent stages of tumour development and progression, and may have confl icting eff ects on malig- Aim nancy. The complete repertoire of extracellular proteases through which cells regulate their local environment is The aim of this project is to defi ne new molecular targets for termed the Degradome. Extracellular proteases remain an drug design and to develop novel specifi c interventions that attractive target for intervention against cancer and we are based on thorough knowledge of the pathophysiologi- propose to transfer recent insights into their function to cal roles of target proteases and related molecules, and to pre-clinical and clinical settings. understand how and when to use them. The identifi cation of new molecular diagnostic and prognostic indicators of patient risk, together with new ways to enhance visualisa- Problem tion of tumours in the clinic, will improve health care delivery based on an individualised, patient-oriented approach to The critical defi ning feature of a malignant tumour is the cancer therapy. presence of cells that have broken through tissue bounda- ries and penetrated into surrounding normal tissues. It has long been recognised that cellular invasion of basement Overview of human, chimpanzee, rat and mouse degradomes membranes and connective tissue stroma involves the actions of diverse extracellular proteases from multiple enzymatic classes, including the metalloproteinases (MPs) and the serine, threonine, thiol and aspartic proteases, which can be produced either by cancer cells themselves or by neighbouring host cells. These cellular proteases participate also in the formation of new blood vessels that support the burgeoning energy demands of a rapidly growing tumour, The fi gure represents the complete set of protease and protease homologue genes from the and in the ability of cancer cells to metastasize to distant indicated species. Catalytic classes are indicated at the bottom. organs. They constitute the Degradome – the complete rep- X.S. Puente, L.M. Sánchez, A. Gutiérrez-Fernández, G. Velasco and C. López-Otín, A genomic view of ertoire of proteases that cells and tissues coordinatively the complexity of mammalian proteolytic system. Biochem. Soc. Trans. (2005) 33, (331–334). regulate in order to modulate their local environment.

We now understand that pericellular proteolysis is important in the regulation of: • growth factor activation, bioavailability and receptor signalling; • cell adhesion and motility; • apoptosis and survival mechanisms; • angiogenesis; • specifi cation of cellular identity; • infl ammatory responses and immune surveillance.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 113 The Biology of the Cancer Degradome

Cell differentiation

Signal Cell proliferation transduction and and apoptosis gene expression

The DEGRADOME Invasion and Cell adhesion Proteases, Inhibitors, metastasis and migration Substrates and Receptors

Matrix Angiogenesis remodelling

Recruitment of host cells (inflammatory cells, fibroblasts)

Targets of molecular therapeutics can be found in diff erent aspects of malignant transformation.

Expected results Potential applications

• The determination of Degradome gene expression pat- Several major pharmaceutical companies have been involved terns in human tumour cell lines and mouse models. in the development of synthetic protease inhibitors for can- • A detailed analysis of Degradome gene function using cer therapy over the past decade. However, the vast majority tumour prone mouse models. of trials have shown these fi rst generation compounds to • The analysis of protease inhibitor function in combina- have limited eff ects. What is now clear is that the biological tion with other therapies. activities of extracellular proteases, and their roles in normal • Elucidation of the interplay between proteases and other and diseased tissues, are much more complex than was key molecules of intracellular and intercellular signalling. originally envisioned. The original notion of proteases solely • Determination of the regulatory factors that control pro- as mediators of pathological tissue destruction is an over- tease gene expression in tumours and in the tumour-host simplifi cation: in fact, some proteases have functions that dialogue. inhibit tumour development and progression, and moreover, • Characterisation of the cellular expression of Degradome their natural inhibitors (TIMPs, PAIs, etc) can in some instanc- genes for breast and prostate cancer. es enhance tumourigenesis. The identifi cation of protease • Development of active site-directed inhibitors of metallo- targets for the design of novel and specifi c interventions will proteinases. off er improvements for health care delivery and patient • Development of ligands able to prevent the formation of management. The knowledge obtained in this project can protease-substrate, protease-inhibitor, protease-receptor also be used to identify cancer susceptibility in otherwise complexes. healthy individuals. • Production of radiotracers for protease ligands for in vivo imaging, with transfer to clinical paradigms.

114 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHC-CT-2003-503297 Dylan Edwards Bernd Binder Margareta M. Mueller School of Biological Sciences Dept. of Vascular Division of Carcinogenesis EC contribution University of East Anglia Biology and Thrombosis Research and Differentiation € 10 400 000 Norwich, United Kingdom University of Vienna Deutsches Krebsforschungszentrum [email protected] Vienna, Austria Heidelberg, Germany Duration 48 months Wolfram Bode Peter Andreasen Partners Max Planck Society for Dept. of Molecular Biology Starting date the Advancement of Science University of Aarhus 01/01/2004 Keld Dano München, Germany Aarhus, Denmark The Finsen Laboratory Instrument Copenhagen University Hospital Athanasios Yiotakis Maria Patrizia Stoppelli IP Copenhagen, Denmark National and Kapodistrian Institute of Genetics and Biophysics University of Athens ‘Adriano Buzzati-Traverso’ Project website Francesco Blasi Faculty of Chemistry Naples, Italy www.cancerdegradome. IFOM – Institute of Molecular Oncology Athens, Greece org Milan, Italy Pia Ragno Christoph Peters Istituto di Endocrinologia Jean-Michel Foidart University of Freiburg e Oncologia Sperimentale CRCE – Faculty of Medicine Freiburg, Germany ‘G. Salvatore’, Consiglio Nazionale University of Liège delle Ricerca Liège, Belgium Tamara Lah Turnsek Naples, Italy National Institute of Biology Carlos Lopez-Otin Dept. of Genetic Toxicology F. Xavier Gomis-Rüth Dpto de Bioquimica y Biologia Molecular Ljubljana, Slovenia Consejo Superior de Investigaciones Universidad de Oviedo Cientificas Oviedo, Spain Giulia Taraboletti Madrid, Spain Istituto di Ricerche Gillian Murphy Farmacologiche ‘Mario Negri’ Shu Ye Cambridge Institute of Medical Research Milan, Italy University of Southampton University of Cambridge Human Genetics Division Cambridge, United Kingdom Karsten Brand School of Medicine Universitaetsklinikum Heidelberg Southampton, United Kingdom Karl Tryggvason Heidelberg, Germany Dept. Medical Biochemistry and Biophysics H. Spolders Karolinska Institute Andrew Baker OncoMethylome Sciences SA Stockholm, Sweden University of Glasgow Liège, Belgium Division of Cardiovascular Bertrand Tavitian and Medical Sciences T. Mercey CEA, Département d’Ingénierie Glasgow, United Kingdom Genoptics SA et d’Études des Proteines Orsay, France Gif-sur-Yvette, France Marie-Christine Rio Centre Européen de Recherche Guido Slegers Robert Paridaens en Biologie et en Médecine (GIE) Laboratory for Radiopharmacy Laboratory for Experimental Oncology IIIkirch, France University of Ghent Dept. of Medical Oncology Gent, Belgium University Hospital Gasthuisberg Achim Krüger Leuven, Belgium Institut fur Experimentelle Onkologie Janko Kos und Therapieforschung KRKA d.d., Pharmaceutical Company Olli Kallioniemi Technical University of Munich Novo Mesto, Slovenia University of Turku Munich, Germany Turku, Finland Guido Sauter Hans Brandstetter Institute of Pathology, Cantonal Hospital Proteros Biostructures GmbH University of Basel Martinsried, Germany Basel, Switzerland

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 115 Keywords | Biomarkers | colon cancer | breast cancer | follow-up diagnostics | screening | transcriptomics | genomics | proteomics | metabolomics | data mining |

COBRED allow 10-20% survival rates improvement. In fact, the poten- tial benefi ts of early CRC and BC diagnosis are so high that Colon and Breast cancer Diagnostics a wide range of community and governmental eff orts have been implemented for population wide screening.

Biomarkers are substances found in the blood, other body Summary fl uids (e.g. urine) or tissues that alone or in combination may signal the presence of cancer or the risk for cancer. Diagnos- COBRED aims at the discovery of colon and breast cancer tics based on biomarkers have the potential to signifi cantly biomarkers for patient follow-up (monitoring markers). improve current cancer diagnostic means, providing a higher COBRED will exploit the high-throughput analysis capacity sensitivity (i.e. much smaller tumours can be detected), easier of transcriptomics, proteomics and metabolomics tech- and faster and at a much lower cost. Biomarker discovery nologies in an integrated systems biology approach and and validation, similarly to drug discovery and validation, the expertise of biotech SMEs and academic partners is a long process with high rate (60-80%) of attrition of to discover biomarker candidates. Two clinical institutes candidate biomarkers along the major steps of qualifi cation renowned for their expertise in colon and breast cancer that ultimately ends in the approval by the Food and Drug will participate in the study with the design and execution Administration (FDA) in the US and the European Agency of a prospective clinical collection and will carry out the for the Evaluation of Medicinal Products (EMEA) in the EU. biological and clinical validation of the effi ciency of the Often, seemingly good candidates that have been identifi ed identifi ed biomarkers. After 3 years COBRED will deliver and found valuable in one study do not show the expected a set of biomarker candidates verifi ed in preclinical stud- predictive values in the second study. In fact, the number of ies, ready for large scale clinical validation and further new diagnostics approved per year is decreasing in sharp development for commercialization by the respective SME contrast to the intensifying biomarker discovery eff orts. partners. Furthermore COBRED will have demonstrated Thus, despite having the highest potential value in num- the potential to explore consolidated data resulting from bers, COBRED choose not to pursue the discovery of diff erent high-throughput technologies and clinical pro- screening markers because of economic and logistic fi les with advanced data mining technologies for enhanced impracticalities of a large scale screening-marker valida- biomarker discovery. tion in BC and CRC. Instead, we focus on the second largest clinical need, the improvement of patient follow up, by the Although within the project scope COBRED focuses on discovery of monitoring markers, which are expected to biomarkers for follow-up diagnostics, it has the potential to report relapse, metastasis and minimal residual disease at evolve to an early cancer detection & screening tool. earlier stages, which are more amenable to surgical and chemotherapy treatment, and more likely to improve cancer patient survival. Problem

An apparent paradox of current cancer epidemiology is that Aim while new therapies and diagnostics improve survival rates in common cancers, e.g. colon and breast cancer, the incidence The specifi c RTD objectives are to: rates are also increasing, thus the net eff ect is negative. • design a clinical protocol for prospective clinical BC and CRC collections that fi t the needs of the 3 high-throughput Colorectal cancer (CRC) is the third commonest cancer type screening technologies used: transcriptomics, proteomics worldwide; in the year 2000 the global incidence was about and metabolomics; 1 million, close to 10% of all cancers, and it resulted in about • identify biomarker candidates (metabolites, proteins, PBL 0.5 million deaths, equalling of about 8% of all cancer mortal- derived mRNAs) capable to detect and assess the status ity. Breast cancer (BC) is the most common cancer in Western of minimal residual disease, metastases and recurrence women. In these patients, it is not the primary tumour, but its after surgery and chemotherapy; distant metastases that are the main cause of mortality. The • develop a centralized database to integrate the data yearly incidence rate is over 0.5 million (630 000 new breast generated by the 3 technology platforms with the cancer cases) that results in about 0.2 million deaths. Recently, anatomo-clinical information of the clinical collections; the rates of metastasis and mortality in BC patients have • discover biomarkers with better specifi city and sensitivity decreased as a result of early diagnosis by mammographic using across-platform advanced data-mining techniques screening and the implementation of systemic adjuvant ther- on the combined data from the consolidated database; apy similarly to CRC. There is ample, but ‘only’ circumstantial • validate the biological relevance and diagnostic poten- evidence that derives from survival data of patients with early tial of the identifi ed biomarkers by testing their specifi city stages of cancer, suggesting that earlier diagnosis would on tissue arrays and in relevant preclinical models.

116 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Expected results Project number LSHB-CT-2007-037730 Specifi c project results will include: • sets of biomarkers (gene signatures, proteins, metabo- EC contribution lites or a combination of these) that will be considered € 2 985 102 clinically relevant for early diagnosis of primary BC and CRC and relapses; Duration • central repository system hosting the results from the 36 months technological platforms and the relevant clinical data; • prospective clinical collection of BC and CRC; Starting date • clinical validation for the diagnostic potential of subsets of 01/03/2007 the identifi ed biomarkers in comparison to existing biomar- kers and to currently available imaging techniques; Instrument • preclinical models for the biomarker evaluation and STREP biological studies. Project website www.cobred.eu Potential applications

Diagnostic kit for the detection of cancer recurrence and metastasis, with the longer term goal to develop early cancer detection tests amenable for population screening.

Coordinator

Mariana Guergova-Kuras Fabienne Hermitte Laszlo Fesus BioSystems International Ipsogen University of Debrecen 4 rue Pierre Fontaine Luminy Biotech Entreprises Department of Biochemistry 91058 Evry cedex, France Case 923 – 163, av. De Luminy and Molecular Biology [email protected] 13288 Marseille Cedex, France Medical and Health Science Center [email protected] Egyetem Ter 1. Partners 4010 Debrecen, Hungary Xavier Sastre-Garau [email protected] Andras Guttman Institut Curie University of Innsbruck Cell Biology Department Jaak Vilo Horváth Laboratory Department Translational Research University of Tartu of Bioseparation Sciences 26 rue d’Ulm, Ülikooli 18 Institute of Analytical Chemistry 75248 Paris cedex 05, France 50090 Tartu, Estonia and Radiochemistry [email protected] [email protected] Leopold-Franzens University Innrain 66, David Malka Bruno Cucinelli 6020 Innsbruck, Austria Institut Gustave-Roussy Arttic SA [email protected] 39 rue Camille Desmoulins 58A rue du dessous des berges 94805 Villejuif Cedex, France 75013 Paris, France Klaus Weinberger [email protected] [email protected] Biocrates BIOCRATES Life Sciences GmbH Innrain 66/2 6020 Innsbruck, Austria [email protected]

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 117 Keywords | Clinical diagnosis | cancer | infrared spectroscopy | infrared microscopy | infrared imaging | synchrotron radiation |

DASIM Project number Diagnostic Applications of Synchrotron LSSB-CT-2005-005326 EC contribution Infrared Microspectroscopy € 280 000

Duration 36 months Summary Starting date DASIM is a Specifi c Support Action to coordinate research 01/07/2005 eff ort of all Europe’s synchrotron light sources in the fi eld of infrared microspectroscopy of pathological samples as an Instrument aid to clinical diagnosis. SSA

Project website Problem www.dasim.com

Diagnosis of disease is the basis for all clinical medicine. The primary requirement is reliability of diagnosis in order to Expected results ensure that therapies are appropriate and successful. How- ever, the modern requirements of clinicians from diagnostic • Signifi cant acceleration of the rate of progress in the services go beyond a simple ‘yes’ or ‘no’ to the presence of fi eld by coordinating the research eff ort. a particular indication. Successful therapy requires informa- • Dissemination of knowledge through meetings, courses, tion on disease subtype classifi cation, assessment of the website and publications, informing clinicians in particular. disease stage and extent such as the grading of tumours, as • Reliable assessment of the potential of this technique as well as the monitoring of disease progress and therapeutic a guide for future EU science funding policy. success. The speed of pathological analysis can also be amongst the requirements arising as a result of a time-limited therapeutic window beyond which therapy may be less or Potential applications no longer eff ective. Such constraints are particularly appar- ent in the treatment of cancer and infectious diseases. Clinical diagnosis, particularly typing, staging and grading Post-mortem diagnosis is also an aspect to be included, of tumours. since there remain some diseases that can only be unequiv- ocally diagnosed post mortem, and in these cases the retrospective diagnosis plays a central role in improving therapies through the accumulation of clinical experience. Coordinator

Aim David Moss Ganesh Sockalingum Forschungszentrum Karlsruhe Université de Reims In the last ten years there has been considerable progress in Karlsruhe, Germany Reims, France the application of infrared microspectroscopy to the analy- [email protected] sis of human tissues in the context of disease diagnosis, and Marco Colombatti it has been convincingly demonstrated in many studies that Università di Verona infrared spectroscopy has the potential to contribute signifi - Partners Verona, Italy cantly to this fi eld. The aim of DASIM is to coordinate this Representing a consortium of more than research eff ort by networking the existing centres of excel- 70 scientists and clinicians from 10 European Fiona Lyng lence across Europe, by providing a forum for the necessary countries (Italy, France, Germany, Sweden, UK, Dublin Institute of Technology multidisciplinary exchange of expertise between clinicians, Ireland, Greece, Poland, Switzerland, Norway). Dublin, Ireland spectroscopists, biologists and physicists on the European scale, and by facilitating access to synchrotron facilities for Augusto Marcelli Sheila Fisher scientists and clinicians in countries that do not have their INFN – LNF University of Leeds own synchrotron facility. Frascati, Italy Leeds, United Kingdom

118 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Tumour cell dissemination | micrometastases | minimal disease | biobanking | genomic profi ling | microarray analysis | circulating nucleic acids | bioinformatical synopsis |

DISMAL Problem

Molecular Signatures as Diagnostic Investigations during the last decades have shown that the metastatic cascade is a complex pathobiological process and Therapeutic Targets for and highly dependent on the type of tumour. Some tumours, such as breast cancers, have a proclivity for parallel dissemi- Disseminated Epithelial Malignancies nation to the haematogenous and lymphatic compartment, starting in the earliest phases of tumour development. In other tumour types, such as in head and neck cancer, this pattern is very diff erent and haematogeneous dissemi- Summary nation appears to result from metastases in the lymphatic compartment. For these reasons we selected three tumour Disseminated tumour cells (DTC) occur at very low num- types: one as an extreme example of parallel, independent bers in the blood and particularly in the bone marrow, and dissemination (breast cancer), one as an extreme example can be detected using sensitive immunostaining and PCR of sequential dissemination (head and neck cancer), and methods. However, the sensitivity and specifi city of this one intermediate type (colorectal cancer). approach need to be improved. Combining the expertise of 11 academic partners with long-term expertise in microme- tastasis research, the DISMAL project will establish an Aim improved platform for DTC detection with an increased sensitivity and, in particular, with a greatly improved specif- The main objective of the DISMAL-project is to improve the icity. Besides DTC detection, the combination with analysis specifi city and sensitivity of current platforms for DTC of circulating tumour DNA and RNA as well as the expres- detection in patients with epithelial tumours, the predomi- sion profi ling of tumours are being explored to improve the nant form of cancer in Europe, whilst also identifying novel assessment of minimal disease. We will focus on epithelial markers at the DNA, RNA or protein level that allows a more tumours, as they are the most common types of solid precise detection of DTC with a high risk for metastatic tumours in the EU, investigating the carcinoma types that progression. display diff erent modes of metastatic spread. Dissemina- tion via the blood circulation will be analysed using bone The programme will focus on markers associated with hae- marrow as this is the most important indicator organ epi- matogenous dissemination (using bone marrow as the most thelial tumour cells home in on. Using genomic-based well defi ned indicator organ) because these markers have approaches, novel diagnostic target molecules will be iden- the potential to become novel targets, not only for diag- tifi ed on these cells and validated in functional models. We nostic purposes but also for therapeutic interventions. The will complement immunocytochemical DTC detection by markers functionally associated with metastatic progression additional genotypic and phenotypic markers relevant for of DTC are likely to be promising targets for therapy. These metastatic progression. To further increase diagnostic pre- specifi c markers could be further developed as therapeutic cision, we will analyse whether this improved platform can targets in collaboration with SMEs and larger pharmaceutical be combined with the analysis of tumour characteristics industries. that were revealed by microarray profi ling, and with evalu- ation of circulating tumour-associated DNA or RNA. With regard to cancer therapy, two key issues will be Besides the primary focus on improvement of DTC-based addressed. First, it will be evaluated whether it is possible to diagnostic platforms, it is important to realise that these eradicate DTC by an immunotherapeutic approach, opti- cells are the target cells for any kind of adjuvant systemic mised for success in a mouse model. Secondly, we will therapy, including chemotherapy and targeted biologi- investigate whether DTC are susceptible to current systemic cal therapies. In innovative DTC models, the effi cacy of therapies (for example chemotherapy) and develop novel DTC treatment will therefore be analysed and potential approaches for their specifi c eradication. Current adjuvant improvements studied. The translation of scientifi c know- chemo- or radiation therapy aims at hitting the most overt ledge into commercial products will be ensured by three property of tumour cells their unrestricted potential to SMEs with unique technological capabilities. proliferate. According to our current knowledge, DTC in the bone marrow are non- or slowly proliferating.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 119 Expected results Project number LSHC-CT-2005-018911 Primarily, the result of DISMAL will lead to improved disease staging and when implemented in clinical practice to per- EC contribution sonalised medicine. As a long-term goal, reaching beyond € 4 200 000 the duration of this proposal, the newly discovered diagnos- tic markers will be further evaluated for their suitability as Duration targets for therapeutic intervention, specifi cally aimed to 36 months eradicate minimal residual disease (MRD) in patients with solid tumours. DISMAL will provide: Starting date • knowledge about the biology of the metastatic process, 01/11/2005 particularly genes that determine early dissemination, homing and survival of epithelial tumour cells at diff erent Instrument sites; STREP • identifi cation of relevant genes and signalling pathways associated with tumour cell dissemination via the blood Project website vessels to distant organs (bone marrow); www.dkfz.de/dismal • improved estimation of prognosis and need for therapy of cancer patients with minimal disease through the development of a novel diagnostic platform for DTC detection which includes the information on the biology Coordinators of micrometastasis and metastatic progression; • basic information about new therapeutic strategies for Klaus Pantel Roland Eils preventing metastasis formation through the identifi ca- Institute for Tumour Biology German Cancer Research Centre tion of functionally relevant therapeutic targets that are University Medical Centre Heidelberg, Germany frequently expressed on DTC. These targets might there- Hamburg-Eppendorf fore be explored for the development of new forms of Hamburg, Germany Wolfgang Deppert adjuvant cancer therapy aimed at specifi cally eradicat- [email protected] Heinrich Pette Institut ing minimal disease with less severe side eff ects than Hamburg, Germany current chemotherapy; Ruud Brakenhoff • a unique, large-scale biobank of freshly frozen and paraffi n- VU University Medical Center Raoul Charles Coombes embedded epithelial primary tumours and autologous Dept. Otolaryngology Imperial College London samples of common sites of micrometastatic spread, Head-Neck Surgery London, United Kingdom including bone marrow (cells) and blood (cells and serum). Amsterdam, The Netherlands The biobank will be complemented by computerised stor- [email protected] Jean-Pierre Vendrell age of data on patients and tumour characteristics, Catherine Alix-Panabieres including histopathological analyses and clinical follow up University Medical Center information. Partners Lapeyronie Hospital Montpellier, France Björn Naume Potential applications Radium Hospital Oslo Paddy O’Kelly Oslo, Norway Applied Imaging Apart from the ultimate goal of DISMAL (the delivery of an Newcastle, United Kingdom improved diagnostic platform for minimal disease detec- Laura van ’t Veer tion), the sensitive detection tools might also be applied to Netherlands Cancer Institute Rainer Uhl a broad range of other biotechnology applications that involve Amsterdam, The Netherlands TILL Photonics the detection of rare cells. One fi eld might be, for example, Grätelfing, Germany the screening for cancer cells in body fl uids as a tool for Hans Tanke primary cancer diagnosis, or more sensitive and specifi c Leiden University Medical Center Bernhard Sixt detection of tumour cells in the lymph compartment. Leiden, The Netherlands Agendia Amsterdam, The Netherlands Monique Slijper Utrecht University Michael Speicher Utrecht, The Netherlands Medical University of Graz Graz, Austria

120 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | DNA-methylation | breast cancer | prognosis | therapy prediction |

DNA METHYLATION Aim

Epigenetic profi ling of breast cancer: To implement the epigenetic DNA-methylation analyses in the clinical setting to benefi t both the individual patient by prognostic and therapeutic applications optimising their therapy concept, and the society as a whole by minimising treatment-related side eff ects and maximising cure rates. Summary Expected results Breast cancer is a genetic as well as an epigenetic disease. A prominent epigenetic alteration is DNA-methylation in The achievements expected are the improvement of patient the promoter region of a gene that prevents the gene from prognosis by better risk assessment, and more specifi c ther- being expressed. Recently, high-throughput methods to apeutic approaches based on newly developed targeted analyse the methylation status of genes in a large number therapies and better therapy selection. of samples simultaneously have been developed. We formed the present consortium, which encompasses members of the European Union and associated Member States, to take Potential applications a multidisciplinary and innovative approach to study the DNA-methylation of breast tumours in order to improve Methylation-based predictive tests are highly suited for clin- the prognosis and treatment possibilities of the patients. ical routine application since the DNA-based methodology The participating centres are contributing complementary is very robust in a routine setting as they can be accurately state-of-theart proprietary technical expertise, large and and sensitively detected in paraffi n-embedded material. well-documented tissue resources, and intense clinical Large volume testing would be feasible for routine testing expertise. through an automated high-throughput approach.

Problem

Today, the choice of treatment for individual breast cancer patients is based on a number of traditional clinical and pathological determinations. Stratifi cation is not suffi cient since approximately 90% of patients with lymph-node nega- tive disease are grouped into a high-risk group and are consequently recommended adjuvant systemic therapy, even though it is known that only about 30% of node- negative patients will eventually experience disease recur- rence. In addition, markers are needed that can predict which patient will respond to a specifi c type of systemic endocrine or chemotherapy, both in the adjuvant and metastatic setting.

The fi fth base in the genome: Methylation of the carbon 5 position is the epigenetic modifi cation in the mammalian genome that contributes to cancer. © Epigenomics AG, Berlin.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 121 Binary epigenetic predictor: Project number Predictive DNA methylation patterns LSHC-CT-2003-504586 identifi ed during this project and indicated by the barcode here can guide the clinician EC contribution to decide whether or not to treat and € 2 533 758 to determine the best type of treatment for the individual patient. Duration © Epigenomics AG, Berlin. 36 months

Starting date 01/01/2004

Instrument STREP

Project website www.erasmusmc.nl/ interne_oncologie/ FP6/index.htm Coordinator

John A. Foekens Fred C.G.J. Sweep Dept. of Medical Oncology Dept. of Chemical Endocrinology Erasmus MC University Medical Center Nijmegen Josephine Nefkens Institute Nijmegen, The Netherlands Rotterdam, The Netherlands [email protected] [email protected] Sabine Maier Epigenomics AG Partners Berlin, Germany [email protected] John W.M. Martens Dept. of Medical Oncology Tanja Cufer Erasmus MC Dept. of Medical Oncology Rotterdam, The Netherlands Institute of Oncology [email protected] Ljubljana, Slovenia [email protected] Manfred Schmitt Nadia Harbeck Frédérique Spyratos Dept. of Obstetrics and Gynaecology Centre René Huguenin Technische Universität München Laboratoire d’Oncobiologie Klinikum rechts der Isar St-Cloud, France München, Germany [email protected] [email protected]; [email protected] Joe Duffy Nuclear Medicine Department Nils Brünner National University of Ireland Royal Danish Veterinary and St.Vincent’s University Hospital Agriculture University Dublin, Ireland Institute of Pharmacology [email protected] and Pathobiology Frederiksberg C, Denmark Serenella Eppenberger-Castori [email protected] Urs Eppenberger Stiftung Tumorbank Basel Riehen, Switzerland [email protected]

122 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Urology | clinical analysis | anticancer therapy | prognonsis | microarray |

Drop-Top enormous, major impact on survival has been restricted to haematopoietic malignancies, some pediatric tumours, and Integration of DNA, RNA and protein very few solid tumours. Improvement in survival can be attributed not only to advances in standard chemo- and markers in a tool for the prognosis radio-therapy and to the recent implementation of targeted- drug therapy, but also to advances in diagnosis and the and diagnosis of human disease identifi cation of high-risk groups, which allow for earlier and better treatment selection.

In contrast, the overall prognosis of the most common can- Summary cers, such as lung, colon, prostate, breast and bladder cancers remains poor, specially when the tumour cannot be The management of patients with superfi cial bladder cancer cured by surgery. One limitation is that the pathologist’s is diffi cult. No reliable means exists to determine whether interpretation of the tumour’s histological features remains a tumour will progress towards an infi ltrative form, which the ‘gold standard’. Recent advances in microarray technol- requires radical surgery (cystectomy), or whether it will ogy together with information derived from the sequencing remain superfi cial, which requires only conservative surgery of the human genome have raised hopes that this situation (resection). In addition, no dependable marker exists to pre- will change dramatically in the coming years. For these dict whether a primary tumour will reappear or not during hopes to be realized, it is essential to make appropriate use the years following surgical resection, forcing patients to of information, technology and clinical resources. We believe undergo constant revisions that reduce their quality of life that resources are often wasted because of inappropriate and overburden health care systems. approaches and inadequate collaboration between clinical, academic and industrial partners. Numerous markers of various types (genes, transcripts and proteins) have been analyzed in bladder cancer studies. Transcriptome analysis by DNA microarrays has been suc- Some of them have been found to harbor potential for cessfully used for the identifi cation of biomarkers of tumour the prognosis (progression and recurrence) of superfi cial progression. However, and due to the use of diff erent micro- tumours. However, analyses have often been limited to a sin- array platforms and patient selection strategies, among gle type of marker or even to a single marker. To the best of others, the biomarkers identifi ed for a given clinical condi- our knowledge, no study has attempted to integrate diff erent tion vary from study to study. Therefore, their application to types of markers for an increased predictive power. common clinical practice has not yet taken place, and requires prospective studies. The Drop-Top proposal intends The main scientifi c goal of Drop-Top is to identify a set of to overcome the above limitations by a double approach: markers with high predictive power for tumour progression • prospective validation of the information acquired and recurrence. To this end, we propose to collect tumour through retrospective studies. For this, a collaborative and urine samples from bladder cancer patients with multicentre eff ort is essential; a detailed clinical record, to measure in them markers of • integration of biomarkers from genome, transcriptome diff erent types, to fi nd statistically signifi cant correlations and proteome analysis in a single predictor set. Even between measurements and clinical records, and to select though each of these three analyses by itself will likely a predictor set. contribute, it is expected that the combination of biomar- ker types will result in an enhanced predictive power. In addition, Drop-Top pursues an ambitious technological This type of strategy has scarcely been used due to: challenge: the development of a prognosis microarray for • the high cost of microarray technology; the detection of said predictor set. In order to achieve this • the need to have access to diff erent platforms for we propose to measure all three types of marker biomole- the detection of diff erent biomolecules; cules by means of a single type of probe: oligonucleotides. • the fragmentary nature of most of the published Specifi cally, we propose to use short, long and aptamer oli- work (multiple DNA, mRNA and protein markers gonucleotides for the detection of gene, transcript and studied, but only individually and in most cases protein markers respectively. weakly associated to disease phenotype); • the lack of bioinformatics and biostatistics tools to handle heterogeneous data; Problem • the limited amount of clinical and follow-up informa- tion usually available. In addition, most of these studies Cancer is the second cause of death in the Western world are performed without taking into consideration poten- and its incidence is increasing due to the overall aging of the tial bias in the patient population under study (i.e. large population. Although advances in our understanding of the tumour cases are more likely to be studied than small mechanisms of tumour onset and progression have been tumour cases for sample availability reasons).

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 123 Aim The DroP-ToP strategy should be applicable to the study of any tumour type, and more generally to any disease with Drop-Top has two major objectives, one technological and a genetic or gene-expression component. However, and as one scientifi c. Regarding the former, we propose to develop a proof of concept, we propose to apply it to bladder carci- a tool for multiparametric analyses (mRNA levels, large noma because it represents a paradigm of the need for genetic rearrangements, genetic mutations, genetic poly- useful biomarkers in the clinical setting: morphisms, protein levels and post-translational modifi cations) • it is one of the best models of tumour progression; of biological samples, to better predict tumour progression • its incidence ranks fi fth among all cancer types (the and recurrence (see Figure 1). The evaluation of such hetero- fourth most common in males and the ninth in females); geneous parameters will be performed on a single microarray: • despite widely variable outcome, the diagnosis and the triple microarray, an oligonucleotide microarray for prognosis tools used in the clinic are few and the same, simultaneous DNA, RNA and protein assessment). The triple and they are invasive even for asymptomatic patients microarray constitutes the test surface of a workstation that (cystoscopy); integrates technology for the hybridization, scanning and • it is the most expensive cancer type, as it can recur many detection of biomarkers. Its simplicity should facilitate a wide times after treatment; implementation of this tool in the clinic. • its evolution is very diffi cult to predict, whereas the ther- apeutic approach for its two forms is completely diff erent: As scientifi c objective, we propose to identify a set of when invasive at the time of diagnosis, it has a poor biomarkers with power for the prediction of clinical behav- prognosis and requires aggressive surgery (cystectomy); iour of bladder cancer. Selection of such set of biomarkers when non-invasive, prognosis is favourable and it only will be the end point of a fi ve-phase endeavour: requires conservative surgery (resection); • identifi cation of candidate biomarkers for bladder can- • its recurrence is also diffi cult to predict, which leads to cer progression and recurrence from the scientifi c unnecessary visits and cystoscopies for about 50% of literature and from existing data generated by two patients, whose tumours will never recur; Drop-Top partners specialized in bladder cancer; • a number of highly promising biomarker candidates have • pre-selection of biomarkers on the basis of the strength already been identifi ed and reported in the literature. of their association to tumour behaviour and on the sci- entifi c and technical quality of the study; • measurement and validation of said candidate biomark- Expected results ers in a set of samples from patients with a detailed clinical record and follow-up; Cancer is the second leading cause of death worldwide. In • application of bioinformatics and biostatistics tools for the year 2002 there were 10 million new cases of cancer in the identifi cation of a set of biomarkers with a strong the world, 6 million deaths and approximately 22 million association to tumour behaviour. people living with cancer worldwide. It is estimated that by year 2020 there will be 15 million new cases per year, and 10 millions deaths. Bladder cancer is a highly common neo- plasia, mainly among men, and its incidence is rising in several countries in Europe. Approximately 125 000 new cases with bladder cancer are diagnosed each year in the EU.

Despite continued interest in the development of novel tests to better predict bladder cancer prognosis, there has been very limited progress. This is in part due to the fact that all tests developed until present are based on the detection of only one type of biomolecule (i.e. RNA, DNA or protein). Our approach is radically diff erent: from a systematic review of current knowledge on biomarkers of bladder cancer and existing research results of the participating academic part- ners, we propose to develop a microarray that can detect the 3 major types of molecules in human biological samples. Figure 1 | Triple microarray and Integrated station for improved multiparametric This should provide a much more solid basis to identify analyses of biological sample. molecular predictors of the disease.

124 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME after diagnosis. Subsequently, the frequency of medical examinations varies according to the evolution of the dis- ease. Therefore, a test that would allow the early detection of recurrences and an improved establishment of prognosis would be applied very frequently to the patients. The Drop- Top proposed test could even be used more commonly than cystoscopies are performed today given that it would not be invasive. Its availability would allow demonstration of the concept that early detection of tumour recurrence is associated with improved overall outcome.

Potential applications

A Drop-Top research at work. Diagnosis and prognosis for the bladder cancer and others disease.

The Drop-Top proposed technology will bring about three main improvements: • the number of invasive tests will be strongly reduced, leading to a reduction in costs by decreasing hospital admissions and the number of occupation hours lost; • reduction in the number of invasive tests will also dimin- ish morbidity and improve the quality of life of patients; • a better prognosis will allow more adequate choice of treatment i.e. avoiding therapy to patients who do not need it and applying more aggressive therapy to patients at risk.

While most patients develop bladder tumours with a rela- tively good prognosis in terms of survival, their management is very expensive because of the multiple recurrences that most patients suff er, the need for invasive follow-up proce- dures, and the frequent hospitalizations. Overall, bladder cancer patients generate the highest cost/patient and life- time among patients with cancer. In conclusion, bladder cancer generates very high costs to society.

At the present time, there is no test recommended or approved to help establish the prognosis of patients with bladder cancer. Over the past 10 years several products have been approved by the FDA for use in the early detection of bladder cancer recurrence (i.e. nmp22, BTA, Diagnocure Immunocyt, Vysis). However, none of these tests is yet used routinely in the clinical setting because they do not provide a substantial benefi t. Therefore, there is a tremendous need for better tests.

Patients with bladder cancer develop multiple (up to 30) tumour recurrences, thus requiring continued follow-up after the initial diagnosis. For this reason, most patients undergo at least two medical visits over the fi rst few years Preparation of the sample.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 125 Coordinator Project number LSHB-CT-2006-037739 Gorka Ochoa Melanie Hilanio Progenika Biopharma, S.A. University of Geneva EC contribution Parque Tecnológico de Bizkaia B 24 rue General-Dufour € 1 834 331 Edificio 801 B, Derio-Vizcaya Geneva, Switzerland 48160, Spain [email protected] Duration [email protected] 36 months Zivko Popov University Cyril and Methodius-Faculty Starting date Partners of Medicine 01/01/2007 Department of Urology Francois Radvanyi Vodnjanska 17 Instrument Institut Curie-CNRS Skopje, Former Yugoslav Republic STREP 26 Rue d’Ulm, of Macedonia 75248 Cedex 05 [email protected] Project website Paris, France www.drop-top.net [email protected] Hader Kless NuAce Tecnologies, Ltd. Nuria Malats 14 Moskovitz St. Institut Municipal d’Investigacio Medica Rehovot, Israel Universitat Pompeu-Fabra [email protected] Doctor Aiguader 80, Barcelona, Spain Jörg Hoheisel [email protected] Deutsches Krebsforschungszentrum Im Neuenheimer Feld 280 Gordana Cerovic Heidelberg, Germany Genewave [email protected] Bat 404-XTEC, École Polytechnique Palaiseau Cedex, France [email protected]

126 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Neuroblastoma | medulloblastoma | retinoblastoma | nephroblastoma | rhabdoid | Ewing | translational research |

E.E.T.-Pipeline Problem

European Embryonal Tumour Pipeline Second to accidents, cancer is still the leading cause of death for children in Europe. Approximately 30% of childhood malignancies are embryonal tumours (ET), often demonstrat- ing resistance to conventional treatment approaches and Summary being associated with lower survival rates compared to other childhood cancers. Thus, novel diagnostic and therapeutic Treatment of embryonal tumours (ET) is a challenge for the options are urgently needed in particular for this group of pediatric oncologist. Innovative translational research is tumours in order to improve survival rates and quality of life of required to exploit available genomic data and implement pediatric cancer patients. The limitations of current treatment state-of-the-art technologies to overcome the defi cits of approaches include, in particular, a lack of validated post- current diagnostic and treatment strategies. We will set up genomic technology available for routine diagnostics and a Consortium of leading European institutions and SMEs a large gap between target identifi cation in basic research with extensive clinical and technological expertise in order eff orts and resulting pre-clinical development of novel drugs. to establish a unique pipeline for the comprehensive devel- opment and validation of novel diagnostic tools in addition Beyond defi ning characteristic gene expression signatures, to effi cient preclinical drug development for ET. only a limited number of studies have addressed the func- tional analysis of identifi ed target genes. The genetic low Our holistic approach includes: complexity of ET tumours provides a suitable system to • validation of a chip-based diagnostic platform tailored identify druggable targets. Conclusive diagnosis using his- specifi cally for ET, including analysis of genes previously tology alone is diffi cult due to the uniform morphologies of shown by the Consortium to be aff ected in ET; the diff erent ET entities, identifying ET as an important area • validation of a chip-based diagnostic platform tailored to complement current strategies with modern post-genomic specifi cally for ET, including analysis of genes previously approaches. shown by the Consortium to be aff ected in ET; • extension of an existing database designed to ware- Our approach is of particular importance for ET, as the ET house complete clinical and experimental data for entities are orphan diseases, meaning each entity does not neuroblastoma to include all ET entities; have a large enough market to justify the costs of drug devel- • implementation of a virtual ‘ET-Biobank’ to improve opment by a private company. The identifi cation of potential sharing of patient samples; targets for all ET entities should be more economically • functional characterisation of the most promising molec- attractive for private companies. Common molecular path- ular targets previously identifi ed by the partners as ways such as myc- and RB-signalling and chromosomal a foundation for entry into a drug development pipeline; deletions including 1p36 and 11q loss have been previously • integration of existing disease-specifi c mouse models identifi ed in diff erent ET entities by the Consortium members to evaluate new treatment modalities in vivo; and others, supporting a rationale integrating all ET types. • initial evaluation of a screening method and antibody aff ecting ET cell invasion; • application of novel bioinformatic solutions for meta- Aim analysis; • dissemination of the novel tools to researchers and The multimodal genomic and proteomic approaches pro- clinical study centres in Europe. posed here provide a promising alternative for more successful tumour diagnosis, subclassifi cation and drug Our coordinated eff ort can achieve the critical mass to development for ET. This STREP will provide a coordinated facilitate the necessary integration of research capacities strategy for the translation of basic research results into the for translating ET genome data into signifi cant medical pre-clinical arena, focusing on the implementation of state- progress. Involvement of clinical study centres will ensure of-the-art diagnostic tools, improvement of access to clinical a direct link to the bedside, aimed at improving child health material, and the effi cient combination of post-genomic and quality of life. research approaches with pre-clinical drug development.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 127 Project number A B LSHC-CT-2006-037260

EC contribution € 4 000 000

Duration 36 months

Starting date C D 01/01/2007

Instrument STREP

Project website www.eet-pipeline.eu

Custom-made tissue microarray for validation of identifi ed novel target proteins in embryonal tumor tissue.

Expected results Coordinator

The E.E.T.-Pipeline provides a comprehensive, multi-team Angelika Eggert Heinrich Kovar approach for improving ET diagnostics and treatment by University Children’s Children’s Cancer the integration, assessment and validation of information Hospital Essen Research Institute generated by basic research utilising high-throughput tech- Essen, Germany Vienna, Austria nologies. In this integrated post-genomic research eff ort, we [email protected] conceive dual pipelines concentrating on: Olivier Delattre • state-of-the-art diagnostics; Institut Curie • innovative drug development and pre-clinical testing, in Partners Paris, France order to channel these eff orts. We aim to close the gap between basic and clinical research by focusing on the Manfred Schwab Massimo Zollo initial evaluation and characterisation of a selected sub- German Cancer Research Center Ceinge-Biotecnologie set of identifi ed genes, proteins and biological pathways Heidelberg, Germany Avanzate S.C. a.r.l. contributing to malignant transformation or progression Napoli, Italy of ET. Roland Eils German Cancer Research Center Frank Speleman Heidelberg, Germany Centre for Medical Genetics Potential applications Gent, Belgium Saso Dzeroski This integration of research capacities is expected to enable Jozef Stefan Institute Björn Cochlovius the participating SMEs to develop novel, biology-based Ljubljana, Slovenia Affitech AS therapies for disseminated disease, which will complement Oslo, Norway current protocols with more specifi c and less toxic alterna- Michael Grotzer tives. We aim to provide a platform to support the initial University Children’s Alessandro Bulfone phase of development of new, well tolerated disease- and Hospital of Zurich Bioflag Srl patient-adapted anti-tumour strategies. Zurich, Switzerland Pula, Italy

128 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Brain tumour diagnosis | DSS | MRS | genetic microarrays | HR-MAS | eTUMOUR using DNA microarrays to determine the tumour phenotype may create new subtypes not currently distinguished by Web Accessible MR Decision Support standard histopathology. A more precise metabolomic anal- ysis of tumour tissue is possible ex vivo by using MRS at high System for Brain Tumour Diagnosis and fi elds (> 11T) and this may further improve our understanding of the tumour biochemistry and may also refi ne the classifi - Prognosis, Incorporating in vivo and cation of brain tumours. To determine how the metabolomic and genomic profi les of tumours are related, and how they ex vivo Genomic and Metabolomic Data can be used to classify optimally individual tumours, requires a large database of both in vivo and ex vivo MR spectra and microarray analysis data. Finally, it is important to look for correlations of patient survival with these detailed tumour Summary characteristics, to assess whether there are better prognostic indicators than those of the current grading system. Diagnosis and treatment of brain tumours is based on clinical symptoms, radiological appearance, and often a histopatho- logical diagnosis of a biopsy. However, treatment response Aim of histologically or radiologically similar tumours can vary widely, particularly for childhood tumours. 1H magnetic reso- eTUMOUR aims to create a comprehensive web-accessible nance spectroscopy (MRS) is a non-invasive technique for Decision Support System (DSS) for analysis and interpretation determining tissue biochemicals (the metabolomic profi le). of magnetic resonance spectroscopy and imaging (MRS and 1H MRS can be performed along with clinical MR Imaging but MRI) data of brain tumours, which includes a database of clini- widespread use is hampered by specialised analysis require- cal, histological and molecular phenotype data from brain ments and poor dissemination of the skills needed to interpret tumour patients. The DSS will facilitate evidence-based clinical the data. In addition, the genomic profi le of tumours can be decision-making using MR and include new criteria such as determined with DNA microarrays. eTUMOUR will bring genetic-based tumour classifi cations. The DSS will be also together the expertise required to study the genomic and designed with agent technology to create a secure distributed metabolomic characteristics of brain tumours, with a multi- database accessible trans-nationally by collaborating centres. centre collaboration to acquire statistically signifi cant data, particularly for rare tumour types. Based on these charac- teristics, a new web-accessible DSS will be developed, Expected results incorporating genomic and metabolomic data. • Development of a web-accessible Decision Support Sys- tem (DSS) which has a graphical user interface (GUI) and Problem a database of MRI/MRS, clinical, histological and molecu- lar phenotype data (anonymised) from brain tumour The lifespan of the European population is increasing and, patients. accordingly, diseases that become prevalent in old age, such • Facilitation of evidence-based clinical decision-making as brain tumours, will affl ict a larger percentage of this pop- (for example diagnosis, prognosis, optimal treatment ulation. Brain tumours do not have a lifestyle-associated strategies, etc.) using MRSbased molecular imaging and etiology so prevention is not yet possible. Gold standard incorporating new criteria, such as genetic-based tumour diagnosis is based on histological analysis of tumour biop- classifi cations, and related clinical information, such as sies, which is an invasive procedure that carries risks. patient outcome. Magnetic resonance spectroscopy (MRS) provides a non- • Introduction of DNA microarray analysis of tumour biop- invasive method to obtain a profi le of the biochemical sies as an adjuvant in tumour classifi cation. constituents of the tumour and has been shown to improve • Introduction of high fi eld MRS of biopsy tissue to improve the accuracy of diagnosis in specifi c instances. However, MR understanding of tumour biology, classifi cation and grad- spectra are complex and require skilled interpretation, hence ing, and to aid diagnosis and prognosis using new high routine clinical use of MRS is still low. A decision support fi eld (3T) whole body MR systems. system that provides an automated classifi cation of MR spectra in terms of tumour type and grade should facilitate the uptake of MRS by clinicians. Tumour tissue is generally Potential applications heterogeneous and there are a large number of diff erent tumour types and grades. Thus to develop automated clas- Molecular imaging by MRS can potentially improve tumour sifi cation methods that are generally applicable, data from diagnosis, aid in tumour delineation, as well as monitor several hospitals must be combined to fully characterise the response to treatment, and so can aid clinicians and neuro- variability of tumour spectra. Furthermore, the possibility of surgeons in the treatment of brain tumours. The MR DSS to

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 129 be developed by eTUMOUR is likely to become a powerful Project number tool for accurate diagnosis, prognosis and treatment selec- LSHC-CT-2004-503094 tion and monitoring. The development of a web-based decision support system is innovative in itself and will pro- EC contribution mote the concept of how a multi-centre, web-distributed € 7 499 982 database of clinical information can be accessed, used and updated within healthcare systems with their unique and Duration stringent constraints of data security and privacy. New crite- 60 months ria for classifying brain tumours will arise from eTUMOUR by determining the metabolomic and genomic profi les of Starting date tumours and relating these to prognosis and treatment 01/02/2004 response. Particularly signifi cant will be the DNA microarray data, which may suggest the most appropriate genes to be Instrument used as markers for tumour classifi cation and may lead to IP development of new or customised microarrays for routine clinical use. Genomic and metabolomic data is comple- Project website mentary to standard WHO pathological classifi cations. The www.uv.es/etumour combined molecular and clinical data is likely to produce www.etumour.net a new and more complete methodology for classifi cation and grading of all types of tumours and should also increase our understanding of tumour biology and its variation. Coordinator

Bernardo Celda Christoph Segebarth Peter Kreisler François Berger University of Valencia Unité Mixte INSERM Siemens AG, Medical Solutions INSERM U318 Dept. of Physical Chemistry Université Joseph Fourier U594 Erlangen, Germany Grenoble, France Valencia, Spain Neuroimagerie Fonctionnelle [email protected] [email protected] [email protected] et Métabolique Grenoble, France Arno Klaassen Jorge Calvar [email protected] Scito S.A. Fundación para la Lucha contra Partners Grenoble, France Enfermedades Neurológicas de la Infancia Magí Lluch [email protected] Buenos Aires, Argentina Carles Arús MICROART, S.L. [email protected] Universitat Autònoma de Barcelona Barcelona.,Spain Montserrat Robles Unitat de Ciències [email protected] Universidad Politécnica de Valencia Witold Gajewicz Departament de Bioquímica Valencia, Spain Medical University Lodz i Biologia Molecular Antoni Capdevila [email protected] Lodz, Poland Bellaterra, Spain Hospital San Joan de Deu [email protected] [email protected] Esplugues de Llobregat, Spain Semmler Wolfhard [email protected] Deutsche Krebsforschungszentrum Franklyn Arron Howe Heidelberg St George’s Hospital Medical School Gilda D’Incerti Heidelberg, Germany Basic Medical Sciences Pharma Quality Europe, s.r.l. [email protected] London, United Kingdom Florence, Italy [email protected] [email protected] Martial Piotto Bruker Biospin SA. Arend Heerschap Luigi Visani Wissembourg, France University Medical Center Nijmegen Hyperphar Group SpA. [email protected] Nijmegen, The Netherlands Milan, Italy [email protected] [email protected] Richard Grundy Institute of Child Health Lutgarde Buydens Sabine van Huffel University of Birmingham Stichting Katholieke Universiteit Katholieke Universiteit Leuven Birmingham, United Kingdom Dept. of Analytical Chemistry Research and Development [email protected] Nijmegen, The Netherlands Leuven, Belgium [email protected] [email protected]

130 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Diagnostics | glycome | blood | glycan | mass spectrometry | disease markers |

GLYFDIS can signifi cantly contribute to prognosis determination and on-line evaluation of therapeutic regimens. Developing Glycans in Body Fluids- Potential eff ective tools to screen for cancer is an important endeavor and there is much research taking place to develop these for Disease Diagnostics tools. The goal is to detect the cancer when it is localized to the organ of origin without invasion of surrounding tissues or distant organs.

Summary The GLYFDIS project will make use of glycans. Its unique diversity compared to genome or proteome makes the Developing eff ective tools to screen for cancer is an impor- glycans ideal for diagnosis and monitoring of cancer. Cancer- tant endeavor and there is much research taking place to associated changes in the glycome of the tumoural tissue develop these tools. GLYFDIS project’s objective is to are very frequent. Currently the main hindrance could be develop methods for earlier diagnostic and eff ective dis- the present glycome-analysis technologies that fall behind ease screening of prostate and pancreatic cancer that will the rapidly developing genome- and proteome-analysing lead to better treatment outcomes. Early diagnosis of technologies. cancer is of far greater prognostic importance than any attempts to treat the disease in its late stages. Even in cases The group hopes to develop a non-invasive method for the where the eventual outcome cannot be changed, treatment early diagnosis of prostate and pancreatic cancer based on is simpler and quality of life improved for those cases where glycan analysis. early diagnosis is achieved. For this purpose, GLYFDIS pro- posed a method of a simple noninvasive blood testing. Accurate monitoring of a cancerous state following diagno- Aim sis can signifi cantly contribute to prognosis determination and on-line evaluation of therapeutic regimens. GLYFDIS’ main objectives are: • To optimise high-throughput methods of glycan analysis The most widespread and diverse post-translational modi- for the diagnosis of prostate and pancreatic cancer by fi cation is glycosylation. The location and variation of the analysis of glycans in blood. glycans place them in a position to mediate cellular and • Identifying cancer associated glycome markers in serum intracellular signalling events, as well as participate in dif- samples of prostate and pancreatic cancer patients. ferent biological processes including pathology states such • Developing and validating protocols for lectin-based as cancer. Therefore, we propose to use analyses of glycans microarrays intended for large scale screening of cancer for the diagnostics and monitoring of cancer. associated glycome markers in serum samples.

Problem Expected results

Cancer is a signifi cant burden on individuals, families and • To identify biomarkers using glycomic and proteomic society. The economic impact of cancer is substantial. In 2002, methods together with computer based algorithms. the overall cost of cancer, as published by the National Can- • To develop a non-invasive, modest, diagnostic kit that cer Institute, was 172 billion dollars. This does not account will identify specifi c markers for cancer in the blood. for the psychological toll that it takes on individuals and • Constructing a website and a glycome bio-bank integrat- families. ing GLYFDIS results and serving as basis for a continuously growing public glycome data-bank. Early detection and diagnosis of cancer is based on the • Dissemination of the information to the scientifi c com- observation that treatment is more eff ective when the dis- munity and community at large. ease is detected earlier in its natural history, prior to the development of symptoms, than in an advanced stage. Diagnosis of cancer in the early stages of the disease infl u- Potential applications ences on many aspects of life. It can signifi cantly decrease cancer-associated morbidity and mortality and to relieve The project will generate knowledge relevant for non-invasive the burden from patients, their families and the society. diagnosis of cancerous states with the eff ort in developing Accurate monitoring of a cancerous state following diagnosis a standard protocol for diagnosis of serum samples.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 131 Project number LSHB-CT-2006-037661

EC contribution € 2 793 724

Duration 36 months

Starting date 01/11/2006

Instrument STREP

Project website www.glyfdis.org

Coordinator Partners

Angel Porgador Rakefet Rosenfeld Jasna Peter-Katalinic Ben-Gurion University of the Negev Procognia Ltd. Muenster University Beer-Sheva, Israel Ashdod, Israel Muenster, Germany [email protected] [email protected] [email protected]

Pauline Rudd Julien Taieb NIBRT RNTech Diagnostics Dublin, Ireland Charleroi-Gosselies, Belgium [email protected] [email protected]

132 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Technological sciences | health sciences | physical sciences | medical imaging |

HI-CAM Problem

Development of a high-resolution The state-of-the-art in the fi eld is represented by a range of commercial systems, usually having large fi eld detectors Anger camera for diagnosis and (~40x50 cm2). These systems are best exploited while per- forming whole-body SPECT studies since their large, heavy staging of cancer diseases based on PMT-based detector heads and bulky gantries present diffi - culties in operating close to the patient’s skin for dedicated state of the art detector technology studies of specifi c, small tissues such as in parathyroid imag- ing, brain scanning and investigation of kidney cancer in infants. In a realistic clinical setting, at an imaging distance usually rather greater than 20 cm, the overall eff ective spa- Summary tial resolution is typically 10-16 mm (7-10 mm for brain studies). When a single detector head is used for dedicated The purpose of the project is the development of a com- scintigraphic studies of small organs, permitting a closer pact and high-resolution Anger camera to be used in clinical imaging distance, the overall eff ective spatial resolution is and research environments and which allows earlier and limited by both the intrinsic spatial resolution of the system more reliable diagnosis and therapy planning of cancer dis- and the collimator. eases in specifi c applications where high overall spatial resolution (less than 3 mm) and system compactness (less than 10 x 10 cm2 fi eld of view) are required. Aim

The gamma camera is based on the well-established The aim of the project is therefore the development of a new Anger architecture, where a collimator acts as a mechani- compact and high position resolution (<1mm) gamma cam- cal sieve for incoming gamma photons, a continuous era based on the new SDD photodetector technology. The scintillator uses the energy of each selectively passed fi rst technological objective is the development of an gamma photon to generate visible photons, and an array extended array of SDDs with large cell size (1 cm2), charac- of photodetectors emits electric signals in response to terised by high detection effi ciency to the scintillation light the absorption of the visible photons. The improvement and low electronic noise. The low noise level is a result of of performances is based on the use of a particular type specialised advanced semiconductor processing, as well as of photodetector, the Silicon Drift Detector (SDD), which of the integration of an on-chip JFET in the detector chip has recently demonstrated its ability to provide better which allows us to fully exploit the intrinsic low capacitance performance, by comparison with commonly used photo- of the SDD, by the minimisation of parasitic capacitances of multiplier tubes. the connection between detector and electronics.

The camera is intended for use both single-handedly for The other key technological objectives addressed by the planar scintigraphic studies and inserted in an annular project are: holder (gantry) of small diameter for SPECT imaging. • the realisation of a high-resolution collimator. The aim is Thanks to its compactness and high spatial resolution, to obtain a parallel hole collimator whose spatial resolu- it off ers potential applications in early diagnosis of cancer tion equals ~2 mm at an imaging distance of 5 cm with diseases aff ecting areas of the human body which can a sensitivity higher than 20cpm/uCi. Pinhole collimators only be imaged with diffi culty using the large and heavy will be also realised; imaging heads and gantries of commercial Anger cameras. • a very compact geometry of the detection module, The camera to be developed in the present project also based on a thin substrate where the SDD array and VLSI off ers promising perspectives of integration at the system readout circuits will be assembled, and a single CsI(Tl) level with MRI instrumentation, thanks to the relative crystal (potentially substituted by the more recently intro- insensitivity of the SDD photodetectors to large magnetic duced LaBr3:Ce) will be coupled to the photodetector fi elds. array; • the introduction of a thermoelectric system to attain The research activity will be organised as follows: the fi rst moderate cooling (~ -20°C) during operation of the gamma two years of the three-year project will be dedicated to the camera; development of the SDD-based Anger camera, while the • the development of dedicated VLSI electronics for ampli- third year will be dedicated to the experimentation of the fi cation and fi ltering of the detector signals, followed camera in selected imaging applications related to cancer by processing electronics based on FPGA for the event diagnosis and research. reconstruction;

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 133 • the design of a compact assembly of the complete Project number Anger Camera. The compactness of the assembly will LSHC-CT-2006-037737 allow ease of positioning of the instrument close to the patient’s body surface; EC contribution • the realisation of image-reconstruction algorithms and € 1 715 000 user interface software running on a common personal computer. Duration 36 months

Expected results Starting date 01/03/2007 • Development of large-areas low-noise Silicon Drift Detectors. Instrument • Development of high-resolution collimators. STREP – SME • Development of a high-resolution and compact Anger Camera based on state-of-the-art technologies. Project website • Improved diagnostic capabilities thanks to the use of the www.hi-cam.org camera.

Potential applications

• Improved possibility to implement an eff ective therapy with higher capability to detect as small as possible con- centrations of tumour cells. • Eff ective imaging on reduced volume of the biological tissues: less than 10 x 10 cm2 area of the planar view (in scintigraphic investigations with one single imaging head); less than 10 cm total extent on the coronal plane Principle scheme of the Anger camera based on Silicon Drift Detectors technology of the patient’s body being imaged by the acquired developed in HICAM. scans (after appropriate rotation of the camera/s on the annular holder in the tomographic arrangement). Coordinator • Measurements on anatomical sites of the target which usually lead to severe space constraints during acquisition Carlo Fiorini Brian Hutton of the scan. Politecnico di Milano University College London • Improved use of imaging instrumentation in those con- Milano, Italy London, United Kingdom ditions where the patient’s age, condition or physical [email protected] [email protected] disabilities (e.g. patient on wheelchair) prevent an eff ec- tive use of large detector heads and gantries without Ugo Guerra compromising patient comfort. Partners Ospedali Riuniti di Bergamo • Brain tumours. Bergamo, Italy • Thyroid cancer, particularly diff erentiated carcinomas, Carla Finocchiaro [email protected] with 99mTc-perthecnetate. CF consulting Finanziamenti • Parathyroid cancer with 99mTc-sestamibi for preopera- Unione europea srl Ignasi Carrió tive localisation of parathyroid adenomas with the aim of Milano, Italy Institut de Recerca de l’Hospital de la Santa surgical planning in MIP interventions (minimally invasive [email protected] Creu i Sant Pau parathyroidectomy). Barcelona, Spain • Breast cancer with 99mTc-labelled lipophilic cations (Sesta- Leonardo Pepe [email protected] MIBI or tetrofosmin). The most promising application of L’ACN L’accessorio Nucleare S.R.L. the proposed system concern its use in preoperative or Cerro Maggiore, Milano, Italy Giovanni Lucignani postoperative sites. [email protected] Università degli Studi di Milano Milano, Italy In addition, the project off ers innovative approaches to the Lothar Strüder [email protected] diagnosis of tumours in infants and children. Max-Planck-Gesellschaft zur Foerderung der Wissenschaften eV Munich, Germany [email protected]

134 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Mammography | breast imaging | photon counting | tomosynthesis | contrast mammography | breast cancer | dual-energy |

HighReX detection through mammography screening. An early detection makes the subsequent therapy more successful High Resolution X-Ray Imaging for and also mitigates bi-eff ects and facilitates breast conserv- ing surgery in contrary to mastectomy. There is currently Improved Detection and Diagnosis scientifi c evidence for a decrease of mortality of between of Breast Cancer 30% and 40% in the screened population. Currently fi lm is the most common image receptor in mam- mography, but this is now being replaced by digital mammography. In mammography screening, 70-90% of the Summary cancers are detected. The undetected cancers are mainly in women with dense breasts where the contrast resolution of Breast cancer is currently the most common cause of death state-of-the-art equipment is limited by overlapping tissue. from cancer for women below 70 years of age, and currently Recent results from the so called ACRIN trial show that this over 100 million European women are screened every year challenge can to some extent be met with the advent of for early detection through mammography. The objective of digital mammography. The improvements are however the proposal is to increase the effi ciency in detection and modest and the problem remains. What makes the problem diagnosis of breast cancer and thus to decrease the mortality worse is that the risk of breast cancer is almost a factor of in breast cancer. three higher for women with dense breasts.

To achieve this we will develop novel imaging methods One way of solving the problem would be to increase the based on recent results in the research fi elds of nano-tech- radiation dose to increase contrast resolution. However, in nology, x-ray optics, detector technology and integrated dense breasts, this would also increase the noise caused by electronics. The new modality, which will be designed by overlying tissue. Moreover, the radiation dose in mammogra- leading European industries and SMEs in these areas, will phy is a growing concern, and increasing the radiation dose develop the only European detector platform for digital would mean an increased risk of radiation-induced cancers. mammography commercially available today into a leading This is particularly true for women below the age of 50 who, technology platform for tomorrow. The novel method will on average, have much denser breasts and who, because of provide signifi cantly increased contrast and spatial resolu- their age, are signifi cantly more radiation-sensitive compared tion, compared to current state-of-the-art breast imaging, to older women. Due to the limitations of the current tech- through elimination of noise from electronics as well as from nology, in many EU countries breast cancer screening is overlapping tissue and by way of utilising the signal more presently only off ered to women older than 50. effi ciently through fast single photon counting integrated circuits. Aim To make sure that the project targets the right issues in breast imaging, experienced mammography doctors from We propose to solve the current dilemma in mammography several European breast imaging centres are involved in the by increasing the image quality in terms of contrast and project and they will also test and evaluate the new imaging spatial resolution while lowering the radiation dose. This will system and compare it to current state-of-the-art mam- be achieved by using results from fundamental research in mography, as well as ultrasound and MR imaging of the nano-technology, x-ray optics and detector technology breast. The clinical trials will involve an enriched population obtained over the last few years. The only European detec- of symptomatic women and the potential impact on Euro- tor platform currently available commercially for digital pean screening for and diagnosis of breast cancer will be mammography will be drastically improved and developed estimated from the results. into a detector system for the next generation of breast imaging equipment. Problem Expected results The incidence of breast cancer currently increases in all Euro- pean countries: according to the European Breast Cancer An increase in breast cancer detection rate in screening of Network (EBCN), every year 50,000 women are diagnosed just 1% in Europe would mean that in the order of 500 oth- with breast cancer. Around 40% of these women will die from erwise undetected cases would be diagnosed annually, with the disease, making it the second most common cause of a potential of 100-300 lives saved. It may however be death for women between the ages of 20 and 70. The most expected that the increase in detection rate is signifi cantly effi cient weapon against breast cancer is currently early higher than 1%, maybe even exceeding 10%.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 135 Potential applications Project number LSHC-CT-2007-037642 We believe that the competitiveness of the European tech- nology platform will manifest itself more strongly in the EC contribution second generation of mammography and that the pro- € 3 635 200 posed project will be able to deliver a standard for 3D mammography that will be unsurpassed for quite some Duration time to come. There is also no reason why the photon- 36 months counting advantages in mammography should not be benefi cial as well in other imaging applications, such as CT Starting date and chest x-ray imaging. This project may provide the 01/03/2007 example needed for the technology to spread also to those areas. Instrument STREP – SME

Project website www.sectra.se/medical/ mammography/highrex

Coordinator

Mats Danielsson Walter Heindel Sectra Mamea Münster Universität Stockholm, Sweden Münster, Germany [email protected] Ulrich Bick Charité Universitätsmedizin Berlin Partners Humboldt University Berlin, Germany Mikko Juntunen Detection Technology Brigitte Séradour Li, Finland Association pour la Recherche et le Dépistage des Cancers du Sein Edvard Kälvesten Marseille, France Silex Microsystems AB Järfälla, Sweden Nico Karssemeijer Radboud University Roeland van der Burght Nijmegen, The Netherlands Artinis Zetten, The Netherlands Ruben van Engen Stichting Landelijk Referentie Centrum Matthew Wallis voor Bevolkingsonderzoek Addenbrooke’s Hospital Nijmegen, The Netherlands University of Cambridge Cambridge, United Kingdom Karin Leifland Capio Diagnostics Radiology Sweden Kenneth Young Stockholm, Sweden Vision of clinical application for breast cancer detection with 3D photon counting tomosynthesis Royal Surrey County based on research in the Highrex project. Hospital NHS Trust Ulf Strand Guildford, United Kingdom Avalon Product Development Helsingborg, Sweden

136 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Colon cancer | breast cancer | migrating cancer stem cells | mouse models | beta catenin | miRNA | kinome | phosphatome | single-cell analysis | epigenetics |

MCSCs Problem

Migrating cancer stem cells (MCSCs) • Which signal transduction pathways underlie the onset of CSCs? in breast and colon cancer • Which additional genetic and epigenetic factors modulate their invasive behaviour? • How does the tumour micro-environment, and therefore the cancer patient’s genetic background, aff ect the Summary capacity of MCSCs to successfully invade and metastatise distant sites thus determining good vs. poor prognosis? Carcinomas of the colon-rectum and breast represent among the most prevalent malignancies in the western world. A stepwise accumulation of genetic alterations in Aim oncogenes and tumour suppressor genes is considered as the driving force behind tumour initiation, progression and • To prospectively isolate and characterise intestinal and metastasis. mammary cancer stem cells. • To elucidate the mechanisms underlying the aberrant However, although formally correct, this model does not behaviour of cancer stem cells during tumour initiation take into account other essential characteristics of human and progression to malignancy. cancers, i.e. tumour heterogeneity and the role played by a subpopulation of tumour cells, the cancer stem cells (CSCs), in determining local invasion into surrounding tis- Expected results sues and distant metastasis. Tumours are not autonomously acting proliferation machines, but are very heterogeneous, • The isolation of intestinal and breast CSCs from both both in their morphological and functional aspects. In fact, experimental mouse models and cancer patients. an individual tumour shows distinct sub-areas of prolifera- • The establishment of expression, genomic and epigenetic tion, cell cycle arrest, epithelial diff erentiation, cell adhesion signatures for CSCs and their micro-environment. and dissemination. • The generation of new animal models for breast and colon cancer that closely reproduce the natural history According to this more dynamic model (see Figure), the of cancer stem cells and their progression towards majority of tumour types, and in particular breast and colon malignancy and metastasis. cancer, arise within stem cell niches characterised by • The development of diagnostic and prognostic tests a tightly coordinated balance between self-renewal, migra- based on the early detection of MCSCs and the predic- tion, proliferation, diff erentiation and apoptosis. The initial tion of metachronous metastases in breast and colon and rate-limiting mutation aff ects this balance and leads cancer patients by specifi c antibodies. to a relative increase in stem cells without drastically com- promising their diff erentiation capacity. This imbalance eventually leads to the formation of a partially diff erentiat- ed and heterogeneous tumour mass that, in response to additional somatic mutations and micro-environmental fac- tors, progresses towards malignancy. Tumour cells are shed from this heterogeneous mass into the micro-environment. However, they will refl ect the heterogeneity of the primary tumour, and only few will retain the necessary plasticity to undergo trans-diff erentiation and enable homing and metastasis in distal organs.

This ‘Migrating Cancer Stem Cells’ (MCSCs) model is cen- tral to our proposal and experimental plans. Our MCSCs consortium has been designed and assembled to address these issues by exploiting the unique expertise, experimen- tal models and collections of human cancer samples of the diff erent participants, in order to develop tailor-made diag- nostic and therapeutic strategies for breast and colorectal cancer patients.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 137 Project number LSHC-CT-2006-037297

EC contribution € 2 169 569

Duration 36 months

Starting date 01/11/2006

Instrument STREP

Project website www.mcscs.eu

Tumor initiation, progression to malignancy, and metastasis: the ‘cancer stem cell’ view.

Coordinator Partners

Riccardo Fodde Alberto Bardelli Erasmus MC/JNI University of Torino Dept. of Pathology Torino, Italy Rotterdam, The Netherlands [email protected] Thomas Brabletz University of Freiburg Freiburg, Germany

Manel Esteller CNIO Madrid, Spain

Christoph Klein University of Regensburg Regensburg, Germany

138 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | HNPCC | familial gastric cancer | mismatch repair |

MMR-related cancer Project number Prevention, Detection and Molecular LSHC-CT-2005-018754 EC contribution Characterisation of Mismatch € 2 620 200

Repair-Related Hereditary Cancers Duration of the Digestive System 36 months Starting date 01/02/2006

Summary Instrument STREP This project focuses on hereditary cancers of the digestive system associated with microsatellite instability, hereditary Project website non-polyposis colorectal cancer (HNPCC) and familial gastric www.rug.nl/umcg/ cancer (FGC). onderzoek/internationale Microsatellite instability is the result of a defective mismatch projecten/europese repair (MMR) system. Germline mutations in MMR genes are projecten/mmr/index found in families with HNPCC characterised by development of colorectal cancer and extracolonic malignancies, particu- larly cancer of the endometrium. Evidence is accumulating that also a subset of FGC is MMR- related as families have been identifi ed with tumours showing Expected results microsatellite instability. MMR gene mutations have not yet been identifi ed in these families. Our proposal will thus improve genetic testing, improve early detection of polyps/tumours in individuals at risk for these cancer syndromes and improve clinical management of Problem HNPCC and FGC patients.

In HNPCC, identifi cation of MMR gene mutations has helped in identifying individuals at risk when a clear pathogenic Potential applications mutation was found. The assays and the data generated will be set up and used Many families, however, in particular those with less pene- in diagnostic laboratories and by clinical geneticists all over trant HNPCC, remain genetically unresolved. Furthermore, Europe and the world. in a large proportion of families, mutations are identifi ed whose pathogenic nature is uncertain (unclassifi ed vari- ants). Although we have made great progress in the genetic delineation of this cancer syndrome, it has scarcely improved early diagnosis or treatment of cancer. Coordinator

Robert M.W. Hofstra Lene Juel Rasmussen Aim University Medical Roskilde University Center Groningen Roskilde, Denmark The objectives are to improve genetic testing by: Dept. of Medical Genetics • determining the role known MMR genes play in both can- Groningen, The Netherlands Niels de Wind cer syndromes and identifying new HNPCC or FGC-related [email protected] Leiden University Medical Center genes; Leiden, The Netherlands • setting up comprehensive functional assays to determine the role of unclassifi ed variants in MMR related genes; Partners Raquel Seruca • identifying tumour cells at very early stages in faeces by University of Porto, Institute of Molecular enhancing the sensitivity of MSI determination; Lauri A. Aaltonen Pathology and Immunology • profi ling mutations accumulating in tumours as a conse- Haartman Institute Cancer Genetics Group quence of MMR defi ciency, in order to get a better insight Helsinki, Finland Porto, Portugal in tumour development, which can be instrumental in clinical management/tumour treatment.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 139 Keywords | Pancreatic cancer | molecular diagnostics | molecular imaging | early diagnosis | PanINs |

MolDiag-Paca Expected results

Novel Molecular Diagnostic Tools These approaches will be developed based on large-scale transcriptome, genome and proteome analyses that have for the Prevention and Diagnosis been performed by members of the consortium in recent years in two subsequent EUfunded concerted actions. of Pancreatic Cancer Within these concerted actions, the relevant protocols and processes were optimised and adjusted between the partners and common standards, as well as establishing a network of clinicians, clinical research and basic research Problem groups. From this basis, novel molecular techniques will be developed for the detection of cancer cells or preneo- Pancreatic cancer, molecular diagnostics, molecular imaging, plastic cells in minimal amounts of clinical tissue (fi ne early diagnosis, PanINs Problem Pancreatic cancer has a dis- needle biopsies) or fl uid (pancreatic/duodenal juice or mal prognosis due to the late presentation of the tumours serum) samples. and the absence of satisfactory therapeutic options for advanced disease. Surgical resection of early tumours or pre- neoplastic lesions represents the only curative approach. It is Potential applications currently diffi cult to identify early stages of the tumour and preneoplastic lesions and, once in an advanced stage, there Novel tools will include transcript and epigenetic analyses, are no diagnostic means for a risk stratifi cation of patients chip technology, single or multiple marker protein studies, concerning prognosis or responsiveness to therapy. DNA/RNA PCR analyses, serum proteomics and molecular imaging. The project will use clinical samples such as serum, urine, fi ne needle aspirates and surgically resected materials Aim of pancreatic cancer patients collected in large multination- al European trials such as ESPAC and EUROPAC. During the Here we propose an integrated project joining leading last phase, prospective clinical trials of novel diagnostic groups in European pancreatic cancer research, SMEs and tools developed in the integrated project will be designed industry to develop novel molecular diagnostic approaches and started. for the prevention, early diagnosis and risk stratifi cation of pancreatic cancer.

140 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHB-CT-2006-018771 Thomas Gress Aldo Scarpa C. Bremer Philipps University Claudi Bassi University Hospital of Münster EC contribution Division of Gastroenterology University of Verona Dept. of Clinical Radiology € 8 500 000 and Endocrinology Dept. of Pathology Münster, Germany Dept. of Internal Medicine Verona, Italy [email protected] Duration Marburg, Germany [email protected] 36 months [email protected] Eckhardt Neuhaus Stephan Hahn Advalytix AG Starting date University of Bochum, Medical Faculty Brunnthal, German 01/08/2006 Partners Zentrum für Klinische Forschung [email protected] Molecular-GI-Oncology Instrument Sven Reske Bochum, Germany Taavi Einaste IP University of Ulm [email protected] Asper Biotech Medical Faculty, Abteilung Nuklearmedizin Tartu, Estonia Project website Ulm, Germany Hans-Dieter Pohlenz [email protected] www.moldiagpaca.eu [email protected] Schering AG Berlin, Germany Johan Permert John Neoptolemos [email protected] Karolinska University Hospital Royal Liverpool University Hospital Dept. for Clinical Sciences Division of Surgery and Oncology Ian Fleming Intervention and Technology Liverpool, United Kingdom Cyclacel Ltd Stockholm, Sweden [email protected] Dundee, United Kingdom [email protected] [email protected] Nicholas Lemoine Jens Peter von Kries Institute of Cancer Helmut Friess Jörg Rademann Cancer Research UK Clinical Centre Barts Klinikum rechts der Isar Leibniz-Insitut für Molekulare and The London Queen Mary’s School of Technische Universität München Pharmakologie, FMP Medicine and Dentistry Munich, Germany Berlin, Germany London, United Kingdom [email protected] [email protected] [email protected] [email protected] G. Klöppel Jörg Hoheisel Universitätsklinikum Schleswig-Holstein Linda Sharp Deutsches Krebsforschungszentrum Institut für Pathologie National Cancer Registry Functional Genome Analysis Kiel, Germany Cork, Ireland Heidelberg, Germany [email protected] [email protected] [email protected] John Oultram Paco Real Tepnel Life Sciences plc Nuria Malats Manchester, United Kingdom Centro Nacional de [email protected] Investigaciones Oncológicas Madrid, Spain [email protected] [email protected]

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 141 Keywords | Cancer | cancer screening | capsule endoscopy | biosensing |

NEMO The acceptability of capsule endoscopy, which is pain free, requires no sedation and does not necessarily entail a hospi- Nano based capsule-Endoscopy with tal visit, is attractive for patients. It is likely that they would fi nd such a screening method much more acceptable than Molecular Imaging and Optical biopsy screening colonoscopy for example.

It would be very helpful if capsule endoscopic video imaging could be combined with more sensitive and specifi c methods Summary for detection of early cancer to avoid the need for biopsy.

Gastrointestinal (GI) malignancy imposes a signifi cant impact on the well-being of the European members. Age- Aim ing of the population means that death rate will continue to rise. A report of the IARC (France) indicates insuffi cient The aim of the NEMO project is to develop a new advanced compliance to colorectal cancer prevention programs, due cancer screening method friendly enough to signifi cantly to the lack of a simple, patient friendly diagnosis method. increase compliance, simplify the diagnosis procedure and increase the sensitivity and specifi city of early detection. The objective of the NEMO project is to develop an advance The system will miniaturize and merge a variety of techno- cancer screening method friendly enough to signifi cantly logical platforms: Nanotechnology for targeting and marking increase compliance , simplify the diagnosis procedure and the precancerous tissue capsule endoscopy and capsule increase the sensitivity and specifi city of early detection. manoeuvring technologies to detect the marked disorder. The concept of the NEMO approach is to combine capsule By fusion of image with data of molecular analysis a new endoscopy with nano-based molecular recognition that will medical diagnostic tool may be formed. The use of specifi c highlights cancerous and precancerous lesions in the GI optical fi lters used in conjunction with light emitting diodes tract thus considerably increases the accuracy and ease of (LEDs) will be explored to make a miniature narrow band diagnosis. The system will merge few technological plat- imaging device which can be contained within a capsule forms: Nanotechnology for targeting and marking the endoscope. Narrow band imaging reduces the surface infected organ, Capsule Endoscopy to detect the marked refl ection of broad band illumination and can allow small or disorder, Capsule manoeuvring technologies to move the fl at precancerous lesions to be seen clearly when they are autonomous NEMO capsule backwards and forwards in the diffi cult to see with conventional illumination. The combina- gastrointestinal tract, as well as miniaturization and low tion of conventional and narrow band imaging may be able power technologies. to provide an overview of the gastrointestinal tract indicat- ing one of many sites of interest. It could be alternated with A major task of the project is to develop nanocontainers, conventional imaging. labelled with targeting agents and fi lled with dyeing mate- rial. The administered nanocontainers will be tailored to react with the target and mark the infected organ. Another Expected results task is to develop a capsule based on Narrow Band Imag- ing. This advanced capsule will provide both: visual images It is expected that the new Capsule Endoscopy screening of the GI tract and molecular characterization of the disor- method will provide information on the presence or absence der. Fusing image and molecular information together, of cancerous or precancerous situations with high sensitivity a new medical tool for early cancer detection with high and specifi city. We hope to develop a combination of minia- sensitivity and specifi city will be developed. ture spectral and Magnetic Resonance nanotechnology to create ‘virtual biopsy’ methods and incorporating these within the capsule endoscope. Problem It is also expected that the new autonomous NEMO capsule Earlier detection of cancer using screening methods is likely will be able to move backwards and forwards in the gastroin- to be the most practical way of addressing the epidemic of testinal tract, for example to re-examine a suspicious lesion. gastrointestinal cancers. Gastrointestinal cancers are detected mainly by gastroscopy or colonoscopy followed by biopsy. There is good evidence that such screening can fi nd early Potential applications cancers and that lives can be saved if such early cancers are discovered and removed. Many patients however are reluctant Conventional endoscopies are usually performed in hospitals; to have screening gastroscopies and colonoscopies because require trained doctors and a nursing staff for monitoring and of the discomfort of the procedures. Women especially are cleaning the equipment. Endoscopy generally requires insuf- reluctant to undergo screening colonoscopy. fl ations to expand the folds of tissue and enhance examination.

142 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME The procedure is usually associated with sedation because Project number it is painful or at least uncomfortable for the patient and LSHB-CT-2006-037362 requires time off work to recover from the anaesthesia. Anxiety about the discomfort of endoscopy, especially of EC contribution colonoscopy, greatly reduces the uptake by patients off ered € 2 832 020 this type of cancer screening. Duration The aim of the NEMO project is to develop a system off ering 36 months an improved clinical solution; Wireless capsule endoscopy is painless, does not need to be administered in hospital and Starting date does not require a team of nurses to clean the devices since 01/11/2006 it is disposable, nor does it require great skill to perform (although skill in interpretation of the images is needed). Instrument Thus it addresses the private clinics as well as institutions. STREP

The main applications will be to replace FOBT, colonoscopy Project website or gastroscopy as fi rst line screening methods. http://fcs.itc.it/NEMO/

The combination of wireless capsule endoscopy with advanced optical technologies is likely to make earlier detec- tion much easier and more eff ective than current fl exible endoscopic technologies.

Moreover, combining its capability to analyze secretions with the localization, the solution off ers Pancreatic and liver cancer detection as a by-product of stomach screening.

Coordinator

Elisha Rabinovitz Meike Reimann-Zawadzki Paul Swain Given Imaging Ltd. Fraunhofer-Gesellschaft zur Foerderung Imperial College of Science, Technology Yoqneam, Israel der Angewandten Forschung e.V. (FhG) and Medicine [email protected] Institute for Biomedical Engineering (IBMT) Imperial College London Sulzbach, Germany London, United Kingdom [email protected] [email protected] Partners Alberto Lui Heinz Jochim List Ake Sivard Fondazione Bruno Kessler (Istituto Indivumed GmbH Zarlink Semiconductor AB Trentino di Cultura) Hamburg, Germany Jarfalla, Sweden Trento, Italy [email protected] [email protected] [email protected] Emil Katz Avraham Rubinstein Jutta Keller Novamed Ltd. The Hebrew University of Jerusalem Israelitisches Krankenhaus Jerusalem, Israel Jerusalem, Israel Hamburg, Germany [email protected] [email protected] [email protected] Elie Berdugo Ernst & Young (Israel) LTD. Tel Aviv, Israel [email protected]

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 143 Keywords | Ovarian cancer | molecular diagnosis | minimal disease | chemotherapy | gene expression | signature | proteomics | CGH | mutation | methylation | targeted therapy |

OVCAD Problem

Ovarian Cancer – Diagnosis of Diagnosis at advanced stages and a high mortality rate is the tragedy of ovarian cancer. After initial surgical therapy, a Silent Killer 25% of patients relapse within six months and 75% die with- in fi ve years, mainly due to resistance to chemotherapy. Available methods for the detection of recurrent disease lack both sensitivity and specifi city and usually miss minimal Summary disease as a fi rst sign of therapy resistance.

In Europe each year, 63 000 ovarian cancer cases are diag- nosed and 41 000 ovarian cancer patients die. Seventy-fi ve Aim per cent of patients are diagnosed at advanced stages due to an asymptomatic course and 75% of these patients die The aim of this project is to defi ne clinically useful molecu- within fi ve years. Treatment involves surgery followed by lar-orientated early detection of minimal residual disease chemotherapy. However, 25% of patients relapse within six (MRD) in ovarian cancer that can identify patients not months after initial treatment and there is doubt as to responding to the standard (state-of-theart) therapy at the whether these patients benefi t from this therapy at all. time of surgery. This will disburden the patients from the Recurrent disease is diagnosed by clinical evidences or by very toxic and ineffi cient standard chemotherapy and even- CA125 dynamics. But detection is limited due to a lack of tually lead to alternative therapy modalities, which can really sensitivity and specifi city, as is the case with primary bring benefi ts to this group of patients. ‘Signatures’ that sig- diagnosis. nal the presence of MRD will be investigated at various molecular levels (DNA, RNA and protein) and in a broad Currently, there is no method to detect minimal disease, the spectrum of biological materials (tumour tissue, disseminated fi rst indicator of therapy failure and a precursor of recur- tumour cells, sera, white blood cells, ascites) from ovarian rence, which inevitably leaves specifi c traces throughout cancer patients. the body. There is a strong need for molecular-oriented research to detect minimal disease in order to disburden Specifi cally, the project is aiming at: patients from an ineffi cient and toxic therapy. • development and/or validation of several molecular diagnostic methods to identify MRD in ovarian cancer patients; • defi nition of a new ‘diagnostic state-of-the-art’ by corre- lating the diagnostic results with the clinically-defi ned response of the patients to standard therapy, consisting of primary surgery, followed by standard platinum/Taxol- based chemotherapy; • early discovery and characterisation of MRD by molecular diagnostics leading to additional therapeutic interven- tions, ultimately improving patients’ prognosis and quality of life; • better understanding of the mechanisms that cause MRD and therapy failure; • identifi cation and evaluation of new potential therapy targets.

Ovarian carcinoma – immunohistochemical staining of L1on ovarian carcinoma and its metastases in adjacent organs (Source: J. Sehouli, Berlin; M. Fogel, Rehovot and P. Altevogt, Expected results Heidelberg). Defi nition of a diagnostic method consisting of one or sev- eral molecular tests for early detection of minimal disease as an early indicator of therapy failure.

Potential applications

Diagnostic molecular tests and immunotherapy.

144 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2005-018698

EC contribution € 4 259 625

Duration 36 months

Starting date 15/12/2005

Instrument STREP Immunohistochemical staining of disseminated tumour cells isolated from blood • Comparative genomic hybridisation to detect genomic loss and gain. Project website • GeneStiX Imager for analysis of gene methylation (Sources: G. Hager and R. Zeillinger, Vienna; C. Theillet, www.ovcad.org Montpellier; Biofocus GmbH, Recklinghausen).

Coordinator

Robert Zeillinger Mina Fogel Hans Dieplinger Medizinische Universität Wien Kaplan Medical Centre Vitateq Biotechnology GmbH Dept. of Obstetrics and Gynaecology Institute of Pathology Innsbruck, Austria Vienna, Austria Rehovot, Israel [email protected] Burkhard Brandt Lothar Prix Universitätsklinikum Andreas Schuetz Hamburg-Eppendorf Partners Biofocus GmbH Institute of Tumour Biology Recklinghausen, Germany Hamburg, Germany Jalid Sehouli Dominique Koensgen Charles Theillet Alexander Mustea Centre Régional de Lutte contre Charité le Cancer de Montpellier Universitätsmedizin Berlin Montpellier, France Berlin, Germany Viktoria Weber Ignace B. Vergote Centre for Biomedical Technology Toon van Gorp Danube University Krems Katholieke Universiteit Leuven Krems, Austria Leuven, Belgium Bernd Mayer Jean-Paul Borg Emergentec biodevelopment GmbH Anthony Gonçalves Vienna, Austria Institut Paoli-Calmettes Institut de Recherches sur Fritz Kury le Cancer de Marseille Labordiagnostika GmbH Marseille, France Vienna, Austria

Peter Altevogt Els Berns German Cancer Research Centre Erasmus Medical Center Heidelberg, Germany Rotterdam, The Netherlands

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 145 Keywords | Prostate cancer | markers | diagnosis | prognosis | serum | urine | proteomics | mass spectrometry |

P-MARK men in the USA. However, the value of screening for Pca has not been established yet and is currently the subject of Validation of recently developed investigation in the European Randomised Study of Screen- ing for Prostate Cancer (ERSPC). A major drawback of the diagnostic and prognostic standard diagnostic tools for Pca is the detection of small non-aggressive or non life-threatening cancers, leading to markers and identifi cation of novel over-diagnosis and over-treatment, as well as the detection of tumours that are too advanced to cure. Currently, there markersfor prostate cancer using are no serum or urine markers available for the prognosis of Pca at early disease stages apart from PSA. It is apparent European databases that improved diagnostic and prognostic serum or urine markers are required that can discriminate men with clinically irrelevant Pca, curable Pca, or life-threatening Pca. Summary Aim The current diagnostic markers for prostate cancer have a low specifi city and lead to over-diagnosis and over- For three years, P-Mark will search for improved diagnostic treatment due to the detection of small non-aggressive or and prognostic Pca markers by the identifi cation and evalua- non life-threatening cancers. In addition, there are currently tion of novel markers as well as the evaluation and validation no effi cient serum or urine markers available for the prog- of recently developed promising markers. Novel serum and nosis of this malignancy. The P-Mark project will address urine markers will be identifi ed in clinically well-defi ned bio- the growing need for improved diagnostic and prognostic materials using innovative mass spectrometry tools, and markers for prostate cancer. antibody-based immunoassays will be developed for these markers. The novel markers will be evaluated for their clinical importance using these assays. Recently developed, promis- Problem ing markers that prove their clinical value during the evaluation will be validated on a sample set derived from two European In Europe, prostate cancer (Pca) is the second most fre- screening studies (the ERSPC study and the ProtecT study). quent lethal malignancy in men. Yearly about 40 000 men Eventually, the markers arising from this project will be off ered die of Pca in the EU countries. There is a slow increase of to SMEs for commercialisation and to ongoing large European mortality and in addition, due to an ageing population, clinical studies for clinical implementation. a 50% increase in incidence is expected by 2020. So far, the only chance for cure is early detection and treatment by either surgery or radiotherapy. Diagnosis of Pca is made by Expected results ultrasound-guided transrectal biopsy of the prostate for his- tology. An increased level of the serum marker prostate • The establishment of a serum biorepository and a urine specifi c antigen (PSA) often signals the presence of pros- biorepository for the discovery, evaluation and valida- tate cancer and the need to perform such a biopsy. A major tion of diagnostic and prognostic Pca markers. disadvantage of this diagnostic marker is its low specifi city, • The discovery of novel Pca markers in human body fl uids resulting in a signifi cant amount of false biopsy indications. by innovative mass spectrometry tools. PSA is a normal excretion product of the prostate cells and • The establishment of the clinical utility of recently devel- is therefore not only found in the circulation of men with oped promising Pca markers, including PCA3DD3, bone prostate cancer but also of men with a normal prostate and morphogenetic protein-6 (BMP-6), osteoprotegerin men with benign prostatic hyperplasia, a phenomenon that (OPG), nicked PSA, human kallikrein 2 (hK2) and cyto- is associated with ageing. Nevertheless, PSA is the standard chrome P450 3A5*3 polymorphism (CYP3A5*3). marker for Pca diagnosis and has been demonstrated to be • The validation of Pca markers and identifi cation of risk eff ective in advancing the diagnosis by detecting Pca at groups in the general population in Europe. earlier stages. A growing number of men choose to be • The development of guidelines for cost-effi cient strate- screened for Pca by PSA analysis, even up to 60-70% of gies for Pca detection and therapy.

146 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Establishment of human serum, urine and tissue biorepositories (WP1) Project number LSHC-CT-2004-503011

EC contribution Discovery and evaluation of novel Evaluation of six recently € 3 480 764 Pca markers using innovative developed promising Pca masss pectrometry tools (WP2) markers (WP3) Duration 48 months

Validation and clinical Starting date implementation of Pca markers 01/11/2004 (WP4) Instrument STREP

Expected results: Project website • New validated prostate cancer markers • Novel prostate cancer markers ready for validation www.p-mark.org • Identifi ed risk groups in European population • Guidelines for prostate cancer detection and therapy Identifi cation risk groups (ERSPC) (WP5)

Potential applications Coordinator

P-Mark will evaluate the clinical value of recently developed Chris H. Bangma Ulf-Hakan Stenman promising Pca markers and of novel Pca markers. If a marker Dept. of Urology Dept. of Clinical Chemistry meets the defi ned P-Mark marker criteria (improved sensi- Erasmus MC Helsinki University tivity and specifi city over current markers for diagnosis or Rotterdam, The Netherlands Central Hospital prognosis; indicative for early detection, over-treatment, [email protected] Helsinki, Finland risk for progression or therapy resistance; clinically relevant target in relation to tumour biology; reliable and cost-effi - Kim S. Pettersson ciently determinable in non-invasively obtained specimens; Partners Dept. of Biotechnology stable component in specimen), it will be developed further University of Turku for the validation in a monocentre or multi-centre setting. Hans Lilige Turku, Finland In addition, the marker will be off ered to commercial enter- Dept. of Laboratory Medicine prises for commercialisation. Validation will lead to guidelines Division of Clinical Chemistry Rainer Bischoff for cost-effi cient strategies for detection and treatment as Wallenberg Laboratory, University Hospital Centre for Pharmacy, Analysis of well as recommendations for marker application, that have Malmö Biomacromolecules to be discussed in the public domain of related European Malmö, Sweden University of Groningen professional societies. Validated markers will be off ered to Groningen, The Netherlands the principal investigators of ongoing screening studies in Jack Schalken Europe for implementation in the study. Taken the duration Dept. of Experimental Urology Harri Takalo of P-Mark into consideration (three years), clinical marker University of Nijmegen Innotrac Diagnostics OY implementation will continue beyond this project. Nijmegen, The Netherlands Turku, Finland

Freddie Hamdy Olle Nilsson Dept. of Urology Fujirebio Diagnostics AB University of Sheffield Gödenborg, Sweden Sheffield, United Kingdom

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 147 Keywords | Lung cancer | point of care | quantum dots | UV light source | fl ash lamp | fl uorescence | immuno-diagnosis | multiparameter | blood separation | expert system | molecule coupling | luminescent tags |

POC4life (from Sweden and the UK) gathering around the initiators of the project (the SME CEZANNE, the University of Multiparametric quantum dot bioassay Strasbourg in France and the University of Potsdam in Germany) which have the skills to build a multiparametric for point of care diagnosis device, to develop immunoassays and to design an inter- pretation software.

Summary Aim

This project aims at improving the healthcare of patients Objective 1: Elaborate an innovative medical device: a unique by elaborating a unique POC diagnosis platform which will point of care diagnosis platform which will help specialists help specialists to deliver an earlier diagnosis and to to make earlier diagnosis and provide more appropriate decide for appropriate treatment. The goal is to provide treatments. the clinicians with multiparametric measurement of the main 4/5 essential markers and to support decision with Objective 2: Provide the best possible integration of parame- a software tool. This will be a cost-eff ective breakthrough ters by means of a consortium composed of public and private in the diagnosis market. partners such as research intensive SMEs and academic entities Europe-wide.

Problem Objective 3: Elaborate the new device for a specifi c applica- tion: the primary diagnosis of the diff erent types of lung Each year 377 000 new European citizens develop lung cancer. The project will then have a huge impact on health by cancer and 340 000 die from it. Studies show that early contributing to the fi ght against cancer and the development diagnosis and accurate cancer typing could save number of of gender dimension in research. lives. Laboratories nowadays have a wide panel of repro- ducible diagnostic tests at their disposal: these are mostly The objective of the project is to generalize this approach to routine tests realised in centralized laboratories. The needs combinations of immuno-assay measurements to deliver for early diagnosis, multiparametric analysis of results and a clear diagnosis of the disease or monitoring information. quick monitoring of disease progression or therapeutic sen- The generalization means fi rst that the diagnosis should be sitivity were progressively left aside, whereas they could be accessible to various types of medical practices (medical fulfi lled with using decentralised diagnostic tools, close to doctor to hospitals) and thus a low cost , easy to use ‘Point the patient. of Care’ (POC) device should be developed. However this should not be done to the detriment of quality and precision. Among the possible applications of this new concept, the A homogeneous technology known for high level precision partners have chosen to work on the primary diagnosis of can therefore be a judicious choice. Generalization means the histological types of lung cancer to help to give an also that various pathologies could be addressed: typically improved initial diagnosis and to eliminate the 15-20% prob- from 2 to 4 or 5 immuno-assays. We thus aim at allowing on lematic or late diagnosed cases. The study will pay special the POC device the simultaneous measurement of 4 to 5 care to women (lung cancer death rates for women have immuno-assays with one draw of patient sample (1 droplet). been still increasing in Europe since the 1990s and marker Finally generalization means universality of the measure- patterns may be diff erent). It will then have a huge impact ment technique and of the data reduction process. In this on health by contributing to the fi ght against cancer and the way, fl uorescent measurement based on FRET (Fluorescence development of gender dimension in research. For this pur- Resonance Energy Transfer) seems an excellent choice, since pose, the multidisciplinary project will involve academic it may be extended in the future to other diagnostics such as researchers (from Germany, Spain and France) and SMEs DNA analysis, coagulation, microbiology…

148 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Expected results Project number LSHB-CT-2007-037933 The project should reach the following challenging objectives: • develop a functional prototype of POC multi-parametric EC contribution measurement for immuno assays, based on Homogene- € 2 497 815 ous Time Resolved Fluorescence (HTRF), for which main characteristics are: equivalent to a A4 sheet of paper, Duration cost of less than 2 000 Euros, works with a sample drop- 36 months let deposited on a disposable reagent vessel containing dried reagents; Starting date • defi ne the panel of assays and how to combine them 02/01/2007 into a decision making software (to be developed). Instrument STREP Potential applications Project website Multiparametric diagnostics in the following fi elds: www.poc4life.eu • cancer; • prenatal diagnostics; • sepsis; • cardiac.

Coordinator

Emmanuel Bois Desmond Smith Klaus-Dieter Weltmann Cezanne SAS Edinburgh Instruments Eckhard Kindel Nîmes cedex 1, France Edinburgh, United Kingdom Institute Of Low Temperature [email protected] Plasma Physics Philippe Pieri Greifswald, Germany Centre National de la Partners Recherche Scientifique Rafael Molina Paris, France Hospital Clinic Barcelona Olle Nilsson Laboratory of Biochemistry Fujirebio Diagnostics (FDAB) Hans-Gerd Löhmannsröben Barcelona, Spain Göteborg, Sweden University Of Potsdam Institut für Chemie und Interdisziplinäres Petra Stieber Zentrum für Photonik Institute for Clinical Chemistry Potsdam – Golm, Germany University Hospital Munich-Grosshadern Munich, Germany Yves Caristan Commissariat à l’Énergie Atomique Grenoble, France

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 149 Keywords | Prostate cancer | micrometastasis | minimal residual disease | bioluminescence | multiphoton microscopy | nanotechnology | optoacoustic technology | detection | treatment | MegaFasL | human glandular kallikrein 2 |

PROMET Problem

Prostate cancer molecular-oriented Prostate cancer is one of the most common malignancies in men: in Europe approximately 40 000 men die of it each detection and treatment of minimal year. Due to the aging population, this number will increase signifi cantly to around 60 000 men by the year 2020. There- residual disease fore, prostate cancer is a major medical problem with which the European Community will be increasingly confronted in the forthcoming decades. There are a number of initiatives ongoing to reduce the mortality by detecting the disease Summary earlier, the so-called screening programmes.The clinical evaluation of the usefulness of prostate cancer screening is In the European Union, about 200 000 men are diagnosed being examined in the European randomised study of with prostate cancer every year and that number is likely to screening for prostate cancer and is expected to answer this increase due to a growing population at risk due to ageing. question sometime in 2006. Even though there is a signifi - Because of the progress made in the treatment of the primary cant stage migration in the patient population identifi ed tumour, mortality in cancer patients is increasingly linked to with this disease, mortality has still not dropped in Europe. metastatic disease, often hidden (micrometastasis or ‘mini- mal residual disease’) at the time of diagnosis/therapy of the This is primarily because when the tumour has locally primary tumour. Understanding the complex mechanisms of spread, no curative intervention is available. If the patients metastasis (circulating tumour cells – micrometastasis – are given the time to live, they will ultimately develop bone metastasis) at the molecular and physiological level is crucial metastatic disease that is unresponsive to the currently for the successful detection of minimal residual disease and available androgen ablation-based therapies. Bone metas- for evolving possible strategies for the prevention of their tases cause considerable morbidity characterised by severe development into overt metastasis. bone pain and high incidence of skeletal, neurological and haematopoietic complications (hypercalcaemia, fracture, In this project, we intend to elucidate the mechanisms and spinal cord compression and bone marrow aplasia). These, signature of minimal residual disease in prostate cancer and together with the chronic character of terminal CaP dis- develop novel therapeutic approaches to prevent the devel- ease, have a severe impact on the socio-economical costs opment of minimal residual disease to overt metastasis. for healthcare. In close collaboration of basic scientists with clinical research- ers, the pathways of minimal residual disease will be The objective of this project therefore meets directly with explored using functional genomics and expression profi l- one of the priorities of the life science health programme, ing as technology platforms, advanced experimental models namely to combat a major disease, in this case prostate can- of minimal residual disease using bioluminescence, multi- cer. Prostate cancer is rather unique in its clinical behaviour photon microscopy, nanotechnology and optoacoustic and its molecular genetic background. Relatively few con- technology for detection and treatment. Innovative imag- sistent mutations have been found, which do not occur in ing and therapeutic strategies developed by the industry other cancers, so many cases of indolent tumours are and selected for their potential to enhance detection and described. eradicate minimal residual disease will be tested in preclinical models for subsequent clinical evaluation. Aim The goal is to identify at least two signal transduction targets, to develop a diagnostic test for the detection of the presence Because of the progress made in the treatment of the pri- of minimal residual disease and to defi ne a novel therapeutic mary tumour by surgery or radiotherapy, mortality in strategy for the treatment of this disease in prostate cancer. cancer patients is increasingly linked to metastatic disease. Thus, earlier detection and diseasespecifi c treatment may Malignant tumours are known to be heterogeneous, and decrease morbidity and mortality, and ultimately have an subpopulations with diff erent invasive and metastatic impact on socio-economical costs. potential may alter their biological properties over time and under treatment due to genetic instability and epigenetic infl uences.

150 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME The primary tumour releases a large number of cells into the Potential applications blood stream. However, only a small minority (approx. 0.01%) of the tumour cells entering the blood are thought to be The innovative potential and impact on industry, the health capable of developing into metastatic deposits. The future system and the market lies in: ability to detect minimal residual disease early, to understand • the development of novel diagnostic methods for the the natural history of micrometastasis and, consequently, to detection of minimal residual disease; predict outcome, and ultimately to treat adequately will rely • the implementation of optoacoustics with the help of on investigational eff orts in a context as close as possible to nanoparticles for diagnosis and therapy; the clinical situation. For this a close interaction between • novel targeted therapeutic strategies for micrometastas- clinical experience and basic research, together with the es that take into account the particular knowledge about availability of human tumour tissue specimens from estab- specifi c biology of the disease gained from animal mod- lished tumour tissue banks and adequate experimental els that more closely mimic MRD (translational research); models are crucial to improve current treatment modalities • the optimisation of experimental imaging of living cells or even develop innovative therapeutic strategies. In this tar- by coupling multi-photon microscopy with quantum dot geted approach to combat minimal residual disease in nanoparticle cell tracking to study early pathophysiolog- prostate cancer, we will pursue various levels at which we ical pathways involved in MRD. This will complement attack the malignant process and validate these at a pheno- other methods used by the group, such as whole body typic and functional level. We will be developing novel animal bioluminescent imaging; means of detecting and treating minimal residual disease. • the development of a more sensitive bioluminescence- By integrating a variety of state of the art approaches, we based imaging system for the preclinical investigation of aim to: the biology of minimal residual disease and the in vivo • identify and validate at least two target genes for detec- evaluation of novel diagnostic and therapeutic methods. tion of minimal residual disease in prostate cancer; • develop an integral in vivo model of minimal residual disease allowing the study of the mechanisms and signatures; • evaluate the in vivo detection of minimal residual disease by means of nanoparticles and optoacoustics; • develop a therapeutic strategy for the treatment of mini- mal residual disease in prostate cancer.

Expected results

We expect to identify genes up- or down-regulated in mini- mal residual disease with a potential for use in diagnostics and therapeutic strategies. Furthermore, the expression pat- tern might increase our understanding of the mechanisms and reveal potential novel therapeutic targets. With this work we expect to provide a detection assay with the poten- tial for use in clinical practice based on blood, urine or bone marrow aspirate and evidence that optoacoustics can be applied in the clinical context.

Novel treatment strategies will be developed and we expect to validate at least one treatment strategy in the treatment of minimal residual disease (MRD) that can be applied in the clinical setting. Finally we expect to establish a confocal and deconvolution-based dorsal chamber metatarsal model for the study of homing and growth support of minimal residual disease. Further we intend to establish a dual wavelength bioluminescent imaging system for the simultaneous study of two indicators, enabling the evaluation of the interrelation between these.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 151 Project number LSHC-CT-2006-018858

EC contribution € 4 034 200

Duration 48 months

Starting date 01/04/2006

Instrument STREP Micrometastasis in the bone marrow. Project website www.fp6-promet.net Coordinator

George N. Thalmann Manfred Hennecke Dept. of Urology Berthold GmbH & Co. KG University of Bern Bad Wildbad, Germany Bern, Switzerland [email protected] Joel J. Niederhauser Fukuda Denshi Switzerland AG Basel, Switzerland Partners Petra Zalud Gabri van der Pluijm tp21 GmbH Leiden University Medical Center Saarbrücken, Germany Leiden, The Netherlands David Deperthes Freddie Hamdy Med Discovery S.A. University of Sheffield Crans-près-Céligny, Switzerland Sheffield, United Kingdom Walter Pyerin Marc Colombel Deutsches Krebsforschungszentrum Philippe Clézardin Heidelberg, Germany INSERM University of Lyon Lyon, France

152 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Ewing’s sarcoma | EWS/FLI1 | CD99 | insulin like growth factor | microarrays |

PROTHETS • in the current state of ESFT treatment there is a survival ‘plateau’ (around 60% for patients with localised disease Prognosis and therapeutic targets and 25% for highrisk groups) due to the lack of new drugs and toxicity that impedes more intense use of in the Ewing family of tumours existing drugs. The identifi cation of new targets for inno- vative therapeutic strategies is, therefore, strongly needed for this tumour. Progress is generally hampered by the rarity of the disease (in Europe about 400 cases/year) Summary implying a limited number of cases for eff ective research. Moreover, because ESFT is an orphan disease, no private The project through collaborative studies will defi ne prog- company will develop new therapeutic tools and take on nostic markers and new therapeutic targets in the Ewing’s the costs to conduct pre-clinical investigation. sarcoma family of tumours (ESFT) to provide rigorous sci- entifi c justifi cations for the development of clinical trials for this rare disease, which is mainly manifested in children. The Aim main objective of this project is to evaluate the prognostic relevance of selected markers (EWS/FLI-1, secondary genet- The project will defi ne prognostic markers and new thera- ic alterations, CD99, IGF-IR, NOVH, erbB-2 and TTF1) and peutic targets in the Ewing’s sarcoma family of tumours the eff ectiveness of therapeutic approaches targeting some (ESFT) through collaborative studies to provide rigorous of these molecules. Another major goal of the project is the scientifi c justifi cation for the development of new therapeu- construction of ESFT c-DNA microarrays and tissue arrays, tic strategies for this rare disease, which is manifested for which will be used for the analysis of diff erent histological the most part in children. Goals expected to be achieved: subtypes of ESFT, primary and metastatic tumours and poor • with respect to the problem of toxicity, the project, by and good responders to chemotherapy. This will lead to: identifying the clinical relevance of a number of markers, • the defi nition of forthcoming risk-adapted strategies and may allow the diff erentiation of patients in terms of risk targeted molecular treatments to be advantageously to recur. This will enable more aggressive treatments combined with established therapies; where these are justifi ed, and avoid toxicity in cases • improved quality of life and survival for ESFT patients; where such treatments may be known to be unneces- • prevention of risk in groups at risk. sary, with particularly signifi cant consequences for the quality of life of the patients; • successful treatment of therapy-resistant patients requires Problem new strategies. Indeed, there is a desperate need for new therapeutic approaches in ESFT. A thorough study of the The Ewing’s sarcoma family of tumours (ESFT) includes: pre-clinical eff ectiveness of new targeted therapeutic Ewing’s sarcoma; primitive neuroectodermal tumour; Askin’s strategies will be performed with the aim of the identifi ca- tumour; paravertebral small-cell tumour; atypical Ewing’s tion of the Achilles’ heel in this disease and the consequent sarcoma. ESFT represents a peculiar entity in oncology. development of a tailored biological therapy to be used in In spite of its absolute rarity (about 300-400 cases per year association with conventional chemotherapy; in Europe), ESFT is one of the most frequent solid neoplasm • by providing an organisational framework for collaboration in paediatric age groups. Due to this fact, its impact on the the project will also allow multi-centre collection and anal- health system is particularly important. The adoption of ysis of cases as well as suitable collaborative research to multimodal treatments with very aggressive chemothera- allow genetic studies for the screening of high-risk patients peutic regimens have signifi cantly improved the chance of and patients responding diff erently to chemotherapy. survival of ESFT non-metastatic patients, shifting the fi ve- year survival rates to around 60%. Despite these important clinical results, which are usually diffi cult to obtain in rare dis- Expected results eases, several problems related to histogenesis, prognosis and treatment response are still open. In particular: • The identifi cation of prognostic factors in ESFT as a basis • the histogenesis of ESFT is still uncertain and the normal for the defi nition of individual therapeutic regimens, counterpart of ESFT cells is still unknown; which would limit the incidence of acute side-eff ects and • the lack of prognostic factors obliges the use of non- long-term morbidity as well as the economic and social diff erentiated treatments for all patients, leading to over- consequences of intensive chemotherapy. treatment of those patients who could benefi t from less • The defi nition of patient selection criteria to be used as toxic therapies. The reduction of delayed side-eff ects is a basis for beginning a pivotal clinical trial. particularly important in this disease considering the young • The creation of new therapeutic bullets against ESFT. They age of the patient and their long life expectancy; will be available at the end of the project as new drugs for ESFT treatment, together with the required toxicological

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 153 and pharmaco-kinetics studies. This is an important point Project number because ESFT is an orphan disease and no private com- LSHC-CT-2004-503036 pany will develop new therapeutic tools and take on the costs of conducting pre-clinical investigation. EC contribution • New therapeutic strategies for oncologists to increase € 2 530 500 the survival rate of ESFT patients through the pre-clini- cal evaluation of new drugs and strategies based on an Duration immunological approach. 42 months • New clues in the diagnosis and the screening of high-risk groups through the creation of an extensive tissue bank Starting date and the genetic profi le analysis (cDNA microarray and 01/01/2005 tissue array analyses) of these samples. Instrument STREP Potential applications Project website Therefore the project, aiming to ameliorate treatment of www.prophets.org ESFT, will have an impact on child health. In particular, the main objective of this project is to develop patient-oriented strategies for Ewing’s sarcoma patients by: • integrating diff erent disciplines and advanced technolo- Coordinator gies to develop eff ective approaches or new tools for diagnosis, prognosis and treatment; Piero Picci Heinrich Kovar • elucidating the contribution of specifi c molecular and Dept. of Musculoskeletal Children’s Cancer Research Institute genetic factors to the histogenesis of the disease. Oncology I. F. Goidanich St. Anna Children’s Hospital Istituto Ortopedico Rizzoli Laboratory for Molecular Biology This work will unlock the potential of the individual studies Bologna, Italy Vienna, Austria carried out by each of the consortium partners, and it will [email protected] [email protected] defi ne targeted therapeutic strategies of practical value in clinical settings and the clinical relevance of a number of Bernard Perbal markers that will allow the diff erentiation of patients in terms Partners Université Paris 7 Denis-Diderot of risk of recurrence. It will also unlock the biological and Paris, France clinical information potential behind multi-centre data col- Alain Bernard [email protected] lection and genetic analysis of patients, bringing basic Institut National de la Santé knowledge to the application stage. Progress is generally et de la Recherche Médicale Claude Malvy hampered by the rarity of the disease, implying a limited Nice, France Centre National de la Recherche Scientifi que number of cases for eff ective research. The creation of a [email protected] Villejuif, France multi-centre tissue bank and data collection will help to [email protected] overcome a big obstacle. The application of new technology Frans Van Valen will be used to identify ESFT-related molecular mechanisms. Laboratory for Experimental Marina Gottik The gene expression profi le of ESFT will be analysed and Orthopaedic Research Belozersky Institute of new markers to be used for diagnostic, prognostic and ther- University Hospital of Münster Physico-Chemical Biology apeutic purposes will be identifi ed. Münster, Germany Moscow State University The project made eff orts in the integration of multi-disci- [email protected] Moscow, Russian Federation plinary research capacities across Europe. The consortium [email protected] includes pathologists, oncologists, immunologists, and Sakari Knuutila [email protected] molecular and cellular biologists. Moreover, PROTHETS lays University of Helsinki emphasis on collaboration with small and mediumsized Haartman Institute Sergio Comuzio enterprises (SMEs), devoted to the development of specifi c Dept. of Medical Genetics Tecnogenetics srl tools for prognostic and therapeutic applications. Helsinki, Finland Milan, Italy Finally, the development of evidence-based guidelines will [email protected] [email protected] ensure that the knowledge held and developed by and with- in the project will be distributed as widely as possible to Antonio Llombart-Bosch Agnès Leconte have the highest possible impact on the biomedical world. Dept. Medical School Mabgène S.A. Specifi ed actions of the project are devoted to dissemina- Hospital Clinico Universitario Ales, France tion activities to ameliorate harmonious relations between Valencia, Spain [email protected] cancer researchers and society, with particular regard to [email protected] patient associations.

154 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Neoplasm | stroma | angiogenesis | selective targeting | combination therapy | antibody | small molecules | oncofetal antigens | tumour neovasculature |

STROMA Aim

Selective targeting of angiogenesis In the past, our consortium has developed innovative anti- cancer imaging and therapeutic strategies, based on and of tumour stroma recombinant antibody fragments, which have moved from the bench to the clinic. With the STROMA project, we plan to strengthen and extend the leading position of our European network in research and in the pharmaceutical development Summary of ligand-based, targeted anticancer therapies, with a par- ticular emphasis on the targeting of tumour neo-vasculature Targeted delivery of therapeutic agents to the tumour and tumour stroma. microenvironment is a novel avenue for cancer treatment towards the development of more effi cacious and better- This project focuses on the: tolerated anticancer drugs. • identifi cation and validation of molecular targets which are selectively expressed in the stroma and in neo-vas- This project aims to identify new molecular targets which are cular sites of aggressive solid tumours. Endothelial cells selectively expressed in tumour stroma and in the neo- and stromal cells are genetically more stable than tumour vasculature of aggressive tumours and to develop new cells and can produce abundant markers, which are ideally therapeutic strategies based on high affi nity binding mole- suited for tumour targeting strategies; cules capable of selective localisation in tumour stroma • isolation of high-affi nity binding molecules (small organ- and/or vascular structures. An eff ort to move the most prom- ic compounds, antibodies), which are specifi c for markers ising product(s) generated within this Integrated Project into of angiogenesis and/or the tumour stroma, and are capable clinical trials is the ultimate scope of the project. of selective localisation in the tumour environment, after intravenous administration; Potential application is the pharmacological treatment of • development of therapeutic strategies, based on specif- solid neoplasms, maintaining or improving the present per- ic binding molecules capable of selective localisation centage of respondents, survival, disease-free interval, with around tumour vascular structures and/or in the tumour improved safety and a better quality of life. stroma; • dissemination of the research activities of the project. Problem Potential applications The majority of pharmacological approaches for the treat- ment of solid tumours suff ers from poor selectivity, thus We will consider the project as fully successful if at least one limiting dose escalation (i.e., the doses of drug which are molecule enters clinical development for pharmacological required to kill tumour cells cause unacceptable toxicities to treatment of solid neoplasms, maintaning or improving the normal tissues). The situation is made more dramatic by the present percentage of respondents’ survival, disease-free fact that the majority of anticancer drugs accumulate prefer- interval, with improved safety and better quality of life. entially in normal tissues rather than in neoplastic sites, due to the irregular vasculature and to the high interstitial pres- sure of solid tumours.

One avenue towards the development of more effi cacious and better tolerated anti-cancer drugs relies on the targeted delivery of therapeutic agents to the tumour environment, thus sparing normal tissues. This experimental strategy requires a range of diverse experimental techniques, for the identifi cation of targets, for the isolation of binding mole- cules, and for their conversion into imaging and therapeutic products. Our approach has the potential advantage that immunohistochemistry, imaging and biodistribution data provide information about the selectivity of the anticancer drugs at several stages of the drug development process, and allow a rational optimisation of the most promising lead compounds.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 155 Isolation of specifi c LIGANDS (antibodies-small molecules)

Evaluation of ligand as Characterization of the a THERAPEUTIC AGENT LIGAND/TARGET Project number

by itself LSHC-CT-2003-503233

Conversion of the ligand into EC contribution a THERAPEUTIC MOLECULE € 6 000 000 (conjugation with chemotherapy, citokines, Duration ADEPT) 52 months

Starting date 01/01/2004 PRECLINICAL EVALUATION of the new therapeutic entities Instrument IP

Project website Design of CLINICAL Flow chart, outlining the main expected results, leading from target identifi cation www.stromaproject.org PROTOCOLS to the development of novel anticancer therapeutics.

Coordinator

Raffaella Giavazzi Barbara Pedley Peter Vajkoczy Silvia Marsoni Istituto di Ricerche Farmacologiche University College London Ruprecht-Karls-Universität Heidelberg SENDO Foundation ‘Mario Negri’ London, United Kingdom Mannheim, Germany Milan, Italy Milano, Italy [email protected] [email protected] [email protected] [email protected] Luciano Zardi Hartwig Kosmehl Didi Jasmin Istituto Giannina Gaslini Helios Klinikum Erfurt GmbH European School of Haematology Partners Genova, Italy Erfurt, Germany Paris, France [email protected] [email protected] [email protected] Andreas Bikfalvi INSERM E 0113 Vincent Castronovo Ludger Dinkelborg Talence, France Université de Liège Radiopharmaceuticals Research [email protected] Liège, Belgium Schering AG [email protected] Berlin, Germany Roy Bicknell [email protected] Cancer Research UK Guus van Dongen Institute of Molecular Medicine VU University Medical Center Francisca Vitti University of Oxford Amsterdam, The Netherlands Philogen s.r.l. Oxford, United Kingdom [email protected] Siena, Italy [email protected] [email protected] Matteo Zanda Dario Neri Consiglio Nazionale delle Ricerche Pablo Umaña Department of Chemistry Milano, Italy GLYCART biotechnology AG and Applied Biosciences [email protected] Schlieren-Zurich, Switzerland Swiss Federal Institute [email protected] Zürich, Switzerland [email protected]

156 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Genomics | cancer metastasis | gene expression | RNA interference | cell-based assays |

TRANSFOG to be clarifi ed about the genetic lesions and alterations of cell signalling that lead to aberrant activation of invasive Translational and functional growth, cancer progression and metastasis. It should be also noted that, after completion of genome-sequencing projects onco-genomics: from cancer-oriented for many organisms, genes with an unknown function repre- sent over 70% of all genes. This suggests that current genomic screenings to new diagnostic comprehension of most biological and pathological processes is still very incomplete, particularly in the case of cancer pro- tools and improved cancer treatment gression, where systematic exploration of gene function is likely to yield a huge amount of information in the next few years. In this perspective, a crucial issue is the development of technologies for high-throughput functional analysis. Devel- Summary opment of large-scale functional screens focused on cancer progression will require a coordinated approach involving The TRANSFOG project aims at the systematic identifi ca- complementary competences and establishment of dedicated tion and functional characterisation of novel cancer genes facilities, for which TRANSFOG intends to provide an optimal with high potential diagnostic and therapeutic value in organisational and fi nancial framework. breast, colon and lung cancers. The TRANSFOG partners will bring together world recognised competences and resources to reach the following, integrated research Aim objectives: • identifi cation of novel candidate cancer genes through The fi ve key objectives of the TRANSFOG project are: cancer- oriented genomic screenings, using tumour tis- sues as well as cellular and animal models, to generate • Identifi cation of novel cancer-related genes of high clinical- a prioritised panel of genes involved in breast, colon and diagnostic potential, with a specifi c focus on progression lung cancer progression and metastasis; and metastasis of colon, breast and lung cancers. This • full-length cDNA collection of the identifi ed candidates, will be achieved mainly through extensive gene expres- and setup of systems for high-throughput in vitro and sion profi ling of tumour/metastasis samples and of in vivo gene delivery; cell-based models of cancer progression. To extend the • collection of retroviral expression plasmids encoding exploration range, diff erential proteomics and epigenet- small interfering RNAs, for systematic downregulation ic analysis are also planned. The foreseen outcome is of candidate genes; a ranked list of novel candidate cancer genes emerging • identifi cation of new molecular targets for cancer from integration of the screening results, which will therapy; undergo functional characterisation and/or diagnostic • proteomic analysis of signal transduction and protein- validation. protein interaction, focussed on the candidate cancer genes, which will allow better dissection of aberrant • Set-up of technologies for systematic cancer gene func- cancer signalling pathways; tional analysis and for identifi cation of new molecular • validation of the diagnostic potential of the identifi ed targets. Gene functional analysis will be enabled by cancer genes towards the clinical use of diagnostic assembling collections of full-length cDNAs and of short molecular signatures; interfering RNAs (siRNAs), subcloned in expression plas- • generation of a shared informatics platform for data mids to assess the consequences of gene gain- or handling and gene functional annotation. This will sig- loss-of-function in cell-based and preclinical models. nifi cantly increase European competitiveness, provide a huge structuring eff ect on the ERA in the fi eld of func- • Systematic exploration of oncogenic/antioncogenic sig- tional oncogenomics, and depict several new molecular nalling pathways, epigenetic regulatory mechanisms. targets for anticancer drug discovery and advanced Taking advantage of the FL-cDNA and siRNA collections cancer diagnosis. made available by the project, cellbased experimental systems to study protein-protein interaction, reporter gene expression and epigenetic modifi cations will be Problem exploited for systematic analysis of the candidate genes. This will result in datasets of protein-protein interaction, While extensive analysis over the last two decades led to transcriptional and epigenetic regulation allowing a com- a deep insight into the control of cell proliferation and survival, prehensive overview of the alterations in signalling and and their alterations during cancer onset, much still remains regulatory networks involved in cancer progression.

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 157 • Development of tools for diagnostic validation of molec- complex processes, as in vitro epithelial morphogenesis and ular signatures for cancers of high population impact, angiogenesis. The technologies for systematic gene func- namely of the colon, breast and lung. This will enable tional characterisation developed here will be useful for translation into clinical use of signatures obtained functional studies involving a variety of physiological and through the cancer-oriented genomic screenings per- pathological processes, and will be made available to the formed by the participating units. In particular, the scientifi c community in the frame of a collaborative research project is expected to defi ne and validate prognostic network. The bioinformatic networking endowed with the signatures associated with the tendency of the above- project will enable participating units to share tools for data mentioned cancers to give rise to metastasis. handling, database exploration and functional gene annota- tion. It will also facilitate integration of the present network • Establishment of a shared bioinformatic platform for with other EC-funded networks and with the European and functional oncogenomics data handling and standardi- global post-genomic community. sation. This will require a concerted eff ort towards codifi cation of the various biological assays according to specifi c functional features analysed by each assay, Potential applications using for example the Gene Ontology as a template (www.geneontology.org), and the sharing of analysis soft- A crucial issue in genomics is to develop enabling technol- ware and tools. Towards the same aim, a web-accessible ogies. TRANSFOG will tackle this issue by developing: platform based on the Distributed Annotation System • tools and standards for genomic data sharing, which will (www.biodas.org) will be implemented. allow the results of cancer-oriented genomic screenings carried out by the consortium to be merged or made available in databases, thus generating a prioritised list Expected results of candidate cancer genes; • plasmid collections carrying FL-cDNAs or siRNAs to achieve The project will go through three main phases: gainor loss-of-functions of the identifi ed candidates.

Phase I (year 1): Initial set-up of experimental procedures for Within a few years, competitive research will rely on the systematic cancer gene functional analysis and clinical vali- availability of genome-wide collections enabling systematic dation; establishment of standards and tools for HTP data gene gain- or lossof- function and protein-protein interac- sharing and mining. tion studies. Similarly, only high-throughput biochemical and biological assays will take full advantage of such collec- Phase II (years 2-3): Scaled-up, high-throughput gene func- tions, together with bioinformatic resources to handle and tional analysis and clinical diagnostic validation of new mine the data. A great advantage of a smaller collection cancer molecular signatures, and identifi cation of new focused on cancer gene discovery, like the one proposed molecular targets for innovative cancer therapy. here, is that it will enable functional analysis at a mid- throughput level, with a higher probability of success in the Phase III (year 4): Final collection of results, dissemination of timeframe of the project. The know-how developed in the technologies and deliverables to the European cancer process of generating and employing such a collection will research community and cancer hospitals. Exploitation of provide the basis for competitive, larger-scale studies to be the achieved results, mainly as new cancer diagnosis tools carried out later on at the European level. and the screening of new targets for cancer drug discovery. The willingness to understand and cure cancer will be the The TRANSFOG project will deliver a consistent and inte- driving force for generating functional genomic technolo- grated amount of functional data on genes of, as yet, gies specifi cally aimed at improving management of the unknown activity and biological role. In the process of reach- oncological patient. Indeed, a more precise evaluation of the ing this objective, the participating units will be enabled to tendency of a tumour to give rise to metastases will have set up truly post-genomic eff orts toward systematic gene a great social impact, particularly in helping reduce mortality functional characterisation. New technologies will be devel- and, at the same time, reducing overtreatment of patients oped that will allow exploration of gene regulatory networks, that would not require aggressive anticancer therapy, and protein- protein interactions and high-throughput cell-based promoting direct, early exploration of alternative therapeutic evaluation of basic biological functions, such as motility, strategies in patients with diagnostic signatures that predict growth, apoptosis, invasion, adhesion, polarisation and more poor prognosis.

158 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHC-CT-2004-503438 Guy Storme Marco A. Pierotti Anne Ridley GEIE-LINC (Groupement Européen d’Intérêt Fondazione Istituto FIRC di Oncologia King’s College EC contribution Économique – Liaison Network for Cancer) Molecolare London, United Kingdom € 6 000 000 Brussels, Belgium Milano, Italy [email protected] [email protected] Carl-Henrik Heldin Duration Ludwig Institute for Cancer Research 54 months Rolf Apweiler Uppsala, Sweden Scientifi c Coordinator European Molecular Biology Laboratory [email protected] Starting date Heidelberg, Germany 01/06/2004 Enzo Medico [email protected] Claudio Schneider The Oncogenomics Centre Consorzio Interuniversitario Biotecnologie Instrument Institute for Cancer Research and Treatment George Panayotou Trieste, Italy IP Candiolo (TO), Italy Biomedical Sciences Research Centre [email protected] [email protected] ‘Alexander Fleming’ Project website Vari, Greece Walter Birchmeier www.transfog.org [email protected] Max-Delbrück-Center for Molecular Partners Medicine Berlin Nancy Hynes Berlin, Germany Mariano Barbacid Novartis Forschungsstiftung, [email protected] Centro Nacional de Investigaciones Zweigniederlassung Friedrich Oncologicas Miescher Institute for Biomedical Research Yosef Yarden Madrid, Spain Basel, Switzerland Weizmann Institute of Science [email protected] [email protected] Rehovot, Israel [email protected] Annemarie Poustka Bernhard Sixt Deutsches Krebsforschungszentrum Agendia BV Michaela Renzulli Heidelberg, Germany Slotervaart Medical Center 9D, ALTA Ricerca e Sviluppo [email protected] Amsterdam, The Netherlands in Biotechnologie SRL [email protected] Sienna, Italy Rene Bernards [email protected] Nederlands Kankerinstituut/Antoni Stephan Geley van Leeuwenhoek University of Innsbruck Ziekenhuis Medical School Institute of Pathophysiology Amsterdam, The Netherlands Innsbruck, Austria [email protected] [email protected]

Johannes L. Bos Edvard Smith University Medical Center Utrecht Karolinska Institutet Utrecht, The Netherlands Stockholm, Sweden [email protected] [email protected]

EARLY DETECTION, DIAGNOSIS AND PROGNOSIS 159

Treatment

Two major problems when treating cancer patients are the enormous complexity of the disease (and side-eff ects such as cachexia) and small therapeutic window when using classical cytotoxic drug regimens, resulting in serious toxicity and a strong reduction in the quality of a patient’s life. Depending on the particular type of cancer from which a patient is suff ering, the standard treatments, comprise classical treatment such as surgery, chemotherapy, radiotherapy and combinations thereof. Innovative, so-called targeted therapies that aim specifi cally at cancer or the host’s stroma cells and the processes involved in their survival and metastasis to other parts of the body are urgently needed since most cancers – unfortunately – fi nd ways to resist the often aspecifi c treatment conditions and eventually kill the patient. For several cancers it has been convincingly demonstrated that patient sur- vival rates under such conditions can hardly be improved if at all. The 29 projects in this section address novel means of hitting cancer cells through collaborative research on new delivery and viral technology; by harnessing and optimising anti-cancer responses of the innate and adaptive immune system through the development of specifi c antibodies and vaccines that induce cell death or suppress critical signal transduction pathways that cancer cells need for survival and expansion, as demonstrated for the fi rst time by Gleevec in chronic myeloid leukemia; by dissecting molecular mechanisms in cancer cells that allow resistance to chemotherapy; by developing imaging probes and devices that allow routine visualisation of selective drugs hitting their targets in a clinical setting; by developing treatment biomarkers based on gene expression profi les, diff erential cellular or molecular information obtained from diff erent sources and by diff erent technologies; and fi nally, by clinically validating personalised medicine approaches based on large patient cohorts.

Jan van de Loo Keywords | Gene therapy | non-viral gene therapy | dermatology | biomedical engineering | electropermeabilisation | electroporation | DNA electrotransfer | antiangiogenesis | cancer treatment | new therapies | electric pulses | skin diseases | naked DNA | medical instrumentation |

ANGIOSKIN Problem

DNA Electrotransfer of Plasmids Non-viral gene transfer for the treatment of acquired or Coding for Antiangiogenic inherited skin diseases. Factors as a Proof of Principle Aim

of Non-Viral Gene Therapy for • To electrotransfer proprietary therapeutic antiangiogen- esis genes to cutaneous metastases in humans, using the Treatment of Skin Disease the procedures validated in the ESOPE project, to show its clinical effi cacy; non-invasive biophysical methods will be used to monitor the antiangiogenic eff ects. • To develop new specifi c electrodes for the treatment of Summary skin lesions. • To validate the electrodes (safety, effi cacy) on normal The Angioskin consortium wants to bring the proof of con- skin in animals, and analyse the eff ects of the electro- cept that therapeutic genes can be safely delivered to skin transfer of the antiangiogenetic factor on models of skin by DNA electrotransfer (electrogenetherapy) in order to disease related to excessive angiogenesis, using non- prevent or to treat acquired or inherited skin diseases. The invasive biophysical as well as histological methods to Angioskin proposal is based on the results of the Fifth follow changes in the vascularisation of the lesion. Framework Programme’s (FP5) Cliniporator project (the • Finally, to electrotransfer the therapeutic gene to analysis of the mechanisms of DNA electrotransfer and a benign lesion in humans as a proof of concept of the elaboration of a CE labelled pulse generator) and of the use of non-viral gene therapy to treat acquired or inherited FP5’s ESOPE project (the preparation of the standard oper- skin diseases. ating procedures of Electrogenetherapy, electrotransferring a reporter gene in humans), and on a gene coding for a po- tent human antiangiogenic factor. This factor specifi cally Expected results binds to the αvβ3 and α5β1 integrins involved in angiogenic processes. Electrodes, pulse generators, procedures, proof of concept of a new therapeutic approach, clinical validation of an antiangiogenic factor.

Potential applications

• Research • Biotechnologies • Medicine

162 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHB-CT-2005-512127 Lluis M. Mir Gilles Avenard UMR 8121 CNRS – IGR BioAlliance Pharma SA, EC contribution Villejuif, France Paris, France € 2 780 683 [email protected] [email protected] Duration Damijan Miklavcic 48 months Partners University of Ljubljana Ljubljana, Slovenia Starting date Ruggero Cadossi [email protected] 01/05/2005 IGEA S.r.l. Carpi (MO), Italy Lone Skov Instrument [email protected] Gentofte Hospital STREP Department of Dermatology Jean Rémi Garbay Hellerup, Denmark Project website Caroline Robert [email protected] www.cliniporator.com Institut Gustave-Roussy Villejuif, France [email protected] [email protected]

Véronique Préat Université Catholique de Louvain Unité de Pharmacie galénique Brussels, Belgium [email protected]

Julie Gehl Herlev Hospital Department of Oncology Herlev, Denmark [email protected]

Michael P. Schön University of Würzburg Würzburg, Germany [email protected]

TREATMENT 163 Keywords | Angiogenesis | cancer | ocular disease | arthritis | PlGF |

ANGIOSTOP conditions including ischemia, infl ammation and cancer therefore indicating that the ANGIOSTOP anti-angiogenic Novel Anti-angiogenic treatment strategy targeting PlGF could represent a safer and more for Cancer, Arthritis and Ocular eff ective approach. Neovascularization based on Inhibition Aim

of Placental Growth Factor (PlGF) ANGIOSTOP aims to elaborate a comprehensive approach to the accelerated development of new effi cacious and safer anti-angiogenic medicines that reduce the pathological blood vessel growth and can be used for the treatment of Summary major progressive disorders such as cancer, ocular neo- vascularization (as observed in diabetic retinopathy and ANGIOSTOP proposes an approach to develop a new, safer age-related macular degeneration) and arthritis. The overall and more eff ective anti-angiogenic medicine that reduces objective of ANGIOSTOP is to develop an anti-PlGF mono- the pathological blood vessel formation associated with clonal antibody. The roadmap comprises ‘translational solid tumor growth, ocular neovascularization (diabetic research’ to validate previous proof of concept studies in retinopathy and macular degeneration) and rheumatoid new therapeutically relevant small animal models, both in arthritis. The proposed drug target is Placental Growth terms of safety and effi cacy, to evaluate PlGF expression Factor (PlGF) and the candidate drug is a humanized neu- and its possible upregulation in cancer patients, and to tralizing monoclonal antibody. This drug target selection develop an industrial production process at the GMP level is based on recent basic research on the role of PlGF in for critical path development. pathological angiogenesis and ‘translational research’ that established proof of concept in experimental animal mod- We aim to perform extensive validation studies of our els. Using a lead candidate anti-PlGF antibody, it has been drug candidate to reduce the risk of failure as the drug demonstrated that inhibition of PlGF reduces solid tumour advances into clinical trials and to manufacture this prod- growth, inhibits ocular neovascularization and alleviates uct for clinical trials. The ultimate goal of ANGIOSTOP is arthritis symptoms. ANGIOSTOP will assure the develop- to develop an anti-PlGF monoclonal antibody for the safe ment of an anti-PlGF antibody that may constitute a new, and eff ective treatment of cancer, ocular disease and safer and effi cacious medicine for the treatment of diseases arthritis. The research will focus on a selected drug candi- that depend on PlGF driven angiogenesis such as cancer, date but the new models and strategies will be of more ocular disease and arthritis. general utility for the development of new medicines aimed at increasing or reducing blood vessel formation as well as for the advancement of our understanding of Problem pathologic angiogenesis.

Most anti-angiogenic strategies are focused on blocking the interaction between VEGF and its receptor VEGFR-2. Expected results Despite the success of Avastin, it is unlikely that VEGF- inhibitors alone will be suffi cient to halt tumour angiogenesis. • A lead humanized anti-PlGF antibody will be validated in Firstly, an increasing number of studies document that appropriate animal models. blocking the VEGF pathway leads to the induction of alter- • Toxicology studies will identify a safe clinical dose and native angiogenic signals. Secondly, it has been reported document the cross-reactivity profi le and any toxic that treatment of cancer patients with Avastin signifi cantly eff ects of the lead candidate antibody. upregulates the levels of PlGF. Finally, the currently availa- • Process development and industrial GMP manufacturing of ble angiogenesis inhibitors have serious side eff ects thus the lead candidate antibody for critical path development mandating the development of additional angiogenesis will be carried out. inhibitors. Due to the potential application of angiogenesis • The protein expression of PlGF will be examined in patient inhibitors in disorders other than cancer, where the treat- tumour samples. If PlGF levels correlate with certain ment is expected to start at earlier times after the disease tumour types and associate with grade and prognosis, onset and continue for longer periods, safer anti-angiogenic such information may be benefi cial for identifi cation of drugs without the risk of serious side eff ects are needed. By appropriate patients groups. gene targeting study in mice, it has been shown that loss of • Development of a fully human back-up antibody with PlGF does not cause any vascular defect during develop- a similar or better pharmacological profi le as compared ment, reproduction or normal adult life, while it severely to the lead candidate antibody will be performed for impairs angiogenesis and arteriogenesis during pathological contingency purposes.

164 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Potential applications Project number LSHB-CT-2006-037386 ANGIOSTOP has both strategic and specifi c deliverables and milestones. The new animal models and acquired knowledge EC contribution on pathologic and therapeutic angiogenesis will transcend € 1 993 208 the specifi c aims of the drug development programs and be of strategic signifi cance for angiogenesis research in general. Duration The translational and critical path research program has 28 months a clearly defi ned ultimate deliverable: a new medicine based on PlGF-neutralizing antibody for anti-angiogenic treatment Starting date of certain solid tumours, ocular diseases and arthritis. 01/06/2006

Instrument SME-STREP

Coordinator

Titti Martinsson-Niskanen Christian Fischer BioInvent International AB Charité Universitaetsmedizin Berlin Lund, Sweden Berlin, Germany [email protected] [email protected]

Eric Van Cutsem Partners Katholieke Universiteit Leuven Leuven, Belgium Jean-Marie Stassen [email protected] ThromboGenics Ltd Leuven, Belgium Wen Jiang [email protected] Cardiff University Cardiff, United Kingdom Peter Carmeliet [email protected] Flanders Interuniversity Institute for Biotechnology VZW Leuven, Belgium [email protected]

ANGIOSTOP is exploring the therapeutic potential and pleiotropic mechanism of anti-PlGF, antibodies against placental growth factor (PlGF), a VEGF homologue, which regulates the angiogenic switch in disease but not in health. Anti-PlGF antibodies inhibit tumour growth by blocking angiogenesis. Distinct from VEGF inhibitors, however, targeting PlGF has been found to prevent infi ltration of angiogenic macrophages, and thus do not switch on the angiogenic rescue program responsible for resistance to VEGF inhibitors. This mechanism is illustrated with anti-PlGF (depicted in blue) preventing PlGF (green) binding to its receptor VEGFR-1+ (red) expressed on macrophages (orange).

TREATMENT 165 Keywords | Cancer | gene therapy | signalling | apoptosis | CD40 | phosphoinositide 3-kinase | metastasis |

Apotherapy Problem

CD40 ligand-based modalities for the Cancer has a major health, social and fi nancial impact on Europe and its people. Current treatments include primary treatment of cancer tumour resection and/or aggressive chemotherapy and radi- otherapy in order to achieve both local control and eff ective therapy for distant metastases. Despite improved therapeu- tic regimens, mortality rates are still high. Moreover, the Summary frequency of cancer incidence is predicted to increase and, as a result, its social and economic toll may reach even high- Cancer is a major disease according to the WHO Mortality er levels in the next decades. The growing cancer burden in Data base (2004) and is responsible for approximately 25% Europe underscores the need to develop more effi cient anti- of all deaths in the European Union. Epithelial tumours, such tumour agents with a view to increasing survival and as those of the ovary, lung and oesophagus, have particularly improving the quality of life of cancer suff erers. poor prognosis, with only a minority of patients achieving a fi ve-year survival. Conventional treatments, including chemotherapy and radiotherapy, have limited effi cacy and Aim frequently cause severe side-eff ects in patients. Apotherapy aims to combat cancer through an innovative The Apotherapy project brings together expertise from aca- combination strategy which targets cancer cells at multiple demic and biotechnology sectors across seven European levels. One arm of this strategy is to encourage carcinoma countries with the aim of developing and validating novel cell apoptosis and immune recognition through the optimal anti-cancer agents with a wide therapeutic index and mini- activation of the CD40 pathway and the other is to suppress mal side-eff ects. The focal point of our research is the tumour cell survival mediated by the PI3 kinase signaling utilisation of combined approaches which attack the tumour pathway. This strategy has been designed to achieve maxi- cell at multiple levels, achieving maximal apoptosis while mal inhibition of tumour growth while limiting the risk of limiting the risk of drug resistance. These approaches involve side-eff ects. the effi cient delivery of a pro-apoptotic molecule to cancer cells in combination with inhibitors of anti-apoptotic signal transduction pathways. Expected results

Specifi cally, the project will formulate therapeutic strategies • The Apotherapy project will provide new information which exploit the ability of CD40 ligand (CD40L), a TNF about targeting the CD40 and PI3 kinase pathways in family member, to reduce proliferation, promote apoptosis solid tumours. and activate anti-tumour immune responses selectively in • The project will develop and evaluate viral and non-viral cancer cells. Apotherapy will develop state-of-the-art vehi- vectors for the effi cient and tumour-specifi c delivery of cles for the effi cient delivery of CD40L to cancer cells, such anti-cancer agents in vivo. as CD40L-encapsulated liposome formulations and recom- • Apotherapy will characterise novel antagonists and inhib- binant adenoviruses expressing CD40L, and examine their itors of the anti-apoptotic PI3 kinase signalling pathway. in vitro and in vivo eff ects on tumour cell growth and • An extensive pre-clinical evaluation of CD40L delivery sys- metastasis. tems in combination with PI3 kinase pathway antagonists will be performed, aided by in vivo imaging technology. Apoptosis induced by CD40 engagement is dramatically augmented in the presence of inhibitors of the phosphoi- nositide 3-kinase (PI3 kinase) pathway, which is frequently Potential applications found activated in human tumours. The Apotherapy project will expand on the development of novel PI3 kinase antago- The Apotherapy project will lead to the development of novel nists and evaluate their in vitro and in vivo capacity to kill anti-cancer strategies which will be directly applicable to the tumour cells and to amplify the CD40L-mediated eff ects on clinic for the benefi t of cancer suff erers. The strong focus on carcinoma cell growth, angiogenesis and metastasis. translational research will translate R&D results into tangible benefi ts for health, science and economy in Europe.

166 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT 2006-037344

EC contribution € 1 895 900

Duration 36 months

Starting date 01/10/2006

Instrument STREP

Project website apotherapy.med.uoc.gr

Green-fl uorescence protein- expressing lung tumours in mice are visualised by in vivo imaging. This technology is used to monitor tumour growth following treatment with recombinant adenoviruses.

Coordinator

Aristides Eliopoulos Akseli Hemminki University of Crete Medical School University of Helsinki Heraklion,Greece Helsinki, Finland [email protected] Jiri Ehrmann Univerzita Palackeho v Olomouci Partners Olomouc, Czech Republic

Marco Falasca Angelica Loskog University College London Uppsala University London, United Kingdom Uppsala, Sweden

Massimo Broggini Steffen Panzner Istituto Mario Negri Novosom AG Milano, Italy Halle, Germany

TREATMENT 167 Keywords | Engineered T-cell | recombinant TCR | chimeric immune receptor (CIR) | safety | homing | persistence |

ATTACK include examining the mechanisms of action of the T-cells and improving their effi cacy; Adoptive engineered T-cell Targeting • enhance cytotoxicity, proliferation, survival, tumour homing or other features to increase anti-neoplastic to Activate Cancer Killing activity and safety of engineered T-cells for current and future applications in T-cell therapy trials (WP4); • improve protocols for T-cell selection, expansion and transduction (WP5); Summary • looking into safety of the improved T-cells in mouse models for future clinical trials in patients (WP6). Each year in the EU millions of people are diagnosed with cancer and there are over one million deaths from the dis- ease. Thus research into improved treatments is critical and Expected results immunotherapy research, focusing on the power of the immune system, is one important new approach to treat- The project started in November 2005 and so far a website ment. The ATTACK Project is based on the development of has been created for the dissemination of information within genetically engineered T cells to target cancer. The strate- a secure portal for the members of the ATTACK project and gies that produce engineered T cells employ the transfer of external pages for dissemination to the general public. tumour targeting receptors on the outside surface of the T cells using viral vectors to help the T cells to bypass the The next fi ve years will bring diff erent sets of results estab- mechanisms of immune controls triggered by the tumour. lished in tumour cell lines and in mouse models as well as Whilst the project addresses the scientifi c basis behind this a variety of genetic and molecular data testing performance technology it has clear clinical objectives for the future. and specifi city of the two engineered T-cell strategies.

• Animal models will give important clues on the funda- Problem mental mechanisms of action of the engineered T-cells and the immune response they trigger. Mouse models Cancer is an increasing problem within the EU, and as it is will allow comparison of relative effi cacy of T-cells redi- predominantly a disease of old age this will continue to rected with scFv and TCR specifi c for the same antigen. increase as the population ages. Despite signifi cant progress • Animal studies will also enable the testing of diff erent in the fi elds of early diagnosis and standard treatments protocols aimed at improving the engineered T-cell kill- including radiotherapy and chemotherapy, the outlook for ing function employing chemokines or cytokines that most metastatic cancers remains bleak. In view of this, novel can be applied to the clinic later. State-of-the-art imag- treatment approaches are being actively investigated. ing technology, like the dorsal skin fold window chamber, will be used to follow migration of the engineered T-cells in vivo and in real time experiments. Aim • The development and testing of various products from the commercial partners will defi ne unique protocols for ATTACK aims to improve engineered T-cell function and to the selection and expansion of engineered T-cells. perform pre-clinical studies which will underpin future clini- • Finally important safety data on auto-immunity, immune cal trials. With this in mind, ATTACK will also enhance the response against the diff erent parts of the receptor understanding of the mechanisms involved in tumour evasion introduced in engineered T-cells will be collected from of immune control. the in vivo experiments in order to gather pre-clinical data indispensable for future clinical trials. The overall objectives are broken down within six work • Read outs from these results will be in peer-review pub- packages (WP): lications, popular articles and other published material • optimisation of two receptor-based strategies to endow such as poster presentation at international meetings. the T-cells with tumour specifi city (WP1 and 2). The fi rst strategy is based in engineering T-cells to express recom- binant T-cell receptors complex (TCRα and β) recognising Potential applications MHC restricted antigens at the surface of the tumour cells (WP1). The other strategy is based on chimeric • Early phase clinical trials. immune receptors (CIR), which are scFv or small anti- • Promote and enhance discussions with national ethical body molecules linked to the TCRζ (WP2); bodies to understand and facilitate gene therapy trials • compare the in vivo effi cacy of the redirected T-cells in with further pre-clinical data arisen from the ATTACK physiologically relevant animal models (WP3). This will project.

168 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2005-018914

EC contribution € 11 981 087

Duration 60 months

TUMOR VASCULATURE: 10X TUMOR VASCULATURE: 10X Starting date 01/11/2005

Instrument IP

Project website www.attack-cancer.org

NON-TUMOR VASCULATURE: 20X NON-TUMOR VASCULATURE: 20X T cells engineered to recognise a melanoma antigen and expressing Green Fluorescent Protein. The engineered T cells accumulate in tumor vasculature but not in non-tumor vasculature after T cell transfer. Real-time images were taken immediately after T cell transfer using an intravital fl uorescence microscope. (R Debets, Erasmus MC).

Coordinator

Robert Hawkins Thomas Blankenstein Alberto Mantovani University of Manchester Max-Delbruck-Centrum für Molekulare Humanitas Mirasole SPA Manchester, United Kingdom Medizin Milan, Italy [email protected] Berlin, Germany John Campbell Hinrich Abken Miltenyi Biotec GmbH Partners Klinikum der Universität zu Köln Bergisch Gladbach, Germany Cologne, Germany Zelig Eshhar Katie Binley Weizmann Institute of Science Dorothy Crawford Oxford Biomedica PLC Rehovot, Israel University of Edinburgh Oxford, United Kingdom Edinburgh, United Kingdom Reno Debets Yoram Reiter Erasmus MC Daniel den Hoed Naomi Taylor Technion-Israel Institute of Technology Cancer Center Centre National de la Recherche Haifa, Israel Rotterdam, The Netherlands Scientifique Paris, France Balbino Alarcon Guy Gorochov Consejo Superior de Investigaciones Université Pierre et Marie Curie Janos Szollosi Cientificas Paris, France University of Debrecen Madrid, Spain Debrecen, Hungary Ton Schumacher Anna Mondiano Netherlands Cancer Institute Hans Stauss Fondazione Centro San Raffaele Amsterdam, The Netherlands University College of London del Monde Tabor London, United Kingdom Milan, Italy

TREATMENT 169 Keywords | Baculovirus | gene delivery | insect cells | vertebrate cells | adeno-associated virus (AAV) | prostate cancer | age-related macular degeneration (AMD) | muscular disorders (MD) |

BACULOGENES transfer applications and 2 major established gene therapy vector producing companies in EU. The consortium will Use of baculovirus as a vector devote its eff orts not only to BV gene therapy applications, but also to the development of large scale production, for gene therapy downstream processing, purifi cation and analysis meth- ods. The quality control and validation assays, and all issues related to regulatory aspects required for the clinical exploitation of BV technology will be covered. Summary

Gene therapy is a technique to deliver therapeutic nucleic Problem acids into somatic cells and is one of the most promising therapeutic methods under development for treating a large Validation of BV as a vector for gene therapy and AAV pro- scope of pathologies, ranging from genetic disorders duction implies meeting several challenges including solving (e.g. myopathies) to degeneration syndromes or cancers. production issues. In fact, the use of BVs to be used as new The potential of gene therapy is still not fully exploited effi cient and adapted vectors for gene therapy fully lies on mainly because of signifi cant limitations related to the safe- the demonstration of their ability to: ty, gene delivery capacities and some other properties of • carry large and/or multiple genes; the currently used vectors. Baculoviruses (BVs) are insect • exclusively target selected tissues; pathogenic DNA viruses and are not known to replicate in • deliver the therapeutic gene with a high effi ciency; mammalian cells giving them an advantage in terms of • generate an acceptable immunological and toxicological safety over classical mammalian viruses currently used as response; vectors such as adeno-associated virus (AAV), adenovirus, • show high stability; murine retroviruses and lentiviruses. The most promising • be able to be produced and purifi ed in large quantities. The baculovirus for gene therapy is the well known Autographa BACULOGENES project precisely addresses these issues. californica multiple nucleopolyhedrovirus (AcMNPV). It is inherently safe and can deliver large pieces of DNA on its genome (50 Kbp). BV replication and virus production Aim does not occur in mammalian cells and BV is not known to be associated with any human disease. However, by using The innovative strategy of BACULOGENES relies on the a vertebrate active expression cassette as a part of baculo- original engineering of BVs (AcMNPV) to make them safe, virus genome, effi cient gene expression can also be directed specifi c and effi cient vectors for gene therapy. BACULO- in non-target cells. A large range of vertebrate cells has been GENES approach consists in stabilizing the BV genome shown to be permissive for AcMNPV transduction in vitro through deletion and insertion of specifi c sequences in com- and in vivo. BV technology has been used for years for pro- bination with transgenes relevant to the disease targeted. ducing recombinant proteins and thus large scale production technology is readily adaptable for the exploitation of gene The ‘stabilized’ BVs will then be engineered to: therapy approaches. In addition, BV vectors can be used • enhance the capacity to deliver the therapeutic gene(s) effi ciently for producing other gene therapy vectors such as to the right cells; AAVs. The BV genome is well-known and several selective • optimize the therapeutic gene expression in the right targeting approaches engineered into the virus envelope cells; and capsid have been developed. The BACULOGENES project • make BVs less immunogenic and potentially invisible for aims to develop clinically suitable methods for the develop- the immune system (stealth virus). ment, production, testing and validation of next generation stabilised and selective BV vectors for gene therapy applica- Such improvements of the BV will be obtained through enve- tions as well as to optimize production of new AAV serotype lope protein, capsid and genome modifi cations. In parallel, vectors. Target diseases for in vivo gene delivery with selec- the baculovirus expression system will be optimized for the tively targeted BV include muscle disorders, age-related production of diff erent serotypes of AAV by using stabilized macular degeneration and prostate cancer. The BACULO- constructs. In addition, the development of baculovirus con- GENES consortium consists of 8 partners from 6 countries, structs allowing the production of recombinant AAV without including pioneers in the use of BVs for mammalian gene the concomitant production of baculovirus is planned.

170 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Expected results Project number LHSB-CT-2006-037541 The BACULOGENES project will strengthen the European leadership, knowledge and competitiveness in BV technology EC contribution through the delivery of novel and validated effi cient vectors € 2 499 746 and platform technology for the exploitation of potential clinical applications of gene therapy. This project will thus Duration pave the way for the BVs to clinical applications, which has 36 months never been experimented as of yet and will provide an opti- mized BV based AAV platform for gene therapy purposes. Starting date The project will also provide the biotech community with 01/01/2007 a highly effi cient manufacturing process and associated QC methods for BVs processing. Instrument STREP

Potential applications Project website under preparation Optimized production platform for next generation bacu- loviruses have wide applications in gene delivery, protein production and virus particle generation.

Coordinator Partners

David Kombi Nick Hunt ACIES SAS Altonabiotec Lyon, France Hamburg, Germany [email protected] Paula Alves Annsi Mähonen Instituto de Biologica Experimentale Ark Therapeutics Limited e Tecnololgica – IBET London, United Kingdom Oeiras, Portugal [email protected] Monique van Oers Laboratory of Virology Wageningen University Wageningen, The Netherlands

Kari Airenne University of Kuopio Kuopio, Finland

Lindsay Georgopoulos YCR Cancer Research Unit University of York York, United Kingdom

Otto-Wilhelm Merten Genethon Evry Cedex, France

TREATMENT 171 Keywords | Bioinformatics | pharmacology | grid technology | library design | in-silico prediction of drug-like properties | prediction of ADME parameters | predictive toxicology | creation of virtual libraries |

CancerGrid could dramatically increase the hit rate as well as open the way to identifying selective inhibitors/antagonists within the Grid-aided computer system for target families.

rapid anti-cancer drug design The idea of ‘focused libraries’ or ‘targeted libraries’ of mole- cules emerged in recent years as a ‘compromise’, or as an attempt to bridge between two seemingly confl icting approaches to drug discovery: Summary • high Throughput Screening (HTS), by which hundreds of thousands of compounds, mainly in big pharma, were In the three years of this multidisciplinary research project, tested against a (hopefully validated) biological target the 10-member Consortium plans to develop and refi ne such as a protein or a cellular system. The basic assump- methods for the enrichment of molecular libraries to facili- tion of HTS is that large numbers and diversity should tate discovery of potential anti-cancer agents. Using cover chemical space well enough to fi nd, at least, ‘hits’ grid-aided computer technology, the likelihood of fi nding (that are active in micromolar concentrations) which anti-cancer novel leads will substantially increase the trans- may subsequently be transformed to ‘leads’ (with affi ni- lation of basic knowledge to application stage. ties in the nanomolar range and with reasonable drug-like properties) and fi nally to drug candidates. Combinatorial In particular, through the interaction with novel technolo- chemistry has also been on the side of HTS, presenting gies and biology, the R&D consortium aims at: the ability to synthesise huge amounts of derivatives • developing focused libraries with a high content of anti- based on specifi c ‘scaff olds’; cancer leads; • rational drug design approaches such as structure-based • building models for prediction of disease-related cyto- design and ligand-based design. The fi rst takes into con- toxicity and of kinase/HDAC/MMP and other enzyme sideration the detailed atomic structure of the target and (i.e. HSP90) inhibition or receptor antagonism using the possibilities for forming physical interactions (i.e., HTS results; hydrogen bonds, Van der Waals interactions, electrostatic • developing a computer system based on grid technolo- complementarity, hydrophobicity, etc.) between small gy, which helps to accelerate and automate the in silico molecules and specifi c sites on the targets, while the sec- design of libraries for drug discovery processes, and ond depends more on properties of known active which is also suitable for future design of libraries for molecules and uses similarity ideas (including ‘pharma- drug discovery processes that have diff erent biological cophore’ searches) to discover new active molecules. The targets (the result is a new marketable technology). substantial reduction in discovering new chemical entities by big pharma in recent years has been in part attributed to the failures due to very low hit rate in both the HTS and Problem Combichem, on the one hand, and on the inability to properly taking into account the pharmacokinetic (ADME/ After the completion of the sequencing stage of the human Tox) eff ects as well as entropy, solvation and target fl exi- genome project, the major focus of discovery eff orts turned bility in structure- and ligand-based designs. to the identifi cation of the druggable portion of the genome that is linked to pathological states and is able to interact with A landmark in introducing pharmacokinetic considerations the drug-like chemical space, restoring normal functions. to drug design and development has been the ‘Rule of 5’ of Lipinski. This idea, which is now less than a decade old, also Apparently, the druggable genome is a subset of the 30 000 provided an immediate tool to reduce the size of combinato- genes in the human genome that express proteins and rep- rial libraries and of HTS candidates by ‘fi ltering’, i.e., requiring resent, in many ways, an unprecedented gift and exceptional that all molecules must pass the Lipinski rule (three out of opportunity for drug discovery scientists and for patients four conditions for the limiting of molecular weight, calcu- who are hoping for therapies of diseases currently uncured. lated lipophilicity, and the numbers of H-bond donors and That subset (estimated as ca. 3 000 proteins) is able to bind acceptors) in order to be in the proper bioavailability range. drug-like molecules as characterised by the Lipinski’s rule- of-5 criteria. The molecules that passed the Lipinski fi lter were thus tar- geted on oral bioavailability, and their numbers were much In order to fi nd more rapidly small molecule modulators to smaller than those for the initially planned experiments. The the newly emerging validated targets, the high-throughput idea of ‘fi lters’ thus gained momentum, and additional fi lters screening provides a reasonable solution to screen large such as those of Veber (limiting the number of rotatable compound libraries. However, it seems most of the targets bonds and the size of polar surface area), also for bioavilabil- can be classifi ed into large target families such as kinases ity, were suggested. Both Lipinski and Veber rules did not and GPCRs: thus, development of target focused libraries consider directly any conformational aspects (3-dimensional

172 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME descriptors of the molecules to be tested, but pharma- cophore searches (ligand-based design) and virtual docking and scoring (structure based design) serve as subsequent fi ltering processes in 3D that cover the ‘affi nity’ part of drug action, while the other fi lters mostly deal with ‘drug transport’ issues.

These two properties are, to a large extend, orthogonal. Thus, one may regard the fi ltering process as beginning with huge numbers of molecules, which are reduced to a smaller set by chemical descriptors. This smaller set may then be studied with more detailed conformations at the pharma- cophore level, reducing it further to a group of molecules which may be docked virtually to the assumed target, fi nally leaving a small set of substantially ‘focused’ or ‘targeted’ lead candidates.

But, even that approach suff ers from many drawbacks. Lipinski and Veber rules can not distinguish well between drugs and non-drugs, and are clearly not appropriate indi- Typical fold of matrix metalloproteinases structured in 3 α-helices (red) and 4 parallel cators of ‘drug-likeness’. Neural networks have been applied and 1 antiparallel β-sheets (yellow). The binding site is represented by a white surface while specifi cally to this problem and managed to distinguish the zinc ion is shown as a light-gray sphere and the three catalytic histidines are rendered properly between drugs and non-drugs, but have the disad- as ball-and-stick. vantage of ‘hidden layers’ which do not enable to plan and design novel molecules. Expected results A drug-like index has been suggested but is based on frag- ment identifi cation and therefore limited in its ability to Novelties and added values of the project: discover novel structures. Structure-based approaches can • virtual focused libraries of anti-cancer agents; consider small molecule fl exibility, but are still inappropriate • potential anti-cancer agents; for dealing with the fl exibility of the protein targets, espe- • HTS technology; cially with the fl exibility of backbone and of larger loops. • data for model building purposes; The scorings in docking methods have recently been • models able to predict anti-cancer properties; exposed to much criticism. Using single conformations in • CancerGrid System: a grid-based computer aided tool pharmacophore searches is clearly inappropriate, because it that able to provide anti-cancer candidates faster and in has been shown that small molecules bind to proteins in a more effi cient way, also suitable to develop candidates conformations that are higher in energy than their global for other targets. minima. Toxicity predictions have not yet reached enough reliability to prevent major toxicity threats by drugs. The need for selectivity has not yet been properly addressed in Potential applications the preparation of focused libraries. The models developed within the framework of this project Therefore, although many companies nowadays are off er- can be used for fi ltering large discovery libraries to fi nd ing focused libraries for kinases, GPCRs and other families anti-cancer drug candidates, and to design anti-cancer of molecules, there is a great need to improve the produc- focused libraries. The CancerGrid computer system will be tion of such libraries in order to shorten the time for able to support the design of lead compounds in general, discovery and to save enormous expense. A main stumbling not only in the anti-cancer fi eld, but in any other activity block on the way to solving such issues is the complex area. Thanks to its grid-based architecture, the system will combinatorial nature of the problem of library construction be able to predict molecular descriptors for compound and drug design. libraries, containing a large number of molecular structures, in a short time. When calculating 3D molecular descriptors, In this proposal, we include methods that deal directly with the system will take all major conformers into account. the combinatorial nature of the problems, that have been This enables the calculation of information-rich molecular shown to solve combinatorial problems in a highly satisfac- descriptors, and the development of reliable linear and non- tory manner, that discover the global minimum in most linear models. The system will also be able to apply these cases and retain a large set of best results, many of them models to predict the biological activity or chemical/physical excellent alternatives to the global minimum. property of the compounds.

TREATMENT 173 Project number LSHC-CT-2006-037559

EC contribution € 2 804 075

Duration 36 months

Starting date 01/01/2007

Grid Based IT Support for Drug Discovery. Instrument STREP – SME

Project website www.cancergrid.eu Coordinator

István Bágyi Amiram Goldblum AMRI Hungary University of Jerusalem Hungary research and development INC Jerusalem, Israel Budapest, Hungary istván.bá[email protected] Saverio Minucci DAC s.r.l. Milano, Italy Partners Angelo Carotti Mart Saarma University of Bari University of Helsinki Bari, Italy Helsinki, Finland Ferran Sanz Balazs Borsi University Pompeu Fabra GKI Economic Research Co Barcelona, Spain Budapest, Hungary Sándor Cseh Peter Kacsuk TargetEx Computer and Automation Budapest, Hungary Research Institute Hungarian Academy of Sciences Budapest, Hungary

174 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Therapeutic vaccine | immunomonitoring | DC | CTL | CD4 | Treg | melanoma | tumour escape | Ag processing |

CANCERIMMUNOTHERAPY Aim

Cancer immunology and The ultimate objective of this Integrated Project is to develop a therapeutic cancer vaccine with defined tumour antigens immunotherapy that would provide a clinical benefit in at least 40% of patients. This threshold of 40% of vaccinated patients showing an objective tumour response, in the absence of unacceptable toxicity, would definitely qualify immunotherapy as a stand- Summary ard cancer treatment. Further improvements could come from refining the vaccinations, and from combining tumour The first part of the project consists of clinical trials of vac- vaccines with other modalities of cancer treatment. cination, to compare various vaccines, such as peptides and RNA, with diff erent types of immunological adjuvants and dendritic cells. Safety and clinical efficacy will be the pri- Expected results mary endpoints of these trials. A large eff ort will be devoted to monitoring the anti-vaccine T-cell responses, as examin- We believe that the principal objective of our project is ing the correlation between immunological and clinical reachable, for the following reasons: responses to the vaccines will be crucial to understanding • the preliminary observation that vaccination with tumour which factor(s) limit tumour regression. A second part of antigens can be associated with tumour regressions, the project,tightly connected to the clinical trials as it uses and in a few cases with sustained remissions, is encour- biological material from the vaccinated patients, consists of aging, as it indicates that the vaccines tested so far have optimising tumour vaccines and combating immune eva- an anti-tumoural activity. Considering that vaccine- sion. Foreseeable mechanisms of tumour escape will be induced immune responses and tumour regressions analysed and correlated with the clinical results. Improved seem to be correlated, and that the immune responses modalities of vaccination will be tested and new target anti- that have been detected so far appear to be quantita- gens will be identified. All these results will help to design tively weak, it is reasonable to hypothesise that vaccines improved vaccines. Finally, considering the complexity of with a greater immunogenicity, such as those we plan to mechanisms that may lead to or prevent tumour regression investigate, will also have a greater clinical efficacy; in vaccinated patients, we propose to explore more funda- • our project will build a close interaction between the mental aspects of the anti-tumour immune response. This research laboratory and the clinic, which allows new ide- includes the cross-presentation of tumour antigens by den- as emerging from observations made in either of these dritic cells, recruitment of cells of the innate immune system, two fields to be integrated rapidly into new projects; involvement of suppressor T-cells, and development of • our consortium comprises groups with an excellent murine models of inducible tumours. If new concepts record in clinical trials, T-cell immunology, dendritic cell emerge from this work, they will also help in the design of biology, and mechanisms of tumour resistance. Many of better vaccines. these groups have a longstanding experience of collabo- rative programmes with each other, both in the laboratory and the clinical trial fields. Problem

Cancer is a major life-threatening disease and the second Potential applications greatest cause of mortality in Europe after cardio-vascular diseases. Classical cancer treatment still relies on surgery, Development and validation of surrogate end-points is chemotherapy and radiotherapy. Despite clear progress in a high priority in cancer vaccine research. The project will some cancer types, cancer therapy in general often fails to contribute to this goal by promoting standardised assays prevent disease progression to metastatic disease. In addi- and methods for the immunomonitoring of clinical trials. tion, these approaches are by themselves very toxic, In practice, validation of these surrogate markers may prove imposing a heavy burden of side eff ects on the patient. extremely useful for meaningful comparisons of various There is clearly a need for new therapeutic approaches that immunisation modalities and as markers of consistency for would be more efficient and less toxic. a given product.

TREATMENT 175 Project number LSHC-CT-2006-518234

EC contribution € 12 185 102

Duration 48 months

Starting date 01/03/2006

Instrument IP

Project website www.cancerimmuno therapy.eu

Cancer immunotherapy with defi ned tumor antigens: antigens that have been identifi ed as specifi cally expressed by the tumor cells are used in therapeutic vaccination trials to stimulate anti-tumor lymphocytes. Patients are monitored for signs of tumor regression and for the induction of anti-tumor immune responses.

Coordinator

Thierry Boon Vincenzo Cerundolo Cornelis Melief Kris Thielemans de Duve Institute University of Oxford Leiden University Medical Center Vrije Universiteit Brussel Brussels, Belgium Oxford, United Kingdom Leiden, The Netherlands Brussels, Belgium [email protected] Alexander Eggermont Chiara Castelli Hélène Sicard Erasmus MC Rotterdam Fondazione Istituto Natzionale Tumori Innate Pharma SA Partners Rotterdam, The Netherlands Milan, Italy Marseille, France

Hans-Georg Rammensee Carl Figdor Gerold Schuler Brigitte Dreno Eberhard-Karls-Universität Tübingen Stichting Katholieke Universiteit Friedrich Alexander Universität Centre Hospitalier Tübingen, Germany Nijmegen, The Netherlands Erlangen-Nürnberg Universitaire de Nantes Erlangen, Germany Nantes, France Sebastian Amigorena Federico Garrido Ludger Johanness Fundacion Virgen de las Nieves Thomas Wölfel Jochen Probst Institut Curie Granada, Spain Ugur Sahin CureVac the RNA people Paris, France Hansjoerg Schild Tübingen, Germany Günter Hämmerling Johannes Gutenberg-Universität Mainz Marc Bonneville Dirk Schadendorf Mainz, Germany Vincenzo Russo Anne-Marie Schmitt-Verhulst Bruno Kyewski Fondazione San Raffaele Institut Nationale de la Santé Deutsches Krebsforschungszentrum Eric Tartour del Monte Tabor et de la Recherche Médicale Heidelberg, Germany Université René Descartes Milan, Italy Paris, France Paris, France Ulrich Keilholz Pedro Romero Charité Universitatsmedizin Berlin Muriel Moser Ludwig Institute for Cancer Research Berlin, Germany Université Libre de Bruxelles Epalinges, Switzerland Brussels, Belgium

176 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Cancer chemotherapy | drug resistance | toxicity | lung cancer | melanoma |

CHEMORES resistance not been identifi ed, but also the development of clinically useful tools to predict response to chemotherapy Molecular mechanisms underlying has been largely unsuccessful. chemotherapy resistance, therapeutic The diff erent aspects of the chemoresistance problem are well illustrated in the two model tumours that will be studied. escape, effi cacy and toxicity The two main subtypes of lung cancer are small cell lung can- cer (SCLC) which is highly chemosensitive with response rates of 80% to chemotherapy; and non-small cell lung can- cer (NSCLC) that is moderately chemosensitive with response Summary rates of 30-60%. For all stages and types of lung cancer (NSCLC/SCLC), relapse after primary therapy is common, at The CHEMORES project aims to improve the outcome of which stage most patients have developed an acquired resist- cancer chemotherapy by developing novel tools to predict ance to chemotherapy and seldom respond to second line tumour response to treatment as well as individual toxicity treatment. In lung cancer, a therapeutic plateau has thus been to chemotherapy. The project will thus seek to identify and reached with existing cytotoxic drugs and further improve- validate mechanisms of intrinsic and acquired chemotherapy ments in survival are dependent on our understanding of the resistance, as well as predictors of effi cacy and of individual molecular mechanisms of chemoresistance. toxicity. There is no eff ective systemic therapy for metastatic This is achieved by integrating the work of groups conduct- melanoma and only a small minority of patients with ing large clinical trials with preclinical research groups, as melanoma respond to chemotherapy, which also has no dis- well as with state-of-the-art platforms for genomic and pro- cernible impact upon median overall survival. In the adjuvant teomic analyses and bioinformatics. The participants have setting interferon-alfa (IFN) is the only agent that has dem- chosen to focus on melanoma and lung cancer as model onstrated a consistent eff ect on relapse-free survival, but tumours of separate histogenetic types exhibiting intrinsic without a signifi cant impact on overall survival. We have as resistance and/or a high degree of acquired resistance to yet no tools to identify the patient population that benefi ts chemotherapy. from treatment with IFN. Thus, improved knowledge regard- ing mechanisms of resistance is needed in order both to Candidate mechanisms of drug resistance and therapeutic develop predictive tests and to modulate resistance and effi cacy will be identifi ed using genomic and proteomic thus improve the therapeutic outcome in melanoma. analyses of sequential tumour samples and paired sera obtained before and after chemotherapy, as well as experi- Cancer chemotherapy is frequently associated with severe mental systems, including in vitro studies of tumuor cell toxic side-eff ects. Novel tools to identify individuals with an lines, transplanted human tumours and novel animal tumour increased risk of developing severe side-eff ects are required models. These putative mechanisms will then be validated in order to avoid such adverse events. in further analyses of larger sets of tumour biopsies from patients. Functional studies of novel mechanisms and path- ways will be also performed using in vitro systems and Aim animal models. The result of these activities will thus be a set of clinically and functionally validated mechanisms of The overall aim of CHEMORES is to improve the outcome of chemotherapy resistance and therapeutic effi cacy. cancer chemotherapy by developing novel tools to predict tumour response to treatment as well as individual toxicity Likewise, large-scale genomic analyses of patients receiving to chemotherapy. chemotherapy as part of clinical trials will be performed, in order to validate novel markers of individual toxicity following chemotherapy. Expected results

The novel knowledge obtained through the project will lead Problem to new tools for prediction of treatment outcome as well as toxicity of chemotherapy. This knowledge may also be used Resistance to systemic chemotherapy still remains one of to identify and prepare for pre-clinical development of the greatest problems in clinical oncology, and contributes potential novel modulators of drug resistance based on vali- to the death of a large number of cancer patients. Despite dated mechanisms and pathways. The new information extensive eff orts, no signifi cant prog ress has been made in obtained in CHEMORES will be disseminated to the medical solving this fundamental problem during the last decades. profession and other key stakeholders, such as health care Not only have effi cient means to overcome chemotherapy providers, patient organisations and policy-makers.

TREATMENT 177 Potential applications Project number LSHC-CT-2006-037665 Predictive tests of response to chemotherapy may be used in medical oncology to select patients with an increased EC contribution likelihood to benefi t from therapy. The novel information € 8 710 300 on molecular mechanisms responsible for resistance to chemotherapy may lead to development of modulators of Duration resistance. Both these advances may in turn lead to improved 60 months results of cancer chemotherapy. The development of tools to predict severe drug toxicity will lead to safer cancer Starting date chemotherapy. 01/02/2007

Instrument IP Coordinator Project website Johan Hansson Joakim Lundeberg www.chemores.org Karolinska Institutet Kungliga Tekniska Högskolan Stockholm, Sweden Stockholm, Sweden [email protected] Joost van den Oord Katholieke Universiteit Leuven Partners Leuven, Belgium

Alan Spatz Stefano Fais Institut Gustave Roussy Istituto Superiore di Sanità Villejuif, France Roma, Italy

Guido Kroemer Manfred Schmitt Institut National de la Santé Technical University of Munich et de la Recherche Médicale München, Germany Paris, France Mark Middleton Mariano Barbacid University of Oxford Fundación Centro Nacional de Oxford, United Kingdom Investigaciones Oncológicas Carlos III Madrid, Spain Geoff Margison University of Manchester Alexander Eggermont Manchester, United Kingdom Erasmus Medical Centre Rotterdam Rotterdam, The Netherlands Anna Eidefors Magnetic Biosolutions AB Marco Pierotti Stockholm, Sweden Istituto Nazionale per lo Studio e la Cura dei Tumori Marie-Claire Beckers Milano, Italy Eurogentec SA Seraing, Belgium Piet Borst Netherlands Cancer Institute Alexandre Passioukov Amsterdam, The Netherlands European Organization for Research and Treatment of Cancer Curt Peterson Brussels, Belgium Linköping University Linköping, Sweden

178 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Children | cancer | leukaemia | T lymphocytes | chimaeric T-cell receptor |

CHILDHOPE Problem

Chimaeric T cells for the treatment Intensifi cation of post remission therapy and addition of autol- ogous or allogeneic haematopoietic stem cell transplantation of paediatric cancers (HSCT) have marginally improved outcome in children with relapsed leukaemia or lymphoma. Failure to induce prolonged remissions in a large portion of relapsed children, and the tox- icity of current regimens in this age category with unique Summary physiological parameters, has led to a resurgence of interest in immunotherapies. Leukaemias are the most common cancers aff ecting chil- dren while malignant lymphomas, including non-Hodgkin Administration of tumour-specifi c T cells (adoptive immu- lymphomas (NHL), come in third position after brain notherapy) has proven to be an eff ective cancer treatment: tumours. A signifi cant number of children with leukaemia/ allogeneic HSCT and donor-leukocyte infusion (DLI) can lymphomas still fail current therapies. induce lasting remissions in patients, including children, with a range of malignancies; and Epstein-Barr virus (EBV)- The aim of the CHILDHOPE project is to develop a safe specifi c T cells can cure patients with post-transplant and effi cient adoptive immunotherapy for children with lymphoproliferative disorder (PTLD). However, considerable advanced or refractory malignancies. CHILDHOPE particu- barriers hinder wider application of this promising form of larly focuses on three paediatric tumours: acute B-lineage immunotherapy. It is diffi cult and often impossible to select lymphoblastic leukaemia, non-Hodgkin B-lineage lymphoma and expand tumour-specifi c T cells or, in an allogeneic set- and acute myeloid leukaemia. ting, to separate T cells causing graft-versus-host disease (GVHD) from tumour-reactive ones. Further, tumour cells The CHILDHOPE project is a new approach in paediatric often lack infl ammatory cues and the appropriate environ- cancer treatment since it brings from bench to bedside ment to maintain a persistent immunological rejection. (and back) an innovative technology as yet never applied Absence of a specifi c means of destroying adoptively trans- in children with advanced or refractory haematopoietic ferred T cells in the face of unacceptable toxicity has also malignancies. stalled clinical studies.

The CHILDHOPE translational research project will focus on: Many of these barriers can be now overcome by ex vivo • improving and testing the effi cacy and the safety of genetic engineering of T cells using gene-transfer technol- anti-leukaemia/lymphoma chimaeric T cells in relevant ogy, thanks to pioneering work performed by us and others preclinical models in vitro and in vivo in mice; in the last decade. Initially cumbersome and impractical, this • scaling-up this technology to numbers suitable for technology has matured to the point of eff ective clinical a clinical application in children with haematopoietic application. However little is known about the homing and malignancies; function of the diff erent subsets of tumour-specifi c T cells • based on biological material obtained from our pre- once re-injected in patients. Dissecting the killing mecha- clinical models and from children treated with these nisms of these tumour-specifi c T cells – especially once they genetically engineered T cells, dissecting the interface have been administered in vivo in children – and elucidating between the host’s tumour and immune cells and using some of the reasons for their failure in certain patients will this knowledge to understand the mechanisms of anti- ultimately improve our knowledge of the host-tumour inter- tumour action, validate novel targets and diagnostic face and help design enhanced strategies using engineered tools specifi c to children aff ected with leukaemia or T cells against paediatric and adult cancers. lymphomas.

The CHILDHOPE project is built on the excellence of a net- Aim work of EU-based partners with a broad experience in the fi eld of paediatric haematology and oncology, immunology The CHILDHOPE project builds on the excellence of a net- and cell and gene therapies, and integrates the Internation- work of EU-based partners with broad experience in the al Confederation of parents of children with cancer and an fi eld of paediatric haematology and oncology, immunology SME specialised in project management. and cell and gene therapies. The CHILDHOPE project is unique since it brings from bench to bedside (and back) an innovative technology as yet never applied in children with advanced or refractory haematopoietic malignancies. The CHILDHOPE translational research project will focus on:

TREATMENT 179 • improving and testing effi cacy and the safety of anti- suicide gene system, will provide a safe albeit suffi ciently leukaemia/lymphoma chimaeric T cells in relevant pre- prolonged antileukaemia eff ect in vivo in children with clinical models in vitro and in vivo in mice; relapsed/refractory leukaemia/lymphoma. We anticipate • scaling-up this technology to numbers suitable for a clini- that the antileukaemia/lymphoma eff ects – and consequently cal application in children with haematopoietic malig- the survival of the treated patients – will increase with the nancies; chimaeric T-cell doses. • based on biological material obtained from our preclinical models and from children treated with these genetically In parallel, the CHILDHOPE project will provide preclinical engineered T cells, dissecting the interface between the data comparing the cytotoxic potency of diff erent T-cell host’s tumour and immune cells and using this knowledge subsets (EBV-CTLs, Cytokine Induced Killer T cells and chi- to understand the mechanisms of anti-tumour action, maeric g9d2 T cells) in an eff ort to identify the best immune validate novel targets and diagnostic tools specifi c to eff ector for future clinical application. children aff ected with leukaemias or lymphomas.

The fi nal aim is to develop a safe and effi cient adoptive Potential applications immunotherapy for children with advanced or refractory malignancies. CHILDHOPE particularly focuses on three No animal model can fully dissect the tremendous complex- paediatric tumours: acute B-lineage lymphoblastic leukae- ity of the interactions between a human tumour and its host. mia, non-Hodgkin B-lineage lymphoma and acute myeloid The CHILDHOPE project is the fi rst comprehensive attempt leukaemias. at administrating anti-tumour chimaeric T cells in children with haematopoietic malignancies. It represents a unique opportunity to address in vivo in a complete human environ- Expected results ment some of the most fundamental hypothesis in the fi eld of anti-tumour immunology. Our hypothesis is that target- The originality of the CHILDHOPE project is to exploit the ing CD19 or CD33 will not only kill target cells but will also immunostimulatory properties of EBV-CTLs and retarget contribute to the release of yet unknown tumour-associated them to leukaemia/lymphoma cells, which themselves lack antigens (TAAs), which in turn may generate further immune many of the costimulatory molecules needed to activate activation. This mechanism known as antigen spreading CTLs. Thus, our underlying general hypothesis is that expres- may be of particular interest in tumours known for their pro- sion of chimaeric antileukaemia/lymphoma receptors on pensity to induce antigen-loss variants. As these new TAAs EBV-specifi c CTLs will allow these cells to retain their known may be either leukaemia/lymphoma-associated or have safety and functionality in vivo (ability to expand and regress a broader scope of paediatric tumours, they may provide in response to antigen load, to persist as memory cells, and new targets for future immunotherapeutic approaches. to retain antiviral activity) in children with haematopoietic malignancies while adding safety, specifi city and eff ector While the CHILDHOPE project focuses at this stage on three function directed to the residual leukaemia cells. of the most frequent paediatric tumours (acute B-lineage lymphoblastic leukaemias, non-Hodgkin B-lineage lympho- This strategy seems highly feasible since EBV-specifi c CTL ma and acute myeloid leukaemias), our innovative technology lines have been generated and reinfused in numerous should pave the way for the generation of T lymphocytes patients using robust and clinically validated methodolo- with an antibody-dictated specifi city toward other tumour- gies developed by Brenner, one of our key scientifi c advisors associated antigen for which a monoclonal antibody exists. in the CHILDHOPE project. Unmodifi ed CD19 molecules This in turn should allow us to redirect immune eff ectors have been manufactured and incorporated into EBV-CTLs, towards other malignancies, including solid tumours, for and tested in vitro. Our pioneering project now proposes to which current therapeutic strategies are limited or have extend this approach against CD33+ malignancies, which failed. This includes – but is not limited to – metastatic dis- represent a signifi cant part of hard-to-treat paediatric leu- ease where T-cell therapies have had some success due to kaemias. Another major innovation is that we will investigate their capacity to migrate and infi ltrate distant tumour sites. modifi cations to the chimaeric receptor molecule itself, in eff orts to augment its capacity to enhance the transduction In fact, it is likely that only a combination of therapies that of signals that increase cytotoxic and memory eff ector act at key points of tumour escape pathways may help to function, while maintaining a high-level of safety. The T-cell eradicate tumour cells and also to lessen the dose-intensity proliferation should be strictly antigen-dependent and of current chemotherapy regimen, a critical element of any dwindle after elimination of the antigen. therapeutic approach in developing individuals or in elderly patients who have reached maximum tolerable doses of Finally, the CHILDHOPE project moves the fi eld forward as it anticancer drugs when their disease reoccur. Hence, our brings to clinic this therapeutic modality in a phase I setting. innovative therapeutic approach may provide hope for We are confi dent that the chosen methods of gene transfer a cure for young as well as older patients with advanced or (i.e. retroviral vs. electroporation), in conjunction with our refractory tumours.

180 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2006-037381

EC contribution € 3 208 760

Duration 48 months

Starting date 01/11/2006

Instrument STREP Chimaeric TCR shown in context of native TCR signalling complex. Single-chain variable region (scFv) is composed of heavy and light chain variable domains (VH and VL) which are connected Project website by a short peptide linker. A fl exible spacer connects VL allowing the antigen binding region www.childhope.eu to orient in diff erent directions, improving antigen recognition. The spacer is then connected to the transmembrane and intracellular portion of CD3-z. The native TCR a and b chains are also shown alongside CD4/CD8. An unmodifi ed CD3-z chain and CD3-e and CD3-g chains are also represented. Antigen binding to the native TCR leads to phosphorylation of CD3 immunoreceptor tyrosine-based activation motif (ITAMS, red boxes) which activate ZAP70, which in turn propagates further downstream signalling. Co-stimulation (in this case via CD28) is required for full T-cell activation.

Coordinator

Raphaël F. Rousseau Gustav Gaudernack MD, PhD The Norwegian Radium Hospital Institut d’Hématologie Oslo, Norway Oncologie Pédiatrique INSERM U590 Joël Plumas Centre Léon Bérard Établissement Français du Sang Lyon, France Grenoble, France [email protected] Martin Pule University College of London Partners London, United Kingdom

Christophe Caux Claudia Rossig Centre Léon Bérard Universitätsklinik Münster Lyon, France Münster, Germany

Persis Amrolia Marianne C. Naafs-Wilstra Great Ormond Street International Confederation of Childhood Children’s Hospital Cancer Parent Organisation London, United Kingdom Nieuwegein, The Netherlands

Ettore Biagi Laurence Lapôtre Università Milano ACIES SAS Bicocca Lyon, France Milano, Italy

TREATMENT 181 Keywords | Clinical trials | dendritic cell (DC) | genomics | HIV | immunotherapy | molecular cell biology | pre-clinical studies | proteomics |

DC-THERA Aim

Dendritic cells for novel immunotherapies This NoE, DC-THERA, will integrate the activities of 26 par- ticipant groups of scientists and clinicians and six high quality SMEs across Europe. It will incorporate additional groups as Associated Members of the Network. Their collec- Summary tive expertise and resources will be forged into an ambitious Joint Programme of Activities to restructure the fi eld. Dendritic cell (DC) immunobiology has enormous potential for the development of new immunotherapies for cancer and infectious disease. Europe possesses a critical mass of Expected results leaders in the fi eld who have pioneered many innovative advances and provided initial proof of principle for the The Network will translate genomic, proteomic and bioinfor- approach. This Network of Excellent (NoE), DC-THERA, will matic information, with knowledge from molecular cell integrate the activities of 26 participant groups of scien- biology and pre-clinical models, into therapeutic endpoints: tists and clinicians and six high quality SMEs across Europe. clinical trials of DC-based therapies for cancer and HIV. It will incorporate additional groups, particularly from future Member States, as associated members of the net- work. Their collective expertise and resources will be forged Coordinator into an ambitious joint programme of activities to restruc- ture the fi eld. It will translate genomic, proteomic and Jonathan Austyn Anne O’Garra bioinformatic information, with knowledge from molecular Nuffield Department of Surgery The Medical Research Council cell biology and pre-clinical models, into therapeutic end- University of Oxford National Institute for Medical Research points: clinical trials of DC-based therapies for cancer and John Radcliffe Hospital London, United Kingdom HIV. To this end, four thematic S&T clusters have been Oxford, United Kingdom [email protected] defi ned, with a fi fth for horizontal activities. The latter [email protected] includes development of synergistic links with other net- Francesca Granucci works, providing benefi t to EC programmes by underpinning University of Milano-Bicocca all projects developing new vaccine strategies for major Partners Dept. of Biotechnology and Bioscience killer diseases. The network will implement an IT-based Milan, Italy integrated knowledge management system and provide Gordon G. MacPherson a centralised European resource of databases for the fi eld. Sir William Dunn School of Pathology Gerold Schuler DC-THERA will develop new research tools, integrate exist- University of Oxford Alexander Steinkasserer ing and new technological platforms, recruit additional Oxford, United Kingdom Friedrich-Alexander-Universität support staff , and make these available as shared resources [email protected] Erlangen-Nürnberg for all partners. It will implement an ambitious Education Dept. of Dermatology and Training Programme, including new PhD studentships, Vincenzo Cerundolo Erlangen, Germany a Visiting Scholars Scheme, high quality training courses, The Weatherall Institute [email protected]. and a postgraduate degree in translational DC immuno- of Molecular Medicine uni-erlangen.de biology. DC-THERA will contribute to the European University of Oxford biotechnology sector and have a major impact on European John Radcliffe Hospital Robert Coffin policy-making for the future. DC-THERA will evolve itself Oxford, United Kingdom Biovex into a Centre of Excellence for DC Biology, with a lasting [email protected] Abingdon, United Kingdom and global impact. [email protected] Carl G. Figdor Gosse Adema Catherine De Greef Problem Nijmegen Center for Molecular Life Sciences Brucells SA Radboud University Medical Centre Brussels, Belgium Dendritic cell (DC) immunobiology has enormous potential Nijmegen, The Netherlands [email protected] for the development of new immunotherapies for cancer [email protected] and infectious disease. Europe possesses a critical mass of [email protected] Ugo D’Oro leaders in the fi eld but they are geographically dispersed Chiron Vaccine S.r.l. with localised resources. Muriel Moser Siena, Italy Université Libre de Bruxelles [email protected] Brussels, Belgium [email protected]

182 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Andrea Splendiani Alberto Mantovani Mark Suter Project number Leaf Bioscience s.r.l. Istituto Clinico Humanitas Vetsuisse-Faculty, Veterinary Medicine LSHB-CT-2004-512074 Milan, Italy Milan, Italy University of Zurich [email protected] [email protected] Zurich, Switzerland EC contribution [email protected] € 7 600 000 Charles Nicolette C.J.M. Melief Argos Therapeutics, Inc Leiden University Medical Center Kris Thielemans Duration Durham, United States of America Dept. of Immunohematology Laboratory of Molecular & Cellular Therapy 60 months [email protected] and Blood Transfusion Dept. of Physiology-Immunology Tumour Immunology section Medical School of Starting date Filippo Petralia Leiden, The Netherlands the Vrije Universiteit Brussel 01/01/2005 Sekmed srl [email protected] Brussels, Belgium Milan, Italy [email protected] Instrument [email protected] Philippe Pierre NoE Centre d’Immunologie de Marseille-Luminy Hermann Wagner Sebastian Amigorena CNRS – INSERM – Univ. Med. Institut für Med. Mikrobiologie, Project website Institut Curie Marseille, France Immunologie und Hygiene www.dc-thera.org Paris, France [email protected] Technische Universität München [email protected] München, Germany Maria Pia Protti [email protected] Thierry Boon Cancer Immunotherapy and Pierre Coulie Gene Therapy Programme Laurence Zitvogel Christian de Duve Institute Scientific Instituto San Rafaelle ERM0208 INSERM of Cellular Pathology Milan, Italy Institut Gustave Roussy University of Louvain [email protected] Villejuif, France Brussels, Belgium [email protected] [email protected] Alexander Scheffold [email protected] Andreas Radbruch Paola Ricciardi Castagnoli Andreas Thiel GENOPOLIS Duccio Cavalieri Deutsches Rheuma-Forschungszentrum Università degli Studi di Milano-Bicocca Dept. of Pharmacology Berlin, Germany Milano, Italy University of Florence [email protected] [email protected] Florence, Italy [email protected] [email protected] [email protected] Matthias Mann Max-Planck-Institut für Biochemie Sandra Gessani Caetano Reis e Sousa Martinsried, Germany Istituto Superiore di Sanità Cancer Research UK [email protected] Dept. of Cell Biology and Neurosciences London, United Kingdom Rome, Italy [email protected] [email protected] Benedita Rocha Nicolas Glaichenhaus INSERM U591 Institut Necker Université de Nice-Sophia Antipolis Paris, France Institut Universitaire de France [email protected] Valbonne, France [email protected] Federica Sallusto Antonio Lanzavechia Rolf Kiessling Markus Manz Pavel Pisa Mariagrazia Uguccioni Hakan Mellstedt Cellular Immunology Laboratory Karolinska Institutet Institute for Research in Biomedicine Cancer Center Karolinska Bellinzona, Switzerland Stockholm, Sweden [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected]

TREATMENT 183 Keywords | Dendritic cells | adjuvants | pattern recognition receptors | cancer and infectious diseases |

DC-VACC project. The specifi c objective of work package 1 was to generate tools and methods for appropriate and effi cient Dendritic Cells as Natural Adjustments targeting and antigen delivery for the development of DC vaccine technology. This included the construction of viral for Novel Vaccine Technologies and bacterial vectors, modifi cation of RNA, peptides and proteins, and antibody development for specifi c targeting of DC receptor repertoire. A comparison is now under progress of peptides, proteins, RNA, DNA and antigen mod- Summary ifi cations that allow presentation via MHC molecules. Recombinant bacterial and viral vectors are amongst the The immune system of vertebrate animals has evolved to most suitable vectors for the transduction of heterologous respond to diff erent types of perturbations, such as patho- model antigens into DC. gens, whilst limiting self-tissue damage. Initiation of the immune response is accomplished by unique antigen pre- The second objective, which is the basis of work package 2, senting cells, called dendritic cells (DC) that are resting until was to defi ne optimal reagents and protocols for maturation they encounter foreign micro-organisms or infl ammatory and activation of mouse and human DC in vitro for use in stimuli. Early-activated DCs trigger innate immune responses vaccination so that the optimisation of protocols for both that represent the fi rst line of defence against invading species are compared to rapidly facilitate information from pathogens to limit the infections. Subsequently, activated pre-clinical models being transferred rapidly to clinical trials DCs prime antigen-specifi c immune responses, which clear in future projects. It is fi rst necessary to identify optimal the infections and give rise to immunological memory. maturation stimuli of mouse and human DC by transcrip- tome analysis and functional assays. Thus the defi nition of such signals – including pathogen-derived products that Problem trigger TLRs, ligands that trigger other DC receptors (such as FcR) and/or cytokines or cytokine inhibitors, and T-cell- Targeting of dendritic cells for vaccination and therapeutic derived molecules – is critical. The aim is to obtain a clear intervention in infectious diseases and cancer. understanding of how DCs function to induce pro-infl am- matory versus anti-infl ammatory cytokines, chemokines and their receptors, and then how they function to activate Aim CD4+ and CD8+ T-cells. In addition, it is essential that such activation signals are also be tested for their ability to proc- The aim of DC-VACC project is to develop novel vaccine ess and present antigen to T-cells, leading to a protective technologies and to use DCs as a natural adjuvant with spe- Th1 response. A major unique innovative feature of this cifi city and minimum side eff ects and/or immunopathology. project is the close interaction and exchange between Early clinical trials have indicated that antigen-pulsed DCs groups researching in mouse and human systems, which will do have great potential in the treatment of cancer. Such rapidly facilitate the translation of basic fi ndings to the clinic. information will also be applicable in the eradication of infectious diseases. By defi ning novel reagents and proto- cols for the optimisation of DC as vaccines, this technology Expected results can then be translated to small biotechnology companies participating in this project. The basis of this proposal was The discovery and application of new adjuvants and targeting to develop in situ DC targeting for use as vaccines in infec- molecules, approaches for enhancing anti-tumour therapy tious diseases and cancer. Specifi cally, we are defi ning and also in therapeutic intervention, and for vaccination in improved reagents and protocols for antigen delivery and infectious diseases. Potential applications Enhancing anti- targeting, which improve antigen processing and presenta- tumour therapy, approaches in therapeutic intervention and tion by DC and can be used for vaccine technology. It will for vaccination in infectious diseases. also be necessary to defi ne optimal reagents and protocols for maturation and activation of mouse and human DC in vitro for use in vaccination so that optimisation of proto- Potential applications cols for both species is comparable – thus preparing the way for use in pre-clinical models and clinical trials in future Enhancing anti-tumour therapy, approaches in therapeutic projects. There were, thus, two specifi c objectives for the intervention and for vaccination in infectious diseases.

184 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHB-CT-2003-503037 Anne O’Garra Paola Ricciardi Castagnoli The Medical Research Council University of Milano-Bicocca EC contribution National Institute for Medical Research Dept. of Biotechnology and Bioscience € 2 000 000 London, United Kingdom Milan, Italy [email protected] [email protected] Duration 36 months Gerold Schuler Partners University Hospital of Erlangen Starting date Dermatologische Klinik mit Poliklinik 01/01/2004 Leonardo Biondi Erlangen, Germany Biopolo Scrl – c/o IFOM [email protected] Instrument Milan, Italy STREP [email protected] Anna Ranghetti Sekmed srl Project website Vincenzo Cerundolo Milan, Italy www.biopolo.it University of Oxford [email protected] Weatherall Institute of Molecular Medicine John Radcliffe Hospital Catherine De Greef Oxford, United Kingdom Brucells SA [email protected] Brussels, Belgium [email protected] Carl Figdor University Medical Center Nijmegen Dept. of Tumour Immunology Nijmegen Center for Molecular Life Sciences Nijmegen, The Netherlands [email protected]

Muriel Moser Université Libre de Bruxelles Institut de Biologie et Médicine Moléculaire Gosselies, Belgium [email protected]

TREATMENT 185 Keywords | Vaccine dendritic cells |

Dendritophages can be achieved in some patients resistant to conventional therapies. The preclinical data generated on dendritic cells, as Therapeutic cancer vaccines well as pilot clinical trial data, have driven the dendritic cell immunotherapy technology to reach adequate maturity to enter real standardisation and demonstration of immune effi - cacy. A phase I study of anti-tumour immunisation of patients Summary with melanoma stage III or IV has been initiated during a pre- vious EU Project coordinated by the same team, with The patient’s blood monocytes are transformed into eff ec- autologous DCs (BIO-CT97- 2216, CELLULAR VACCINES, tor monocyte-derived dendritic cells (DC) (dendritophages), 1997). Nine patients had completed the treatment which con- which fi ght the patient’s own disease. The therapeutic cell sisted of four series of injections of dendritic cells pulsed with drug comprises dendritic cells, which are loaded with can- tumour cell lysate and dendritic cells pulsed with HbsAg and cer-specifi c antigens to activate the patient’s immune TetanusT. system after re-injection.

This project aims to demonstrate the immune and clinical Expected results effi cacy, reproducibility and feasibility of anticancer cell vac- cine by choosing the best dendritic cell vaccination strategy Results showed excellent safety and the presence of via adequate pre-clinical studies (DC diff erentiation and immune responses after vaccination, as well as signs of clin- maturation, tumour antigens selection and loading, dose ical responses in some of the patients. It is to be noted that delivered, site and vaccination schedule). It will monitor the one patient showed complete regression of metastases immune response in correlation to the clinical response after four months after the last vaccination, and another one defi ning the most relevant immuno-monitoring techniques, showed stabilisation of the disease. and will demonstrate the immunological effi cacy of DC immunotherapy in prostate cancer, which will be performed We have compared several technologies for obtaining DCs after loading ex vivo dendritic cells with proteic antigen. and selected the most appropriate for GMP development. The initial clinical results have been confi rmed on a ran- This will require the setting up of quality control criteria and domised clinical study conducted in malignant melanoma data base design for the production of the cellular product, stage IV patients immunised with dendritic cells pulsed ex and optimising a GMP process. We will start a clinical trial to vivo with three melanoma cell lines lysates. The results of evaluate the cell drug on progressing prostate cancer this study are based on 49 treated patients, with 15 patients patients. having completed the cycle of six DC vaccinations, the others progressing due to late stage disease. No severe adverse event has been related to the therapeutic protocol nor to Problem the DC product; the most frequent minor side eff ects were injection site reactions. Fourteen patients out of 49 initiated • Select the most eff ective DC preparation. T-cell immune response against the antigens presented and • Develop GMP process. ten patients had disease stabilisation; most of these immune • Show immunogenicity and safety in carcinoma patients. responses and stabilisations were in the group of patients having received six vaccinations.

Aim Studies are ongoing in colorectal and prostate cancer.

The fi nal goal of anticancer therapeutic vaccines is to prevent metastasis development as well as tumour progression and to Potential applications provide long-term protection. Vaccine therapy of metastatic carcinoma. Previous and ongoing clinical studies have shown that there are no side eff ects associated with this type of dendritic autol- ogous cellular drugs, and that immune and clinical responses

186 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHB-CT-2003-503583 Jacques Bartholeyns Reinhard Glueck IDM SA Immuno-Designed Molecules Etnabiotech EC contribution Paris, France c/o Dipartimento di Farmacologia € 1 999 900 Sperimentale e Clinica Facoltà di Medicina Duration Partners Università di Catania 42 months Catania, Italy Andreas Mackensen Starting date Dept. of Hematology/Oncology Thomas Felzmann 01/04/2004 University of Regensburg Children’s Cancer Research Insitute Regensburg, Germany Kinderspitalgasse Instrument Vienna, Austria STREP Miles Prince Centre for Blood Cell Therapies Filippo Belardelli Project website c/o Peter MacCallum Cancer Centre Istituto Superiore di Sanità www.idm-biotech.com Victoria, Australia Laboratory of Virology Rome, Italy

Anne-Cécile de Giacomoni ALMA consulting group Houlbec-Cocherel, France

TREATMENT 187 Keywords | Protein-Protein interactions | small molecule inhibitors | knowledge driven drug design | blood/brain | tumour penetrant |

DEPPICT Problem

Designing Therapeutic Protein-Protein Amongst the range of cancer types, brain and perhaps pan- creatic cancers are especially lacking in eff ective treatments. Inhibitors for Brain Cancer Treatments In particular brain tumours are: • the leading cause of death from childhood cancers among persons under 19; • the second leading cause of cancer-related deaths in Summary males aged 20-39; • the fi fth leading cause of cancer-related deaths in women Protein-Protein interactions (PPI) are central elements in aged 20-39. cellular processes and important targets for selective thera- peutic agents. They constitute a rich area for discovery Although onset of disease varies with tumour type, it can of novel small ligand-based therapies. This proposal seeks occur at a relatively young age causing additional and sig- to utilise such interactions, in particular those featuring nifi cant social and economic problems for both patients and a a-helix binding groove such as p53-MDM2, or more novel their families. targets, e.g. nm23-prune, to develop targeted small-mole- cule libraries with physico-chemical properties appropriate Current standard treatments include surgery, radiation ther- for therapeutic eff ect against various tumour types such as apy and chemotherapy. These may be used either individually the brain cancers of glioblastoma and medulloblastoma. or typically in combination. Brain cancers however present unique problems due to the location of the tumours: surgery Combination of the concepts below should provide an and radiotherapy carry considerable risk to the patient and opportunity to unlock the potential of protein interactions resection is not always possible. Chemotherapy is faced with as key components in signalling pathways via design of the problem of penetration of drugs across the blood-brain selective small-molecule modulators targeting the kinase- barrier (BBB) and of lack of specifi city. The focus for these eff ector interaction instead of the ATP active site. patients is therefore on more eff ective therapies to prevent relapse, and on more effi cient screening and diagnosis to • Develop an understanding of the elements controlling halt the disease at an early stage. selectivity in Protein-Protein signalling networks by developing approaches for design of small molecules that target a-helix binding groove interactions through Aim use of structure-based and fragment-based approaches. • Data-mining of ADME and drug-drug interactions to The main objective of the proposed project is to provide build a predictive database for library design. more eff ective anti-tumour therapies by developing target- • Develop quantitative structure/property relationships, ed small ligand libraries with appropriate physico-chemical with an emphasis on CYP-mediated metabolism, ABC properties for therapeutic eff ect targeted against Protein- transporters at the blood/brain and brain/tumour Protein interactions implicated in various tumour types. The interfaces, mutagenicity, solubility, pKa, and passive research activities will concentrate on knowledge-based permeability, and predictive tools for mutagenicity and approaches supporting translational research aimed at other genetic toxicology end-points. bringing basic knowledge through to applications in clinical • Develop predictive PK and PBPK models to improve practice and public health. The project will thus focus on understanding of BBB and tumour penetration. providing small molecule ligands with minimal side eff ects • In vitro and in vivo PK/PD and TK/TD characterisation as treatments for the brain tumours glioblastoma (GBM) of compounds, to increase understanding of their mech- and medulloblastoma. anism of action and reduce the use of laboratory animals. Expected results Such knowledge-based approaches will also be applicable to design of small molecules for other Protein-Protein inter- The successful integration of the various aspects of this pro- actions utilising a a-helix binding groove both for peripheral posal will provide a robust knowledge-based strategy for tumours and other therapeutic areas. exploiting Protein-Protein interactions as drug targets in the treatment of brain tumours. The strategy should however be suffi ciently generic to be transferable to other disease areas, especially within the CNS, where Protein-Protein interactions provide an entry point into disease-modifying therapies.

188 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2007-037834

Structure Driven EC contribution Drug Design € 3 640 293 Predictive ADME and Drug-Drug Interactions Duration Quantitative 36 months Structure/Property Relationships

Starting date 01/03/2007 Predictive PK & PBPK Models Instrument STREP – SME

Project website In vitro and in vivo PK/PD Protein-Protein Interaction and TK/TD Characterisation www.deppict.eu Inhibitors

The individual components needed to achieve successful knowledge driven drug discovery will be combined to harness the opportunity for Protein-Protein inhibitors as potential small molecule therapies for brain tumours.

Potential applications Coordinator

The design of selective small molecule modulators of Pro- Graeme Robertson Juan Aymami tein-Protein interactions should provide the basis for Siena Biotech SpA Crystax developing new therapeutic strategies against brain can- Siena, Italy Barcelona, Spain cers. They will allow for improving current libraries and for [email protected] building predictive databases for library design of new spe- Roberto Pellicciari cifi c drugs and therapeutic agents with high central nervous University of Perugia system penetration, necessary to reach a higher effi cacy, Partners Perugia, Italy selectivity, responsiveness and lower toxicity. In addition these approaches will represent a powerful system for pre- Gabriele Cruciani Sophie Ollivier clinical data collection, leading to an optimisation of clinical Molecular Discovery Pinner Aureus Pharma trials setting and development. Middlesex, United Kingdom Paris, France

Massimo Valoti Herbie Newell University of Siena University of Newcastle Siena, Italy Newcastle, United Kingdom

TREATMENT 189 Keywords | molecular imaging | drug development | guided therapies | tumour diagnosis | in vivo imaging of gene expression |

EMIL though anatomic imaging can occur in vivo at sub-millime- tre resolution, imaging techniques based on gross physical Molecular Imaging of Cancer diff erences, such as density or water content, perform poorly in producing a contrast which must be based on specifi c imaging agents targeting tumour cells.

Summary Molecular imaging is a new science bridging together molecular biology and in vivo imaging with the aim of The general objective of EMIL is to bring together the lead- detecting the expression of specifi c genes. Imaging sci- ing European research teams in molecular imaging in ence has made suffi cient progress in the last decade to universities, research centres and small and medium enter- bridge the gap between physiology and molecular biology, prises to focus on early diagnosis, prognosis and therapeutic and is now at the stage where it can perform molecular evaluation of cancer. imaging of gene expression in vivo. Signifi cant advances have occurred in molecular imaging modalities, including The 58 partners of EMIL work around a common activity the nuclear medicine techniques of SPECT and PET, MRI programme including: and spectroscopy, which have attained resolution suffi - • integration activities: creation of a network of techno- cient for small animal imaging, and optical imaging, which logical and training facilities favouring the mobility of can now reach unprecedented sensitivities. researchers and the integration of small and medium enterprises; • dissemination activities: training, communication, com- Aim mon knowledge management and intellectual property rights; The potential of molecular imaging is considerable: • research activities: a common research programme mak- • in fundamental research, it allows the visualisation of cell ing use of methodological tools of physics, biology and function and molecular processes in living organisms – in chemistry for the further development of molecular imag- particular the monitoring of the stages of growth and ing (instrument techniques, molecular probes, biological ageing, the response to environmental factors, the engineering), and bringing together cancer imaging exploration of cell movements, etc.; applications (early diagnostic imaging, development of • in experimental medicine it identifi es the molecular deter- new therapies, imaging for drug development). minants of pathological processes in situ, evaluates new molecular therapies (such as gene therapy), and acceler- ates drug development (delivery of active compounds, Problem effi cacy of vectors, etc.).

Cancer is characterised by an uncontrolled proliferation of With the evolution of imaging techniques and the capacity cells. For normal cells, controls operate at spatial level – a cell’s to transfer animal data directly into clinical applications, location is defi ned by its integration in an organised tissue molecular imaging is a promising technique to tackle can- and temporal level – and a cell undergoes controlled divi- cer detection, following the rule of the three Ps: Precocious, sion and death corresponding to its programmed life cycle. Precise and Predictive. The last two decades have witnessed enormous advances • Precocious: several successive mutations are necessary in our understanding of cancer at the molecular level and to make a cell cancerous. By detecting genetic anoma- demonstrated that it results from abnormal gene expres- lies at the very fi rst mutation, molecular imaging could sion in cell clones. Gene expression analysis techniques are permit early diagnosis and prompt intervention at the now witnessing systematic compilation of molecular data start of the cancer-forming process. that can be used to provide accurate diagnosis and prog- • Precise: molecular imaging makes it possible to detect nosis. These techniques are well established and widely precisely, in space and time, the gene or genes that are applied to in vitro biological samples, but they destroy the dis-regulated in the cancer cell. A tumour can be charac- sample during analysis and are not applicable to whole terised with molecular precision. body and longitudinal explorations. Hence they fail to rec- • Predictive: the fi neness of the information obtained by ognise the essential character of cancer development molecular imaging allows it to determine the tumour across time and space. On the other hand, in vivo imaging type and to predict its evolution, adapt the treatment is a repeatable and non-invasive localisation technology and monitor its effi cacy. with the potential to become the preferred means for can- cer diagnostic and follow-up. However, imaging is based on This is essential to: evidencing a contrast between cancer and normal tissue, • validate, in the context of living organisms, the targets and this is quite challenging to perform in vivo in view of the and drugs designed by genome data mining and in vitro fact that cancer cells are a clone of normal cells. Even gene expression analysis through non-invasive methods;

190 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME • acquire fundamental knowledge about the patterns of a Network of Excellence bringing together genome-oriented gene expression in normal tissues and defi ne the changes scientists with various actors of imaging science and clini- in specifi c gene expression in cancer; cians dedicated to formulating novel diagnostic methods • design and develop drugs targeting cancer-related gene based on imaging. expression; • allow precise evaluation of new treatments and new The EMIL Information System called EMIL Net (www.emilnet. anti-cancer drugs that are required for progress in cancer org) will both facilitate the information fl ow between the management, through reliable measures of the cancer partners and contribute to promoting molecular imaging of burden. cancer.

The general objectives of EMIL are: Therefore EMIL Net will be dedicated to two diff erent groups • to coordinate the current eff ort in molecular imaging of of users: the EMIL partners and the public: Cancer in Europe by merging 43 groups from universities, • the public section will allow the free fl ow of information research centres and SMEs coming from diff erent scien- towards the end-users through the Internet site that will tifi c and technical fi elds into ONE virtual excellence centre be used as a ‘shop-window’ of EMIL, the aim being to with dedicated technological training platforms and inte- provide the molecular imaging community as well as the grated dissemination and management activities; public with a tool that will spread excellence; • to advance molecular imaging of cancer to the scientifi c, • the private section will be protected and accessible only technical and economical status that should be expected to the 58 registered members. It will be used for manage- from its value for European citizens, in order to improve ment, knowledge and the Image database. cancer diagnosis follow-up, to promote and assist in the development of new targeted therapies, and translate sci- The EMIL Net private section: ence and technology progress into economical benefi ts; The day-to-day management of the website will be secured • to act as leverage for a strong technological development by the management board to inform the EMIL partners on: that can be fuelled through specifi c research and devel- • research activities within the EMIL network; opment projects. • research outcomes: publications, common protocols, regulatory issues; And more precisely: • career opportunities; • to optimise hardware and software for the integration of • training courses; radiotracer, magnetic resonance and optical imaging • education courses; data; • knowledge management (consultation of documents, reg- • to develop so called ‘smart’ imaging probes which are istrations to EMIL events, on-line reporting, consultation of specifi c for a given molecular process and which can be work packages documents, discussion forum, etc.). detected and localised by at least one imaging modality; • to use further developments of mouse models of human This will have an integrating action on the EMIL members cancer to: who will visit the website to gather information on the net- • improve early detection of small cancer by advanced work’s events and activities. Members’ access will be enforced imaging; progressively, with diff erent levels of security. • directly study alteration of gene expression, tumour cell proliferation and migration in vivo over an extended Once the EMIL website is operating in good conditions, it period of time in the same animal; will be upgraded with the fi nal objective to create the EMIL • to identify in vivo molecular targets of cancer and metas- database. This database will function as a reference server tasis enabling early diagnosis, assessment of disease for molecular imaging of cancer. The web is a unique means progression and response to therapy; to disseminate image information and more particularly ani- • to establish imaging-guided patient-tailored therapies; mated data which cannot be shown on paper. EMIL will • to develop imaging technologies for in vivo drug screening provide unique pharmacokinetics information visible on the using animal models; website. • to apply molecular imaging of apoptosis to cancer. Potential applications Expected results • Tumour diagnosis. The present initiative is taken to capitalise on the extraordinary • Follow-up of tumour progression. opportunity for studying non-invasively gene expression and • Therapeutic evaluation. function in cancer, due to recent advances in molecular imag- ing modalities. Because molecular imaging is fundamentally multi-disciplinary by nature, the instrument for this goal is

TREATMENT 191 Coordinator

Bertrand Tavitian Mathias Hoehn André E. Merbach Carlo Pedone CEA – SHFJ Max-Planck-Society École Polytechnique Fédérale de Lausanne Consiglio Nazionale delle Ricerche Unité d’imagerie ‘in vivo’ MPI for Neurological Research Faculté des Sciences de Base Istituto di Biostrutture e Bioimmagini de l’expression des gènes MRI Laboratory Institut de Chimie Moléculaire Napoli, Italy Orsay, France Cologne, Germany et Biologique – LCIB [email protected] Lausanne, Switzerland Ivan Lukes Bernard Badet Univerzita Karlova – Charles University CNRS – ICSN Gyözö Janoki Faculty of Science Partners Gif sur Yvette, France NCPH-National ‘FJC’ Research Institute Dept. of Inorganic Chemistry for Radiobiology & Radiohygiene Prague, Czech Republic Silvio Aime Jacques Barbet Dept. of Radiopathology Università degli Studi di Torino INSERM & Medical Isotope Use David Parker Dipartimento di Chimica I.F.M. ADR de Lyon Div. of Applied Radioisotopes Durham University Torino, Italy Lyon, France Budapest, Hungary Chemistry Laboratory Durham, United Kingdom Andreas Jacobs Peter Egil Nielsen Frank Roesch Klinikum at the University of Cologne University of Copenhagen University of Mainz Joop A. Peters Dept. of Neurology Faculty of Health Institute of Nuclear Chemistry Technische Universiteit Delft Lab for Gene Therapy Dept. of Medical Biochemistry and Genetics Mainz, Germany Laboratory of Applied Organic and Molecular Imaging The Panum Institute Chemistry and Catalysis Cologne, Germany Copenhagen, Denmark Jean F. Desreux Delft, The Netherlands Université de Liège Clemens Lowik Ivan Rosenberg Coordination & Radiochemistry Ernö Brucher Leiden University Medical Center IOCB-AS of the Czech Republic Liège, Belgium University of Debrecen Dept. of Endocrinology Dept. of Biological Chemistry, Group of Dept. of Inorganic and Analytical and Metabolic Diseases Oligonucleotides Carlos Geraldes Chemistry Laboratory of Rare Earths Leiden, The Netherlands Prague, Czech Republic Centro de Neurociências de Coimbra Debrecen, Hungary e Biologia Celular Adriana Maggi Alexander Tatusyan Lab. of Bioinorganic Chemistry Michael Eisenhut Università degli Studi di Milano Institute of CarcinoGenesis & Biomedical NMR Deutsches Krebsforschungszentrum Centre of Excellence on Lab. of Oncogene Regulation Dept. of Biochemistry Heidelberg Neurodegenerative Diseases Moscow, Russian Federation Coimbra, Portugal Radiopharmaceutical Chemistry Milan, Italy Laboratory Robert Muller Fulvio Uggeri Heidelberg, Germany Bruno Brisson University of Mons-Hainaut BRACCO Imaging S.P.A. Biospace Mesures Dept. of Organic Chemistry – NMR Laboratory Centro Ricerche Milano Eric Buelens Paris, France Mons, Belgium Milano, Italy SkyScan Aartselaar, Belgium Annemie van der Linden Daniel Canet Helmut Maecke Universiteit Antwerpen Université Henri Poincaré, Nancy 1 University of Basel Alexandre Loiseau Dept. Biomedical Sciences Labo. de Méthodologie RMN Radiology & Radiological Mauna Kea Technologies and Dept. Physics – Bio-Imaging Lab Fac. des Sciences Chemistry Division Dept. of Optics Antwerp, Belgium Vandoeuvre les Nancy, France Basel, Switzerland Paris, France

192 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2004-503569 Terry Jones Simone Weber Victoria University of Manchester Forschungszentrum Jülich GmbH EC contribution Wolfson Molecular Imaging Centre Zentrallabor fur Elektronik (ZEL) € 5 800 000 Academic Dept. of Radiation Oncology Medical Imaging Manchester, United Kingdom Jülich, Germany Duration 60 months Juliàn Panes Kevin Brindle Hospital Clinic Provincial de Barcelona The Chancellor Starting date Gastroenterology Department Masters and Scholars of the University 01/07/2004 Barcelona, Spain of Cambridge Dept. of Biochemistry Instrument Peter Friedl Cambridge, United Kingdom NoE Dept. of Dermatology Rudolf Virchow Centre for Rosa Maria Moresco Project website Experimental Biomedicine Fondazione Centro San Raffaele www.emilnet.org Würzburg, Germany del Monte Tabor Centro Ciclotrone PET Arend Heerschap Milano, Italy Stichting Katholieke Universiteit University Medical Center Nijmegen Bernd Rademacher Dept. of Radiology Medres Medical Research GmbH iGR Nijmegen, The Netherlands Köln, Germany

Andrès Santos Hans-Jürgen Wester Universidad Politécnica de Madrid Technical University Munich Dept. Ingenieria Electronica/E.T.S.I. Dept. of Nuclear Medicine Telecomunication Radiochemistry/Radiopharmaceutical Ciudad Universitaria s/n Chemistry Group Madrid, Spain Munich, Germany

Marco G. Cecchini University of Bern Dept. of Urology & Dept. of Clinical Research Faculty of Medicine Urology Research Bern, Switzerland

Alberto Del Guerra University of Pisa Dept. of Physics ‘E. Fermi’ Pisa, Italy

TREATMENT 193 Keywords | Tumour progression | biomarkers | tumour escape | melanoma | prostate cancer | ovarian cancer |

ENACT of downregulation of MHC class I antigens, and in some instances cancer cells that show successive mutations may European Network for demonstrate progressive and complete loss of MHC expres- sion. The current status of our understanding of adoptive the identifi cation and validation cancer immunity also suggests that immune tolerance can equate with lack of response, with possible regulation by of antigens and biomarkers CD4+CD25+T-lymphocytes as well as other regulatory cells. Breaking tolerance through immunotherapy therefore rep- in cancer and their application in resents one possible approach to promote T-cell responses clinical cancer immunotherapy and tumour regression. Aim

ENACT aims to identify markers of response and tumour Summary antigens that associate with ovarian, breast and prostate cancer and melanoma progression and resistance to immu- Prospective clinical material will be collected during the life notherapy. The present application will address these issues of the programme and new and existing tumour tissue, PBMC in a number of ways and directly analyse the important and serum banks will be available for use in the study. This biomarkers that are expressed by cancer and may therefore common resource of material will be distributed to partners be considered as novel targets by establishing a European for the immunological, genomic, biochemical and proteomic network for collaboration. The cancer types to be included analysis of tumour and host response(s) to immunotherapy. will address the issue of sex-related biomarkers associating The results will be subjected to bioinformatic analysis in with resistance to therapy. Cell biological, immunological, the context of clinical outcome of vaccine-based immuno- biochemical and molecular biology-based technologies will therapy trials from fi ve European clinical centres. Analysis of be used and knowledge generated in this project will not the results in the context of gender will allow prominent only result in a desired and highly competitive technological inter- and intra-tumour/host biomarkers to be identifi ed for base for vaccine development (not necessarily restricted to translation back into clinical practice. cancer vaccines), but also will provide a better understand- ing of basic biological mechanisms underlying antigen presentation and recognition of tumours by CD8+ and CD4+ Problem T lymphocytes and NK cells.

Cancer remains a major health problem, with untold physi- cal, psychological and economic costs to society. Elimination Expected results of cancer would reduce health care costs and enhance quality of life. Along with cardiovascular disease and age- • To establish a database for the analysis of clinical and ing, it is currently the most intractable source of suff ering experimental results in order to identify markers related and health care cost. Recent results from immunotherapy to the outcome of immunotherapy. trials would suggest that inducing tumour-specifi c T-cell • To provide clinical material and cancer cell lines for scientifi c responses to tumour antigens can, in some patients, cause investigation conducted within the programme. the regression of tumours or the stabilisation of the disease. • To assess the cellular and humoral immune response in However the mechanisms underlying the failure of immuno- patients undergoing immunotherapy. therapy to control and destroy residual cancer remains to • To identify biomarkers using proteomics and computer be fully established. Experimentally, it can be shown that based algorithms. tumour rejection is mediated by CD8+CTLs aided by • Assessment of the importance of immunological, genetic CD4+Thelper cell activity. However animals that fail to and proteomic biomarkers as indicators of therapeutic respond may fail to demonstrate a pronounced (if any) CTL response related to gender. response. In addition data from many laboratories have • Dissemination of the information to the scientifi c community shown that tumour escape from CTLs can occur as a result and the community at large.

194 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Potential applications Project number LSHC-CT-2004-503306 The use of therapeutic cancer vaccines still has to be fi rmly established and previous clinical trials strongly indicate that EC contribution not all patients benefi t from receiving such treatment. The € 4 166 513 present study will allow us to establish whether the results of ENACT can be used in a clinical setting. The identifi cation of Duration indicators of patient response to immunotherapy would 42 months allow clinicians to target vaccination to those patients who are most likely to respond. The fi ndings of the present study Starting date could result in assays that could be used to predict treat- 01/01/2005 ment outcome and/or monitor patients during the course of treatment. This would benefi t the health care industry and Instrument patient care and the fi ndings may be applicable to cancers STREP other than those included in the research programme. The approach will allow us to gain further scientifi c understand- Project website ing of the immune response to tumour antigens, which may www.enactcancer infl uence the development of future generations of cancer research.org vaccine. This research represents a valuable contribution to the welfare of patients who would be considered to be suitable candidates for vaccine-based therapy.

Coordinator

Robert Rees Rolf Kiessling Federico Garrido Costas Baxevanis Interdisciplinary Biomedical Dept. of Oncology-Pathology Departamento de Analisis Clinicos Dept. of Immunology Research Centre Karolinska Institute Hospital Universitario Hellenic Anticancer Institute Nottingham Trent University Stockholm, Sweden Granada, Spain Athens, Greece Faculty of Science and Land-based Studies [email protected] [email protected] Nottingham, United Kingdom Anthony Walker [email protected] Francine Jotereau Dirk Schadendorf Onyvax Ltd INSERM U463, Institut de Biologie Deutsches Krebsforschungzentrum (DKFZ) St George’s Hospital Medical School Nantes, France Heidelberg, Germany London, United Kingdom Partners [email protected] [email protected] Italo Dodi Elissaveta Naumova Piotr Laidler Gustav Gaudernack School of Science and Technology Laboratory of Clinical Immunology Institute of Medical Biochemistry Dept. of Immunology Nottingham Trent University University Hospital Jagiellonian University Institute for Cancer Research Nottingham, United Kingdom Sofia, Bulgaria Medical College The Norwegian Radium Hospital [email protected] Krakow, Poland Oslo, Norway [email protected] [email protected] Graham Pawelec Abt.Innere Medizin II Zentrum Aija Line Graham Ball für Medizinische Forschung, Biomedical Research Study Centre Loreus Ltd ZMF Universitätsklinikum University of Latvia Nottingham Trent University Tübingen, Germany Riga, Latvia Nottingham, United Kingdom [email protected] [email protected] [email protected]

TREATMENT 195 Keywords | Leukaemia | CML | AML | ALL | CLL | MDS | CMPD |

European LeukaemiaNet and biotechnology to therapeutic progress and to promote research relevant also for solid cancers by large clinical trials. Strengthen and develop scientifi c and Furthermore, meta-analyses of specifi c subaspects, elabora- tion of prognostic scores, recognition of gender-specifi c technological excellence in research diff erences, creation of uniform data sets for trials and regis- tration, introduction of standards for diagnostics and treatment and therapy of leukaemia (CML, AML, and development of evidence-based guidelines will be pro- moted throughout Europe. The proposed network will have ALL, CLL, MDS, CMPD) by integration the expertise and critical mass for European added value and world leadership. It will structure European research durably, of the leading national leukaemia spread European scientifi c excellence in the fi eld of leukaemi- as and can start immediately. The 95 leukaemia trial groups networks and their interdisciplinary and their 102 interdisciplinary partner groups representing several thousand participating centres and ten thousands of partner groups in Europe study patients treated within the trial groups form the back- bone of the network. The network consists of 16 work packages. Of these, six deal with the various diseases (AML, ALL, CLL, CML, MDS, CMPD) and represent sub-networks on Summary their own. Seven work packages represent interdisciplinary platforms which provide the support and research expertise Leukaemias are a challenge to society and a cost factor required for high quality networking and excellence. Three because of their frequency in all age groups. They also serve as core work packages provide central communication and man- a model for a variety of diseases and possess exemplary rele- agement services for the whole network. The integration and vance for basic research and patient care. Leukaemia research interdisciplinary cooperation brings together 133 participants and therapy have achieved high standards and even a leading and approximately 1 000 researchers from 28 countries. The position in several European countries with regard to clinical network will overcome national fragmentation and provide trials, standardisation of diagnostics and molecular studies of the critical mass to achieve research and treatment goals that signal transduction and gene expression. A true European cannot be achieved by single European countries. world leadership, however, has not been accomplished yet due to national fragmentation of leukaemia trial groups, diagnostic approaches and treatment research activities and a need for Expected results central information and communication structures. 1. Establishment of central information and communication structures to create networks and platforms for all leukaemias Problem and their interdisciplinary partners.

Leukaemia trial groups, diagnostic approaches and treat- Integration is mediated by exchange of current trial protocols ment research are currently fragmented. There is a clear and procedures, information on participating centres and need for benchmarking, information and communication recruited patients and employment of uniform common data structures at a clinical level in Europe. sets for comparable study outcomes and evaluations provided by the biometrical center (WP 17). This objective will be achieved through central services: Network Management Center Aim (NMC, WP 1), European Leukaemia Information Center (ELIC, WP 2) and Central Information and Communication Services The objective is to integrate the 95 leading leukaemia trial (CICS, WP 3). The central service groups benefi t from a three groups (chronic myeloid leukaemia (CML), acute myeloid years’ experience in similar tasks for the German Competence leukaemia (AML), acute lymphoblastic leukaemia (ALL), Network for Acute and Chronic Leukaemias funded by the Ger- chronic lymphoid leukaemia (CLL), myelodysplastic syn- man Ministry for Education and Research (BMBF) and provide dromes (MDS), chronic myeloproliferative disorders (CMPD), the basis for a head start of the network. These groups will also their 102 interdisciplinary partner groups (diagnostics, treat- provide training programmes, workshops, symposia, exchange ment research, registry, guidelines), industry and SMEs across of researchers and information programmes, thereby spread- Europe to form a cooperative network for advancements in ing excellence to health care personnel, researchers and to leukaemia-related research and health care. Integration will be other countries not yet participating in the network. With the supported by central information, communication, education support of NMC (WP 1) the network will be managed in a two- and management structures. Other goals are to intensify layer networking organisation. Clinical trial groups for each target and drug discovery, to shorten the time period to leukaemia and their interdisciplinary partner will form their own clinical translation, to apply advanced genomics, telematics European subnet organizations with coordinators, steering

196 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME groups and management structures. These subnets and plat- evidence of lowered levels of SP-A, and SP-D, in the lung forms will then be integrated in the European Leukaemia surfactant of a growing number of types of infection- or Network which will conduct the integrated research programme allergy-mediated lung infl ammation, which strengthens the detailed below. The network will be managed by the Network case for testing the use of recombinant forms of these proteins Coordinator (NC), the Scientifi c Network Manager (SNM) and as therapeutic alternatives to antibiotics. the Steering Committee (SC) consisting of the coordinators (=Lead participants) of the work packages (WP). The University 5. European Registry (all leukaemias). of Heidelberg will provide the expertise for fi nancial, legal and contractual management. A European registry will allow to determine incidence and disease patterns across Europe including gender, age and 2. Set-up of European networks for each leukaemia and ethnic diff erences, investigate familiar aggregations, overlap related syndrome. syndromes or precursor conditions, explore risk factors asso- ciations and diff erences in gene environment interaction, These networks will comprise the national trial groups for using data from cytogenetic analyses (WP 11) and genomic each leukaemia and represent the fi rst stage of networking profi ling (WP 13), perform quality of life assessments, recog- and European integration. nize sub-entities on the basis of cytogenetic or gene profi ling information, follow-up patients for the development of prog- 3. Set-up of European platforms for each interdisciplinary nostic scores for old and new therapies and determine specialty. proportions of patients in individual countries treated on spe- cifi c protocols or with specifi c therapies e.g. SCT (WP 14). These platforms are sub-networks of excellence of diagnos- The registry will be run by the expert group Biometry for tic, therapeutic and biometric research groups on their own Registry, Epidemiology, Metaanalyses and Prognosis (WP 17). and constitute interdisciplinary partners enabling the clinical This group has gained a long-standing broad experience in trial groups to achieve the high quality patient care and collecting data, performing meta-analyses and establishing research required for European leadership. prognostic scores. The database established by the network will have far-reaching implications for research and public 4. Performance of clinical trials (all leukaemias). health planning far beyond the period of EC funding.

Employing uniform common data sets the trial groups will 6. Standardisation. continue their current trials funded by alternative sources and will start new trials using diagnostic standards established by Standardised and quality controlled diagnostic procedures the diagnostic platforms (WPs 10-13). Criteria for accredita- and therapies constitute the basis for improvements of clinical tion of trials will be set up. outcomes. This concerns all diagnostic approaches such as morphological diagnosis of blood and marrow cells (WP 10), Lung infection and infl ammation is a growing problem within cytogenetics (WP 11), detection of minimal residual disease all states of the EU, and the infections are routinely treated (WP 12) and gene expression profi ling (WP 13) as well as ther- with antibiotics. The pharmaceutical industry is interested in apies such as transplantation, anti-infection prophylaxis and the development of protein therapeutics, which can be used as treatment and the testing of new drugs in phase I/II trials alternatives to antibiotics. There is a relatively fragile protective (WP 14 and 15). The establishment of standards for a wide barrier, the alveolar lining layer, which controls the interaction spectrum of diagnostic and therapeutic applications will raise between the atmosphere and the lung. The fi lm, known as lung the quality of research and patient care beyond the period of surfactant, plays two important roles, prevention of lung col- EC funding and will predictively have a profound impact on lapse during respiration and provision of a fi rst line of defence outcome as measured by prolongation of life and cure rates against the extremely varied range of particles, allergens and across Europe. microbes that are present in the environment. The lung sur- factant is a surfaceactive mixture of phospholipids and four 7. Meta-analysis and guidelines. main surfactant proteins – SP-A, SP-B, SP-C and SP-D. The SP- B and SP-C proteins are small, highly hydrophobic, polypeptides, Whenever randomised trials are available for analysis (mostly which are strongly associated with the phospholipid portion of CML and AML), meta-analysis will be performed and published the surfactant, whereas SP-A and SP-D are large (approxi- (WP 17). On the basis of meta-analysis, evidence-based guide- mately 600kDa) and complex, disulphide-bonded, proteins of lines will be worked out and used for the improvement of a more hydrophilic nature. They can bind, via their lectin patient management and for educational purposes (training domains, to arrays of carbohydrate structures on the surfaces programmes, workshops in associated countries, exchange of of pathogenic microbes and to glycosylated allergens, thus researchers and physicians for training purposes). Meta-analysis initiating defence against a range of viral, fungal and bacte- will be also performed on combined data sets with rare rial lung infections and modulating allergic reactions. There is subtypes of leukaemias (WP6).

TREATMENT 197 Coordinator

Rüdiger Hehlmann J.J.M. van Dongen A. Skotnicki H. Kreipe III. Medizinische Universitätsklinik Erasmus University Medical Jagiellonian University, Medical College Medizinische Hochschule Hannover Ruprecht-Karls-Universität Heidelberg Center Rotterdam Krakow, Poland Hannover, Germany Mannheim, Germany Rotterdam, The Netherlands [email protected] J. Steegmann J. Holowiecki A. Ullmann Hospital Universitario de la Princesa Medical University of Silesia Johannes Gutenberg-Universität Mainz Madrid, Spain Katowice, Poland Partners Mainz, Germany J. Thaler M. Jotterand D. Hölzer J. Apperley Klinikum Kreuzschwestern Wels GmbH Hospices-CHUV Universitätsklinikum Frankfurt Imperial College of Science Wels, Austria Lausanne, Switzerland Frankfurt, Germany Medicine and Technology London, United Kingdom A. Tobler C. Fonatsch G. Zini University of Bern Medizinische Universität Wien Università Cattolica del Sacro Cuore A. Gratwohl Bern, Switzerland Vienna, Austria Rome, Italy University of Basel University Hospitals W. Berdel R. Foà U. Holtkamp Basel, Switzerland Universitätsklinikum Münster Università degli Studi di Roma ‘La Sapienza’ Deutsche Leukämie und Münster, Germany Dipartimento di Biotecnologie Cellulari Lymphom-Hilfe e.V. H. Akan ed Ematologia Bonn, Germany Ankara University A. Burnett Rome, Italy Ankara, Turkey Cardiff University U. Mansmann Cardiff, United Kingdom D. Niederwieser Ludwig-Maximilians-Universität München A. Hellmann Universität Leipzig Munich, Germany Medical University of Gdansk M. Sanz Leipzig, Germany Gdansk, Poland Fundación Hospital Universitario ‘La Fe’ A. Berghold Valencia, Spain G. Ossenkoppele Medizinische Universität Graz J. Mayer VU Academic Medical Center Graz, Austria Fakultni nemocnice Brno S. Amadori Amsterdam, The Netherlands Brno, Czech Republic Universitá degli Studi di Roma Tor Vergata B. Simonsson Rome, Italy J. Rowe Uppsala Universitet P. Hokland Fund for Medical Research Development Uppsala, Sweden Aarhus University Hospital P. Ljungmann of Infrastructure and Health Services Aarhus, Denmark Karolinska Institutet Rambam Medical Centre M. Baccarini Stockholm, Sweden Haifa, Israel Universitá di Bologna S. O’Brien Unita Complessa di Istituti di Cardiologia University of Newcastle upon Tyne T. de Witte V. Savchenko ed Ematologia Newcastle upon Tyne, United Kingdom Stichting Katholieke Universiteit National Research Centre for Hematology Bologna, Italy University Medical Center Nijmegen Moscow, Russian Federation M. O’Dwyer Nijmegen, The Netherlands J. Huret National University of Ireland J. Sierra Université de Poitiers Galway, Ireland H. Döhner Institut de Recerca de l’Hospital Poitiers, France Universität Ulm de la Santa Creu i Sant Pau F. Mahon Ulm, Germany Barcelona, Spain A. Hagemeijer Université Victor Segalen Bordeaux 2 Katholieke Universiteit Leuven Bordeaux, France G. Ehninger R. Willemze Leuven, Belgium Technische Universität Dresden Leiden University Medical Center T. Ruutu Dresden, Germany Leiden, The Netherlands E. Montserrat Helsinki University Central Hospital Hospital Clinic Provincial de Barcelona Helsinki, Finland P. Fenaux J. Marie Barcelona, Spain Hôpital Avicenne (CHU Paris 13) Université Pierre et Marie Curie 6 G. Saglio Paris, France Paris, France N. Colita Universitá degli Studi di Torino Fundeni Clinical Institute Torino, Italy Bucharest, Romania

198 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME T. Barbui Monique van Oers M. Béné M. Kneba Azienda Ospedaliera-Ospedali Riuniti Academisch Ziekenhuis bij de Universiteit Université Henri Poincaré Nancy 1 University Hospital Schleswig-Holstein di Bergamo van Amsterdam Nancy, France Campus Kiel Bergamo, Italy Amsterdam, The Netherlands Kiel, Germany W. Gassmann H. Dombret J. Ribera St. Marien-Krankenhaus Siegen H. Hasselbalch Assistance Publique – Hôpitaux de Paris Institut Català d’Oncologia-Hospital Siegen, Germany Odense University Hospital Paris, France Universitari Germans Trias i Pujol Odense, Denmark Barcelona, Spain A. Orfao N. Ifrah Universidad de Salamanca F. Pane Centre Hospitalier Universitaire d’Angers C. Aul Salamanca, Spain CEINGE Biotecnologie avanzate s.c.a.r.l. Angers, France St. Johannes Hospital Duisburg Naples, Italy Duisburg, Germany W. Ludwig B. Labar Charité-Universitätsmedizin Berlin S. Daly University Hospital Center, Rebro, Zagreb C. Bernasconi Berlin, Germany Central Manchester and Manchester Zagreb, Croatia Fondazione Collegio Ghislieri Children’s University Pavia, Italy A. Neubauer Hospitals NHS Trust J. Walewski Philipps-Universität Marburg Manchester, United Kingdom The Maria Sklodowska-Curie Memorial N. Gattermann Marburg, Germany Cancer Centre Universitätsklinikum Düsseldorf R. Apweiler Institute of Oncology Düsseldorf, Germany N. Dastugue European Molecular Biology Laboratory Warsaw, Poland Centre Hospitalier Universitaire de Cambridge, United Kingdom G. Mufti Toulouse, Hôtel-Dieu Saint-Jaques G. Dighiero King’s College London Toulouse, France G. Basso Institut Pasteur London, United Kingdom Università degli Studi di Padova Paris, France T. Lion Padova, Italy C. Preudhomme Children’s Cancer Research Institute M. Hallek Centre Hospitalier-Régional Vienna, Austria S. Ferrari Universität Köln Universitaire de Lille University of Modena and Reggio Emilia Köln, Germany Lille, France J. Harbott Modena, Italy Justus-Liebig-Universität C. Geisler G. Barosi Gießen, Germany J. Hernández HS Rigshospitalet IRCCS Policlinico S. Matteo Fundación de Investigación del Cáncer Copenhagen, Denmark Pavia, Italy B. Johansson de la Universidad de Salamanca Lunds Universitet Salamanca, Spain F. Caligaris-Cappio N. Cross Lund, Sweden Universitá Vita-Salute San Raffaele University of Southampton M. Brune Milan, Italy Southampton, United Kingdom S. Knuutila Göteborg University University of Helsinki Göteborg, Sweden E. Matutes F. Frassoni Helsinki, Finland Institute of Cancer Research Azienda Ospedaliera E. Gluckman London, United Kingdom Ospedale San Martino D. Lillington Association pour la Recherche Genoa, Italy Queen Mary University of London sur les Transplantations Médullaires D. Oscier London, United Kingdom Paris, France Royal Bournemouth and Christchurch M. Le Bousse-Kerdilès Hospital NHS Trust Institut National de la Santé C. Mecucci W. Jedrzejczak Bournemouth, United Kingdom et de la Recherche Médicale Università degli Studi di Perugia Akademia Medyczna w Warstawie Paris, France Perugia, Italy Medical University of Warsaw T. Robak Warsaw, Poland Uniwersytet Medyczny w Lodzi A. Schmitt-Gräff M. Rocchi Lodz, Poland Universitätsklinikum Freiburg Università degli Studi di Bari G. Krivan Freiburg, Germany Bari, Italy St. Laszlo Hospital X. Troussard Budapest, Hungary Centre Hospitalier Universitaire de Caen J. Reilly P. Bernasconi Caen, France The University of Sheffield Universita degli Studi di Pavia Sheffield, United Kingdom Pavia, Italy

TREATMENT 199 Project number LSHC-CT-2004 503216 L. Kanz T. Masszi N. Savva Eberhard-Karls Universität Tübingen National Medical Center Belarusian Research Center for Pediatric EC contribution Tübingen, Germany Budapest, Hungary Oncology and Hematology of Ministry € 6 000 000 of Health of Belarus P. Martiat T. Haferlach Minsk, Belarus Duration Jules Bordet Institute MLL Münchner Leukämielabor GmbH 60 months Free University of Brussels München, Germany U. Ozbek Brussels, Belgium Istanbul University Starting date H. Link Istanbul, Turkey 01/01/2004 A. Levitzki Westpfalz-Klinikum GmbH The Hebrew University of Jerusalem Kaiserslautern, Germany L. Dusek Instrument Jerusalem, Israel Masarykova univerzita NoE P. Klener Brno, Czech Republic A. Locasciulli Ustav hematologie a krevni transfuze Project website Azienda Ospedaliera San Camillo-Forlanini Praha, Czech Republic K. Mills www.leukaemia-net.org Rome, Italy The Queen’s University of Belfast D. Haase Belfast, United Kingdom C. Viscoli Universitätsmedizin Göttingen University of Genoa Georg-August-Universität Göttingen M. Frew Alessandro M. Vannucchi Genoa, Italy Stiftung Öffentlichen Rechts University of Dundee University of Florence Göttingen, Germany Dundee, United Kingdom Dipartimento di Area Critica K. Ward Medico-Chirurgica University College London E. Roman Adriaan w. Dekker Florence, Italy London, United Kingdom University of York University Medical Center Utrecht York, United Kingdom Utrecht, The Netherlands William Vainchenker J. Duyster Institut Gustave Roussy Technische Universität München C. Gambacorti-Passerini Richard Clark Villejuif, France München, Germany Università degli Studi di Milano – Bicocca The University of Liverpool Milan, Italy Liverpool, United Kingdom Darinka Boskovic W. Fiedler Institute of Hematology Clinical Universitätsklinikum Hamburg-Eppendorf K. Indrák Charles Craddock Center of Serbia Hamburg, Germany University Palacky The University of Birmingham Belgrade, Serbia Olomouc, Czech Republic Birmingham, United Kingdom M. Ackermann Jean Gabert Megapharm GmbH M. Mittelman Ana-Maria Vladareanu Université de la Méditerranée Sankt Augustin, Germany Tel-Aviv Medical Center Universitatea de Medicina si Farmacie Aix Marseille II Tel Aviv, Israel ‘Carol Davila’ Bucuresti Marseille, France H. Zwierzina Bucharest, Romania Innsbruck Medical University C. Sambani Henrik Hjorth-Hansen Innsbruck, Austria National Center for Scientific Gertraud Tschurtschenthaler Norwegian University of Science Research (NCSR) ‘Demokritos’ Krankenhaus der Barmherzigen Schwestern and Technology R. Fuchs Ag. Paraskevi Linz Betriebs GmbH Trondheim, Norway St Antonius-Hospital Eschweiler Athen, Greece Linz, Austria Eschweiler, Germany M. Gönül Ogur A. Zaritskey Laimonas Griskevicius Ondokuz Mayis University Medical Faculty F. Hermitte St. Petersburg State Pavlov Medical Vilnius University Hospital Samsun, Turkey Ipsogen University Santariskiu Clinics Marseille, France St. Petersburg, Russian Federation Vilnius, Lithuania Thomas Lion LabDia Labordiagnostik GmbH H. Einsele A. Zaritskey Larisa Fechina Vienna, Austria Bayerische Julius-Maximilians-Universität Federal State Institution Centre for State Institution of Healthcare ‘Regional Würzburg Heart, Blood and Endocrinology named Children’s Hospital #1’ Paul Costeas Würzburg, Germany after V. A. Almazov Ekaterinburgh, Russian Federation Karaiskakio Foundation St. Petersburg, Russian Federation Nicosia, Cyprus

200 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Mantle cell lymphoma | therapy | molecular risk factors | minimal residual disease (MRD) | pharmacogenomics | RNA array profi ling | proteomics |

European MCL Network a global approach to investigate innovative treatment options of MCL and evaluate new predictive (pharmacogenomics, European Mantle Cell Lymphoma minimal residual disease) and prognostic molecular markers (genomic alterations, RNA/proteome profi les) in controlled Network: Translation evaluation prospective studies. This translational approach of the Euro- pean MCL Network will not only lead to more individualised of molecular prognostic factors and therapeutic strategies based on the molecular risk profi le but will also fi nally elucidate the way to future molecular targeted pharmacogenomics in European treatment options in a subtype of malignant lymphoma with interdisciplinary collaboration an otherwise dismal clinical outcome. Expected results

Summary • Prospective evaluation of combined immunochemotherapy and myeloablative consolidation in patients <65 years: Mantle cell lymphoma (MCL) is a subtype of malignant lym- R-CHOP followed by myeloablative consolidation vs. phoma with an especially poor prognosis. Recently, a European R-CHOP/R-DHAP followed by high dose Ara-C therapy. MCL Network of clinicians, basic scientists and pathologists • Prospective evaluation of combined immunochemother- has been established to investigate the clinical as well as apy and diff erent maintenance strategies in patients molecular aspects of MCL. In previous clinical trials, the supe- >65 years: R-CHOP vs. R-FC followed by IFN vs. Rituximab riority of innovative treatment options (high dose therapy, maintenance. combined immuno-chemotherapy) has been confi rmed, and • Regular histomorphological panel review of study cases cell proliferation has been identifi ed as the most important (subtyping according to cytological criteria). prognostic factor. Based on these extensive prerequisites, we • Prospective evaluation of a panel of proliferation-associated have initiated a translational approach to evaluate innovative and new oncogenic markers (immuno-histochemistry). treatment options (like immuno-chemotherapy, radioimmu- • Prospective evaluation of MRD detection (PCR, FACS, notherapy, high dose consolidation and molecularly targeted FISH) in the patient cohort of the European MCL Network. approaches) and molecular prognostic markers in prospec- • Prospective evaluation of the proliferation-associated tive randomised studies. All study cases are subjects of gene signature in the patient cohort of the European innovative molecular analyses and continuous detection of MCL Network (RNA array). minimal residual disease. This translational approach will not only lead to more eff ective therapeutic strategies based on the molecular profi ling but also pave the way to molecular Potential applications targeted treatments. Malignant lymphoma is currently the fourth most frequent malignant disease and displays the highest increase in annual Problem incidence of all hematological neoplasias. In this regard, the exploration of innovative treatment strategies and evalua- Mantle cell lymphoma (MCL) is a distinct, clinically very tion of prognostic markers in the rather rare disease of aggressive subentity of malignant lymphoma with a median mantle cell lymphoma is also a model disease for much survival of three years. However, a small subset of patients more frequent diseases which have a profound impact on represents long-term survivors. So far, the discriminative the public health system as well as the general society. The power of diff erent prognostic parameters has been limited prospective studies of the European MCL Network studies and did not allow the reliable identifi cation of the individual will enable us to gain a deeper understanding of the patho- patient’s risk profi le. Thus, a better understanding of the physiological network of cell programme regulation in underlying molecular mechanisms is eagerly warranted. malignant lymphoma. In addition, applying this multivariate procedure, the critical biological players of malignant trans- formation will be identifi ed which may represent the suitable Aim target genes of future treatment strategies in a disease with otherwise dismal prognosis. Moreover, this collaboration of Based on the previously established European MCL Network outstanding clinical as well as molecular scientists will be of clinicians, basic scientists and pathologists and the recent a paradigm for other fi elds of biological research interlinking development of innovative molecular techniques (matrix CGH, clinical and basic science as well as scientifi c excellence RNA array chips, RQPCR, proteomics), we are performing from all over Europe.

TREATMENT 201 Coordinators Project number LSHC-CT-2004-503351 Martin Dreyling Jose Angel Martinez-Climent Gilles Salles Wolfgang Hiddemann Fundación Para la Investigación Université Claude Bernard Lyon-1 EC contribution University Hospital Großhadern Medica Aplicada Centre Hospitalier Lyon-Sud € 2 493 900 Ludwig-Maximilians-Universität München Centro para la Investigación Service d’Hématologie Dept. of Medicine III Medica Aplicada Pierre-Bénite, France Duration Munich, Germany Laboratorio de Oncologia Molecular 108 42 months [email protected] Universidad de Navarra Brigitte Schlegelberger Pamplona, Spain Medizinische Hochschule Hannover Starting date Inst. für Zell- und Molekularpathologie 01/07/2004 Partners Thomas Meitinger Hannover, Germany GSF National Research Institute Instrument Niels Smedegaard for Environment and Health Reiner Siebert STREP Andersen Rigshospitalet Institut für Humangenetik Ingolstädter University Hospital Schleswig-Holstein University Hospital Copenhagen Neuherberg, Germany Campus Kiel Project website Dept. of Hematology Institute of Human Genetics www.lymphome.de Copenhagen, Denmark German Ott Kiel, Germany Andreas Rosenwald Elias Campo Bayerische Julius-Maximilian-Universität Catherine Thieblemont Hospital Clinic Würzburg Evelyne Callet-Bauchu University of Barcelona Pathologisches Institut Université Claude Bernard Lyon-1 Hematopathology Section Würzburg, Germany Équipe Associée Pathologie Laboratory of Pathology des Cellules Lymphoides Barcelona, Spain Reza Parwaresch Pierre-Bénite, France Wolfram Klapper J.J.M. van Dongen Universitätsklinik Kiel Institut Marek Trnény Erasmus University Medical für Hämatopathologie Univerzita Karlova v Praze Center Rotterdam Würzburg, Germany (Charles University of Prague) Dept. of Immunology 1st Dept. of Medicine Rotterdam, The Netherlands Christiane Pott 1st Faculty of Medicine University Hospital Schleswig-Holstein Prague, Czech Republic Philip M. Kluin Campus Kiel Academic Hospital Groningen II. Med. Klinik und Poliklinik Jan Walewski Dept. of Pathology Kiel, Germany Maria Sklodowska-Curie Memorial and Laboratory Medicine Cancer Center Groningen, The Netherlands Vincent Ribrag Institute of Oncology Institut Gustave Roussy Warsaw, Poland Johannes H.J.M. van Krieken Sce d’Hématologie Stichting Katholieke Universiteit Villejuif, France University Medical Centre Nijmegen Dept. of Pathology Nijmegen, The Netherlands

202 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Hypoxia | HIF | pericellular | human | drug |

EUROXY Aim

Targeting newly discovered The consortium want to develop a new class of anti-cancer agents targeting and disrupting the adaptive mechanisms oxygen-sensing cascades exploited by human cells when exposed to low oxygen for novel cancer treatments tensions. Expected results

Summary Within the remaining three years, the consortium expects to have a better knowledge of the cellular responses to low A fi ve-year eff ort to develop anti-cancer drugs targeting oxygen tension and to know regulatory molecular pathways the hypoxia responsive regulatory pathways in human cells important for cell adaptation to hypoxia. was fi nished the fi rst two years. It has led to a better under- standing of the therapy resistance of cells at hypoxia and The consortium also expects to have developed a technolo- a much more detailed knowledge about the pathways gy platform for measuring pericellular oxygen tensions involved. To work under controlled conditions, in vitro and in vitro and in vivo and to have methods for non-invasive in vivo technology has been developed to keep and record determination of oxygen tensions. the peri cellular oxygen tension. It is still unclear if the pre- ferred target for intervention will be the cells oxygen sensors We further expect to have in vitro and animal tested a few upstream from HIF or HIF itself or one of the downstream novel and patented compounds for cytostatic eff ects on molecules like the hypoxia induced electron pumps for human cancer cells kept at in vivo relevant low oxygen which we are patenting new inhibitors. tension.

We ultimately hope to have compounds that will attract Problem private companies to undertake further development work.

Most solid human tumours have areas where the cells are exposed to low oxygen tension. Low oxygen tension is cor- Potential applications related with a bad prognosis. Hypoxic tumour tissues usually have a lowered susceptibility to conventional treatment with Anticancer drugs. irradiation and cytostatics.

TREATMENT 203 Coordinator Project number LSHC-CT-2003-502932 Peter Ebbesen Anders Damholt Andea Scozzafava Aalborg University Leo Pharma A/S University of Florence EC contribution Aalborg East, Denmark Ballerup, Denmark Florence, Italy € 8 000 000 [email protected] [email protected] [email protected] Duration Patrick Maxwell Ian Stratford 60 months Partners Imperial College of Science Victoria University of Manchester Technology and Medicine Manchester, United Kingdom Starting date Stephane Illiano London, United Kingdom [email protected] 01/02/2004 Sanofi-Aventis [email protected] Vitry sur Seine, France Gerald Urban Instrument [email protected] Stuart Naylor Albert Ludwigs University Freiburg IP Oxford Biomedica plc Freiburg, Germany Arvydas Kanopka Oxford, United Kingdom [email protected] Project website Institute of Biotechnology [email protected] www.euroxy.info/ Vilnius, Lithuania Jan Villadsen [email protected] Silvia Pastorekova ViVoX ApS Institute of Virology Aarhus C, Denmark Roland Wenger Slovak Academy of Sciences [email protected] Max Gassmann Bratislava, Slovakia University of Zurich [email protected] Kai-Uwe Eckardt Zurich, Switzerland Universität Erlangen-Nürnberg [email protected] Erik Pettersen Erlangen, Germany [email protected] University of Oslo [email protected] Oslo, Norway Agnes Görlach [email protected] Deutsches Herzzentrum München München, Germany Lorenz Poellinger [email protected] Karolinska Institutet Stockholm, Sweden Gerhard Jobst [email protected] Jobst Technologies GmbH Freiburg, Germany Peter Ratcliffe [email protected] Adrian Harris The Chancellor Philippe Lambin Masters and Scholars Brad Wouters of the University of Oxford Universiteit Maastricht Oxford, United Kingdom Maastricht, The Netherlands [email protected] [email protected] [email protected] [email protected] Jörn Glöckler Alfons Krug RiNA-Netzwerk RNA LEA Medizintechnik GmbH Technologien GmbH Giessen, Germany Berlin, Germany [email protected] [email protected]

204 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Radiation-induced complications | adult stem cell therapy | cancer therapy |

FIRST and biotechnological developments, only recently it has become apparent that bone marrow transplantation may res- Further improvement of radiotherapy of cue other organs. Moreover, cells from certain tissues may even repopulate the haematopoietic system. Similar fi ndings cancer through side-eff ect reduction by have been reported for stem cells derived from other tissues than bone marrow. However, tissue specifi c cells are only application of adult stem cell therapy available in small numbers. Therefore, bone marrow stem cells have the largest clinical potential to be used for trans- plantation into irradiated organisms or individual normal tissues to provide the organ with suffi cient numbers of cells Summary necessary for regeneration.

Radiotherapy is the second most important treatment modality after surgery in the treatment of cancer. At pres- Aim ent over 50% of all cancer patients receive radiotherapy at one stage in their course. Inevitably normal tissues are also The aim of the project is to develop and optimise techniques exposed to ionising radiation during radiotherapy of to prevent radiation-induced normal tissue complications tumours. This can result in organ failure and hence can using adult stem cell therapy. The tissues of interest will be seriously limit the treatment dose. Reduction of the side- oral mucosa, skin, gut and salivary gland tissues. The fi rst step eff ects of radiotherapy will not only increase the quality of will be to provide proof of principle for the impact of stem life after the treatment but may also result in increased cells on the repair of irradiated tissues. survival of cancer patients as it will allow dose escalation to the tumour. This is true even if the most optimal physi- To this end protocols for the isolation, mobilisation, and char- cal dose delivery (conformal therapy, protons) of radiation acterisation of bone marrow derived stem cells will be is applied. Radiationinduced organ failure is mainly caused performed and developed. Specifi c targeted approaches for by stem cell sterilisation, leading to a reduced reconstitu- transplantation of bone marrow derived stem cells will be tion of functional cells. The innovative vision of this project designed and tested. is to reduce radiation-induced complications through stem cell therapy. Replenishment of the depleted stem cell com- partment should allow regeneration of irradiated tissues. Expected results A successful replacement of stem cells and subsequent amelioration of radiation-induced complications may open • Optimised protocols for isolation, generation, mobilisa- the road to completely new strategies in radiotherapy and tion, characterisation and expansion of stem cells from help combat cancer. bone marrow.

• Demonstration of proof of principle for the use of bone Problem marrowderived stem cells to modifi cate radiation-induced normal tissue damage in animal models. Many attempts have been made to attenuate radiation- induced damage to normal tissues. Although much knowledge has been obtained on the mechanism of radiosensitivity of Potential applications normal tissue, and the pathogenic pathways that eventually result in loss of function, the vast majority of remedies are The resulting scientifi c and (bio)technological knowledge and either inadequate, diminish in time or have not been shown to a successful replacement of stem cells and subsequent amel- be selective for normal tissue only. Therefore a completely ioration of radiation-induced complications may eventually new approach is needed. Today bone marrow transplantation lead to new and improved cancer treatment strategies which is common clinical practice. Due to new scientifi c knowledge will profoundly increase radiotherapy treatment success.

TREATMENT 205 Project number LSHC-CT-2004-503436

EC contribution € 1 500 000

Duration 30 months

Starting date 01/09/2004

Instrument IP

Project website www.rug.nl/med/ onderzoek/ internationaleprojecten/ europeseprojecten/fi rst

The blocks of work (BOW) are divided into work packages (WPs). WPs 1-4 are the normal tissues studied. They use the methods described to determine the success of transplantation. WPs 5-8 concern the diff erent stem cell types and protocols. Common techniques are shared and are distributed to BOW 1. TUD (P5): Medical Faculty Carl Gustav Carus, Radiobiology Laboratory, Prof. Wolfgang Dörr (DE). CEA (P3): Service de Génomique Fonctionnelle, Dr. Michèle Martin (FR). University of Groningen, RSCB (P1): Radiation and Stress Cell Biology, Dr. Robert Coppes (Coordinator, NL). IRSN (P3): Département de Radioprotection de la Santé de l’Homme et de Dosimetrie, Dr. Dominique Thierry (FR). SCB (P2): University of Groningen, Stem Cell Biology, Prof. Gerald de Haan (NL). LH (P7): Université François Rabelais, Faculté de Médecine, Laboratoire d’Hématopoïèse, Dr. Pierre Charbord (FR). 7TM (P9): 7TM Pharma A/S, Hørsholm.

Coordinator Partners

Rob P. Coppes Gerald De Haan Wolfgang Dörr Pierre Charbord University Medical Center Groningen University Medical Center Groningen University of Technology Dresden Université François Rabelais Dept. of Radiation and Stress Cell Biology Dept. of Stem Cell Biology Dept. of Radiotherapy Faculté de Médecine Dept. of Radiotherapy Groningen, The Netherlands and Radiation Oncology Laboratoire d’Hématopoïèse Groningen, The Netherlands [email protected] Radiobiology Laboratory Tours, France [email protected] Dresden, Germany [email protected] [email protected] Jan Wondergem [email protected] Leiden University Medical Center Dominique Thierry Dept. of Clinical Oncology Michèle Martin Institut de Radioprotection Laboratory for Experimental Radiology Commissariat à l’Énergie Atomique et de Sûreté Nucléaire Leiden, The Netherlands Département de Radiobiologie Independent Section of Radiobiology [email protected] et Radiopathologie Applied to Medicine Service de Génomique Fonctionnelle Human Health Protection and Dosimetry Evry, France Fontenay aux Roses, France [email protected] [email protected]

206 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Gene therapy | adenovirus | non-viral vectors | prostate cancer | gene promoters | stealthing | re-targeting |

GIANT Problem

Gene therapy: an integrated approach Prostate cancer, particularly in its advanced stages, remains refractory to conventional therapies and is therefore a good for neoplastic treatment target for gene-based therapies. However, without adequate specifi city and a fundamental knowledge of the parameters which reduce effi cacy when vectors developed in tissue cul- ture are employed in human subjects, these new gene-based Summary therapies will fail to become established in clinical practice.

The translation of genetic knowledge from the human genome into disease-specifi c therapy for untreatable con- Aim genital disorders and acquired diseases is now becoming a reality. However, the gene therapy vectors currently used The aim of the GIANT project is to produce a range of pros- in experimental settings can be developed for safe clinical tate targeted and stealthed viral and non-viral vectors for application only if fundamental problems are solved; i.e. the ultimate testing in Phase I clinical studies. limitation of vector dose by attachment targeting and expression control, and a decrease of non-specifi c toxicity. Minimisation of vector immunogenicity (stealthing) is nec- Expected results essary to reduce bloodstream and immune-mediated reduction of eff ective vector concentration. • New generations of gene transfer vectors, targeted to prostate cancer cells. GIANT will therefore concentrate fi rstly on one uniform • Stealthed vectors that have a longer half-life and effi cacy model system and disease target (prostate carcinoma) for in human tissues. vector testing standardisation and in vitro, preclinical and • International multi-centre, Phase I clinical trials of gene ther- clinical vector comparison. We will use a clinically approved apy for prostate cancer. Acceptance of gene therapy for vector backbone of adenoviral constructs re-targeted to prostate cancer in the European Urological Community. prostate cancer via surface antigens, and hybrid prostate- targeted promoters. The consortium includes a GMP vector production facility and clinical facilities with scientifi c and Potential applications ethical permission to carry out human cytotoxic gene ther- apy trials, guaranteeing effi cient translation of selected • Gene therapy for prostate cancer. vectors into clinical testing. The biomaterials obtained will • Safe, targeted vectors for human gene transfer. serve to develop new assays for vector distribution, effi cacy • A greater understanding of the human immune response and monitoring of the immune response against various against gene transfer vectors. vector systems.

The GIANT participants have a long record of EU-based sci- entifi c collaboration and expertise in ethically approved clinical vector generation. The SMEs own international pat- ents on retargeting vectors and target discovery methods, providing a technology platform for further exploration of promising targets and innovative approaches to facilitate treatment of neoplastic diseases.

TREATMENT 207 Project number LSHB-CT-2004-512087

EC contribution € 9 683 102

Duration 60 months

Starting date 01/01/2005

Immunogenicity testing model. Instrument IP

Project website www.giant.eu.com Coordinator

Norman J. Maitland Stefan Kochanek Jean-Paul Behr YCR Cancer research Unit (Area13) Division of Gene Therapy Laboratorie de Chimie Génétique Dept. of Biology University of Ulm Unité Mixte CNRS & Université University of York Ulm, Germany Louis Pasteur de Strasbourg York, United Kingdom [email protected] Faculté de Pharmacie [email protected] Illkirch, France Karel Ulbrich [email protected] Dept. of Biomedicinal Polymers Partners Institute of Macromolecular Chemistry Patrick Erbacher Academy of Sciences of Czech Republic Polyplus Transfection Chris H. Bangma Prague, Czech Republic Bioparc Dept. of Urology [email protected] Illkirch, France Erasmus MC [email protected] Rotterdam, The Netherlands Leif Lindholm [email protected] Gotagene AB, Holtermansgatan 1B Kerry Fisher Stena Center Hybrid Systems Ltd Thomas Totterman Goteborg, Sweden Upper Hayford, United Kingdom Clinical Immunology Division [email protected] [email protected] Rudbeck Laboratory Uppsala University Wytske van Weerden Uppsala, Sweden Scuron [email protected] Rotterdam, The Netherlands [email protected] Leonard Seymour Dept. of Clinical Pharmacology Alan Raymond Radcliffe Infirmary Pro-Cure Therapeutics Ltd University of Oxford Biocentre Oxford, United Kingdom York, United Kingdom [email protected] [email protected]

Rob Hoeben Ernst Wagner Dept. of Molecular Cell Biology Centre for Drug Research Leiden University Medical Center Dept. of Pharmacy Leiden, The Netherlands Pharmaceutical Biology – Biotechnology [email protected] Munich, Germany [email protected]

208 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Dependence receptors | apoptosis | tumour suppressor |

HERMIONE are very invasive, and advanced stage cancer patients treated with cytotoxic therapeutics are often subject to Novel Anticancer Therapeutics based debilitating side- eff ects. Therefore, there is a great need to develop more precise therapeutics, to reduce side-eff ects on Modulation of Apoptosis through and improve the overall wellbeing of treated patients. Dependence Receptors Aim

The aim of HERMIONE is to understand better how dysfunc- Summary tions in DR-signalling can lead to tumour formation and/or progression. The generated knowledge will be applied to Receptors are usually seen as inactive unless bound by their the development of targeted drugs, to provide safer and ligand. However, a new concept has emerged since 1998, by more eff ective treatments for patients. which some receptors can in fact mediate two diff erent sig- nalling pathways, depending on the presence or absence of The following models, by which DRs regulate tumour initia- their ligand. Studies of such receptors have indeed revealed tion, progression and metastasis, can be surmised from that, in the absence of ligand, signalling initiates an active current knowledge on DR-signalling and illustrate the process leading to cell death via apoptosis, whereas pro- project’s hypothesis that these receptors act as tumour sup- grammed cell death is inhibited in the presence of the pressors via their pro-apoptotic activity: in a normal context: ligand. Therefore, expression of these receptors leads to the receptor is bound by its ligand and induces a positive a state of cellular dependence on their respective ligands, signal (survival, diff erentiation, etc.). In the case of genetic which is why they have been named ‘Dependence Recep- alteration leading to cell transformation and thus cell prolif- tors’ (DRs). The diff erent DRs trigger apoptosis in the eration, the concentration of ligand in the extracellular absence of ligand, suggesting that they may all act as regu- environment becomes insuffi cient to bind all receptors. lators of tumourigenesis. In addition, expression of DRs is In some cases, cells acquire the property to migrate into the lost or decreased in many tumours, suggesting that they blood circulation and/or invade other tissues where the lig- act as tumour suppressors and that their loss represents and is absent. Unbound dependence receptors consequently a selective advantage for tumour cells. trigger apoptosis.

HERMIONE proposes that unravelling the link between dif- According to these models, a selective advantage for a tumour ferent DRs (DCC, UNC5H, KAI1 and RET), downstream cell would be to lose the death activity of DRs by mutation, to molecules and apoptosis will lead to the identifi cation of curb their expression or to acquire autocrine expression of the new potential targets for anti-cancer drugs. The project will ligand. Therefore, Dependence Receptors appear to be origi- provide a better understanding of the signalling pathways nal targets for combating cancer and potential candidates to acting downstream of DRs, observe the association of be studied in the aim of developing novel cancer thera- mutations with the onset and progression of tumours peutics. In order to achieve this, proper understanding of (grade, prognosis), and generate murine models in which the way these receptors induce apoptosis, i.e. deciphering the apoptotic signalling of the DR is turned off to study the the signalling pathways operating downstream, is of great implication of DRs in tumourigenesis in vivo. Through this, importance. HERMIONE will generate knowledge on DR-signalling path- ways involved in the apoptosis of tumoural cells (colorectal, breast, thyroid and prostate cancers) and use the general Expected results concept of Dependence Receptors to select and perform pre-clinical testing of novel anti-cancer drugs. • Understanding the fundamental phenomena: • to yield better understanding of the signalling path- ways that act downstream of dependence receptors. Problem Understanding the way Dependence Receptors are linked to the trigger of apoptosis will provide targets Colorectal, breast and prostate cancer are among the com- for drug development; monest forms of cancer in Europe. Breast cancer is the main • to analyse the status of DR/ligand pairs in human cause of death by cancer, killing over 400 000 women a year. tumourigenesis: is there a selective advantage to los- There is no effi cient treatment against metastatic breast ing expression of the receptor, gaining autocrine tumours and available anti-cancer treatments are imperfect, expression of the ligand or losing death function by therefore the probability of cure is not high. Existing treat- mutation? From these studies, clear links between ments are highly toxic to normal tissue and cause substantial DRs and tumour progression will be established, loss of life quality. Surgery, chemotherapy and radiotherapy thereby generating new markers for prognosis.

TREATMENT 209 • Applying scientifi c knowledge to the identifi cation and Project number pre-clinical validation of novel anti-cancer drugs: LSHC-CT-2006-037530 • generation of new markers for tumours, valuable tools for prognosis; EC contribution • development of peptides and monoclonal antibodies: € 2 364 909 by studying diff erent DRs and their respective ligands, the Consortium will validate targets in mouse models Duration through the development of recombinant proteins and 36 months monoclonal antibodies; • development of anti-cancer agents: the data collected Starting date through this project will provide the basis for the devel- 01/11/2006 opment of small molecules as anti-cancer agents. Instrument STREP Potential applications Project website HERMIONE will enable better understanding of how dys- http://hermionetypo. functions in dependence receptors signalling can lead to prodige.com/ tumour formation and/or progression. The knowledge gen- erated will be applied to the generation of targeted drugs, providing safer and more eff ective treatments for patients. The work performed within this project will include the development of new biomarkers that will provide means for both diagnosis and prognosis. The amount of fundamental knowledge generated within the project will allow better comprehension of the events linking dependence receptors to tumour progression and provide targets to modulate apoptosis of tumour cells. This will provide valuable data to identify Dependence Receptors that could be involved in other types of cancer.

Coordinator

Patrick Mehlen Olivier Donze Centre Léon Bérard Apotech Corporation Lyon, France Epalinges, Switzerland [email protected] Stefan Grimm Imperial College of Science, Partners Technology and Medicine London, United Kingdom Jurg Tschopp Université de Lausanne John Hickman Lausanne, Switzerland Institut de Recherche Servier Suresnes, France Giovanni Romeo Alma Mater Studiorum Raffaella Catena Universita di Bologna Alma Consulting Group Bologna, Italy Lyon, France

Screen for apoptosis genes by highly specialised custom-made robots.

210 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Photodynamic therapy | antibody-photosensitiser conjugates | tumour neovasculature |

Immuno-PDT PDT is a modality of cancer treatment that causes cytotoxic action only locally in the region of exposure to laser light Immunophotodynamic therapy with a specifi c wavelength matching the absorption profi le of the photosensitiser, thus leading to very site specifi c tox- of cancer: concepts and applications icity. The targeted delivery of photosensitisers to suitable neoplastic sites is likely to increase the scope and the effi ca- cy of PDT therapy still further. The antibody-mediated targeted delivery of photosensitisers to the tumour neo- Summary vasculature mediates a rapid occlusion of blood vessels, thus depriving tumour cells of oxygen and nutrients and trig- Photodynamic therapy of cancer, i.e. the generation of reac- gering an avalanche of tumour cell deaths. As an additional tive oxygen species in the tumour environment which follows benefi t, lower doses of photosensitiser can be administered, the irradiation of suitable photosensitising molecules, is an thus reducing problems of skin photosensitivity. attractive modality for the selective ablation of inoperable superfi cial neoplastic lesions. In this project, we have put together a network of academic research groups and com- Aim panies for the development of antibody-based targeted photodynamic therapy modalities. The present project has as objectives the synthesis and con- jugation of novel infrared photosensitisers to the most The planned research activity starts with the synthesis of nov- promising antibodies against vascular tumour antigens el photosensitising molecules suitable for conjugation to obtained by human antibody technology, the immunohisto- antibodies, and with the identifi cation of novel human mono- chemical characterisation, the biodistribution and imaging clonal antibodies capable of a selective targeting of the targeting in vivo, in order to select the best antibody-photo- tumour neovasculature for immuno-PDT applications. Follow- sensitiser conjugates to be taken forward into clinical trials ing an extensive in vitro characterisation of the most promising as a fi nal objective. antibody-photosensitiser conjugates, the therapeutic poten- tial of the best conjugates will be tested in rodent models of In details, the objectives are: cancer, paving the way for future clinical applications. • the synthesis of novel infrared photosensitisers with suf- fi cient water solubility (i.e., not sticky to unwanted cells and tissues), which absorb in the near-infrared light Problem spectrum and which effi ciently generate singlet oxygen and/or other reactive oxygen species; Cancer chemotherapy is generally accompanied by severe • screening of phage display libraries to fi nd the most suit- side eff ects, mainly due to unspecifi c cytotoxicity of classic able antibodies for the project; antineoplastic treatments. Photodynamic Therapy contrib- • investigation of a novel method for the conjugation of utes to a signifi cant effi cacy in the treatment of neoplastic the antibody and photosensitiser molecules. We pro- and abnormal tissues, using a combination of photosensitiser, pose to investigate the coupling of photosensitisers to such as porphyrin, chlorin, bacteriochlorin or phthalocyanine antibodies, based on the non-covalent but stable inter- derivatives, and tissue-penetrating visible laser light. Laser action of photosensitising molecules with specifi c antibody light promotes the photosensitiser to its excited state. The fragments or suitable single domain binders; photosensitiser, in turn, interacts with molecular oxygen and • evaluation of the conjugates in vitro e in vivo. Our novel PDT returns to its ground state, resulting in the generation of agents will be extensively tested in vitro, in order to ascer- the highly localised cytotoxic agent, singlet oxygen, which tain whether non-covalently bound photosensitisers can ultimately aff ords tumour destruction. retain singlet oxygen production activity upon irradiation.

TREATMENT 211 The agents will be tested in rodent models of cancer and, if Project number successful, will open novel therapeutic opportunities for the LSHC-CT-2006-37489 selective treatment of superfi cial tumors in accessible body cavities. EC contribution € 3 000 000

Expected results Duration 36 months Most importantly, there is a reasonable expectation of a med- ical benefi t for cancer patients stemming both directly and Starting date indirectly from this project: 01/10/2006 • directly, since immuno-PDT procedures promise to be invaluable for the selective ablation of inoperable super- Instrument fi cial neoplastic lesions, such as certain head&neck, STREP – SME gastrointestinal, urogenital and gynecological tumours; • indirectly, since the knowledge generated by the validation Project website of novel antibodies for vascular targeting applications is www.immunopdt.net likely to have an impact in other forms of immunotherapy, including the use of full IgGs and antibody-cytokine fusions for cancer therapy. Coordinators

Potential applications Chiara Falciani Luciano Zardi Reinerio Gonzalez Centro Biotecnologie Avanzate When considering immuno-PDT applications in oncology in Philogen Genova, Italy a strict sense, the potential market is directly determined by Siena, Italy the incidence of inoperable superfi cial neoplastic lesions, [email protected] Dario Neri such as certain head&neck, gastrointestinal, urogenital and [email protected] Swiss Federal Institute of Technology gynecological tumors, which would benefi t from a PDT- Zurich, Switzerland based ablation. Partners Peter Vajkoczy In a broader sense, discoveries in terms of new tumour tar- University of Heidelberg gets, new antibodies, new coupling methodologies and new Ross Boyle Heidelberg, Germany photosensitisers will benefi t several areas of biomedical University of Hull development, including non-oncological indications such as Hull, United Kingdom Mahendra Deonarain potentially-blinding angiogenesis-related ocular disorders Imperial College London (age-related macular degeneration, diabetic retinopathy). Gokhan Yahioglu London, United Kingdom Photobiotics London, United Kingdom Christina Kousparou Trojantec Nicosia, Cyprus

212 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Ovarian cancer | thymidylate synthase inhibitor | small molecule inhibitor design |

LIGHTS However the occurrence of resistant cell populations in the tumour, limiting the usefulness of the platinum drug, represents Small ligands to interfere with Thymidylate a growing problem. Resistant cells often become refractory to the initially used drugs and are extremely diffi cult to eradicate, Synthase dimer formation as new tools therefore the use of drug combinations is necessary. for development of anti-cancer agents The combination of cDDP and antifolates such as azidothymi- dine (AZT), a deoxythymidine analogue or, more recently, against ovarian carcinoma pemetrexed (Alimta) that inhibits three enzymes in the de novo purine and pyrimidine pathways, has been shown to synergis- tically aff ect the growth of human ovarian carcinoma cells resistant to cDDP. Due to the role played by the enzymes of Summary DNA synthesis and repair in the occurrence of cDDP-resist- ance, it seems of great priority to develop clinical reagents Ovarian cancer is the fi fth most common cause of death from designed to limit the intracellular level of TS protein which is cancer in women. The standard fi rst-line treatment is a com- associated with clinical resistance, thus sensitising even resist- bination of paclitaxel and carboplatin or carboplatin alone. ant cells to the eff ects of anti-cancer drugs. The ultimate aim In the case of progressive disease or drug resistance treat- of LIGHTS is to directly halt tumour progression and interfere ment with platinum, either alone or in combination, especially with the development of drug resistance upon treatment with investigational compounds should be used. The mechanisms platinum-derived drugs by inhibiting the protein regulatory behind acquired resistance to cisplatin (cDDP) and its deriva- function of TS through small molecule cellular perturbation. tives are not clear yet, although it is evident that the process is multifactorial, including enhanced DNA repair. In the human ovarian carcinoma cell line A2780, a three-fold-cDDP- resist- Aim ance was associated with cross-resistance to the thymidylate synthase (TS) inhibitor 5-fl uorouracil and to methotrexate, The project is clearly oriented to directly halt the progres- a 2.5-fold increase in TS, and an increase in the intracellular sion of ovarian cancer and to interfere with the development pools of the TS cofactor 5, 10-methylentetrahydrofolate and of drug resistance, upon treatment with platinum-derived of tetrahydrofolate. drugs, by inhibiting the protein regulatory function of mono- meric TS. The intermediate objectives are based on employing The ultimate goal of LIGHTS is to directly halt tumour pro- novel medicinal chemistry strategies to identify potential gression and the development of drug resistance upon drug candidates with new mechanisms of action. LIGHTS treatment with platinum-derived drugs, by inhibiting the specifi cally addresses early-phase medicinal chemistry protein regulatory function of monomeric TS through small issues that can critically infl uence the time schedule for molecule cellular perturbation. The scientifi c and technologi- obtaining an investigational drug candidate. Nevertheless it cal objectives will be to design small-ligand libraries to bind is also expected as products of our project that potential to the TS monomer (dimer interface) and thereby disrupt TS. drug candidate(s) with a high-quality in vitro activity profi le The strategy will include, systems pathway analysis, protein can be obtained ready for in vivo pharmacology profi ling. SH-labelling to identify low-affi nity ligands, peptide mimic design and synthesis, and fi ltering for ADME properties. In particular, LIGHTS objectives are: • derivation of small-ligand libraries with ligands designed The multidisciplinary approach will be carried out by to bind to the thymidylate synthase monomer/monomer a Consortium integrating molecular modelling, chemistry, interface aff ecting dimer formation and TS- mRNA inter- chemoinformatics, structural biology and pharmacology, actions; and will apply the knowledge being created by genomics • validation of the integrated, multidisciplinary drug design and other fi elds of basic research to the problem of discov- strategy necessary to achieve previous objective, which ery of anti-cancer agents. The Consortium consists of six poses a highly challenging design problem. The strategy groups from fi ve diff erent countries, including three SMEs. includes protein cysteine SH-labelling to identify low- affi nity ligands, peptide mimetic design, and fi ltering for ADME properties; Problem • identifi cation of small-ligands through in a chemical- biology approach as eff ective perturbing agents to Ovarian cancer is the fi fth most common cause of death from investigate the mechanism of resistance against a panel cancer and the most common cause of death from gyneco- of cis-platinum-resistant ovarian carcinoma cell-lines; logic cancer in women of all ages in the Western world. • development of potential drug candidate(s) with new Single-agent carboplatin (cDDP) has been considered a rea- mechanisms of action for further development as safer sonable option for fi rst-line chemotherapy for ovarian cancer. therapeutic agent(s) for the treatment of ovarian carcinoma.

TREATMENT 213 Project number LSHC-CT-2006-037852

EC contribution € 1 902 150

Duration 36 months

Starting date 01/10/2006

Instrument STREP – SME Cisplatin-resistant human ovarian carcinoma cells stained with Toluidine blue and observed with a Zeiss axiophot light microscope in a phase contrast mode. Project website www.lights-EU.org

Expected results Coordinator

The project provides the integration of diff erent scientifi c Maria Paola Costi areas that are culturally well separated into more established University of Modena medical approaches to impact health determinant in ovarian and Reggio Emilia cancer disease. Modena, Italy [email protected] It supports the discovery of new potential anticancer drugs with non-cross resistance profi les; the new potential drug candidate will be ready to enter the pharmacological phase. Partners If the new identifi ed molecules will be moderately/very active with good bioavailability in vitro against ovarian cancer, Rebecca Wade these products will be very interesting to larger pharmacom- EML Research gGmbH pany and could provide a successful technological transfer Heidelberg, Germany outcome. Paolo Lombardi The proposed research could provide the technical develop- Naxospharma srl ments and innovation, which could have a large impact on Cesate (MI), Italy Biotech industry. The selection of the participating SME partners guarantees that the new knowledge (methods, Hannu Myllykallio potential drug(s) candidate(s)) might be transformed into Institut de Génétique et Microbiologie new technology and new products. Université Paris-Sud Orsay, France

Potential applications Massimo Baroni Molecular Discovery The proposed research can lead to technical developments Ponte San Giovanni (PG), Italy and innovation, which could have a large impact on the bio- tech industry. The selection of the participating SME partners Robert Stroud guarantees that the new knowledge – methods and poten- UCSF-Genentech Hall, UCSF tial drug(s) candidate(s) – will be transformed into new San Francisco, USA technology and new products. The Consortium, in addition to its contribution to the project’s basic research by provid- ing a suitable discovery chemistry programme, will be responsible for further development of the selected promis- ing new chemical entities, comprising intellectual property protection, and chemical and pharmaceutical development.

214 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Quality assurance | clinical validation | IMRT | protontherapy | multimodality image registration | virtual simulation software | Monte Carlo dose calculation TPS | in vivo dosimeters | risk assessment | accurate patient positioning |

MAESTRO Aim

Methods and Advanced Equipment The present project, MAESTRO, proposes innovative research to develop and validate in clinical conditions the for Simulation and Treatment advanced methods and equipment needed in cancer treat- ment for new modalities in high conformal external radio- in Radiation Oncology therapy employing electrons, photons and protons beams.

The project aims at improving the conformation of the dose delivered to the target (tumoural tissues) whatever its shape Summary in order to spare the surrounding tissues. To do this new technologies in the fi eld of patient positionning and organ At the beginning of the third millennium one European cit- tracking, advanced software for treatment planning system, izen out of three will have to deal with a cancer episode in dose calculation and measurement, are to be developed, the course of his/her life. Worldwide the estimated number and linked to the emerging IMRT (Intensity-Modulated of new cancer cases each year is expected to rise from Radiation Therapy) technique. 10 million in 2000 to 15 million by 2020. Cancer is currently the cause of 12% of all deaths worldwide. MAESTRO incorporates major research and technological development programmes involving clinics and manufactur- Within the European Union over 2 million new cancer cases ers which will be linked throughout. The project includes four are diagnosed every year and over 1 million people die of work packages on research and development activities and cancer. The two leading cause of cancers in Europe are two work packages of training and management activities: breast and prostate. Therefore combating cancer is a major • adaptive radiation delivery, tracking and control for radio- societal and economic issue for Europe. To face these new therapy (WP1); challenges strong mobilisation among the scientifi c com- • radiotherapy software development (WP2); munity and industrial manufacturers is needed. • sensors for dose evaluation in radiotherapy (WP3); • clinical requirements, protocols and validation (WP4); Today’s approaches to treat cancer are the surgical remov- • organs at risk assessment studies (WP4); al of the tumour tissue, radiotherapy, chemotherapy, and • clinical workshops for training and dissemination purposes emerging immunotherapy. Among them radiotherapy (WP5); remains a major technique to treat cancer. More than a half • management (WP6). of all cancer patients are treated by radiation therapy thanks to the technical progress made with irradiation equipment in the last years. For external radiation therapy Expected results (RT), high-energy photon or electron beams are mainly produced by linear accelerators, for internal radiation ther- The project has the potential to accelerate development of apy or ‘brachytherapy’, radioactive sources are put in the advanced devices, to ensure their dissemination, to increase tumour with undeniable advantages for the patient in given the compromise between treatment effi ciency and patient situations. safety, to consolidate collaboration between European teams and to spread new methods and knowledge through workshops. Problem A major expected result of the project is to decrease the num- Radiotherapy – on its own or combined with chemotherapy ber of deaths due to primary tumours without metastases. – is involved in almost half of the curative cancer treatments of loco-regional type. An even higher percentage of patients could be cured if further improvements of loco-regional Potential applications treatments involving radiotherapy could be achieved. Such improvements of radiotherapy are the main objective of Advanced and optimised equipment for innovative treatment this project. approaches for external radiotherapy.

TREATMENT 215 Coordinator Project number LSHC-CT-2004-503564 Regis Hugon Marta Bucciolini Mark Fisher Commissariat à l’Énergie Atomique Università di Firenze University of East Anglia EC contribution Paris, France Florence, Italy Norwich, United Kingdom € 7 000 000 [email protected] [email protected] Gloria Bueno Duration Carlo Greco Universidad de Castilla-La Mancha 60 months Partners REM Radioterapia SRL Albacete, Spain Catania, Italy [email protected] Starting date Albert Blondin [email protected] 01/05/2004 Ion Beam Applications SA John Mills Louvain-la-Neuve, Belgium Onori Sandro University Hospitals Coventry and Instrument [email protected] Istituto Superiore di Sanità Warwickshire NHS Trust IP Rome, Italy Coventry, United Kingdom Rob Kreuger [email protected] [email protected] Project website Delft University of Technology www.maestro- and Radiation Technology Olivier Haas Michael Waligorski research.org Interfaculty Reactor Institute Coventry University Centrum Onkologii Oddzial w Krakowie Delft, The Netherlands Coventry, United Kingdom Krakow, Poland [email protected] [email protected] [email protected]

Emilio Migneco Alan DuSautoy Grégoire Malandain Istituto Nazionale di Fisica Nucleare National Physical Laboratory Institut National de Recherche en Catania, Italy Teddington, United Kingdom Informatique et Automatique [email protected] Sophia-Antipolis, France Dimitri Lefkopoulos [email protected] Hanna Kafrouni Institut Gustave Roussy Dosisoft S.A. Villejuif, France Francesc Salvat Cachan, France [email protected] Universitat de Barcelona [email protected] Barcelona, Spain Jean-Marc Fontbonne [email protected] Pavel Olko Centre National de la Recherche Scientifi que Instytut Fizyki Jadrowej PAN Caen, France Sten Larson Krakow, Poland [email protected] Scanditronix Wellhöfer AB [email protected] Uppsala, Sweden Alain Batalla Thierry Leroux Centre National François Baclesse Eldim S.A. Caen, France Hérouville Saint-Clair, France [email protected]

Alfred Hogenbirk Wolfgang Sauerwein Nuclear Research and Consultancy Group Universität Duisburg-Essen Petten, The Netherlands Essen, Germany [email protected] [email protected]

216 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Circadian | clocks | cell cycle | cancer | chronotherapeutics | drug delivery | dynamic models | personalized medicine | chronobiology | pharmacology | anticancer drugs | topoisomerase | cyclin dependent kinases | mouse | patients | transcriptome | proteome | phenome | drug development | systems biology |

TEMPO Problem

Temporal genomics for Non communicable chronic diseases represent the bulk of morbidity, disability and premature deaths in Europe and tailored chronotherapeutics account for 75% of the disability-adjusted life years. Among these, cancer represents the second cause of morbidity and mortality worldwide. Diff erences in the molecular character- istics of the tumor cells as well as diff erences in patient Summary genetic origin, gender, age, lifestyle and circadian rhythms account for large variability in the time courses of cancer Chronic diseases account for 75% of the disability-adjusted diseases and treatment response. years in Europe and cause the premature death of 17 million people worldwide. Diff erences in aetiology as well as patient TEMPO addresses the control of several key dynamic path- genetic origin, gender, age, lifestyle and biological time ways in cancer drug metabolism and cellular proliferation by structure account for large variability in individual time the circadian timing system. This biological system consists courses of the same disease entity. Patient-tailored thera- of a network of molecular clocks that times bodily and cel- peutics is needed to prevent adverse events and improve lular functions along the 24 hours. Chronotherapeutics aim overall therapeutic activity. at the delivery of medications according to the 24-hour rhythms generated by the patient’s molecular clocks in Rather than using pharmacogenomics for excluding patients order both to prevent adverse events and to improve overall from an active treatment option, TEMPO will combine func- therapeutic activity. tional genomics, proteomics, cell signalling, systems biology and pharmacokinetics to optimize therapeutic index in most individual patients. Thus TEMPO will determine 3 to Aim 5 chronotherapeutics schedules with distinct temporal delivery patterns of the same anticancer drug. Each sched- The general objective of TEMPO is to design mouse and in ule is adjusted to a diff erent dynamic class of temporal silico models refl ecting diff erent dynamic classes that pre- genomics and phenomics parameters related to interwoven dict for distinct optimal chronotherapeutic delivery patterns circadian and cell division cycles and drug metabolism. of anticancer drugs. In vivo, in vitro and in silico approaches are integrated through the multidisciplinary excellence in the consortium. Dynamic classes result from the identifi cation of the most discriminant parameters refl ecting cell cycle, pharmacology TEMPO will off er a proof of principle of tailored chrono- and physiology determinants that are controlled by the cir- therapeutics in mouse models for irinotecan, an active drug cadian clock thus impact on the temporal pattern in drug against colorectal cancers, and for seliciclib, currently in cytotoxicity. Optimal chronotherapeutic schedule can diff er clinical testing. TEMPO will gather the corresponding human in mice from diff erent strains or housed in diff erent environ- prerequisites and technology for subsequent application to mental conditions as well as in cancer patients with diff erent patients. gender and circadian timing status. TEMPO will provide a classifi cation based on functional genomics, proteomics Three SMEs play a pivotal role for the impact of TEMPO on and phenomics markers to be selected and validated along European health, economics and society. Novel and com- the development of the project. plementary in silico dynamic models of coordinated clock, cell cycle and pharmacology pathways will identify new TEMPO will off er a proof of concept of tailored chronothera- therapeutic targets and delivery schedules of active mole- peutics with a topoisomerase I inhibitor, and, a cyclin-dependent cules, thus improve drug development processes. New tools kinase inhibitor. will enable personalized medicine to integrate the time dimension in routine implementation. The clinical relevance of the dynamic classes established in mice and in silico will be continuously reassessed along the TEMPO will reduce both therapeutic variability and attrition development of the project, so as to also identify their coun- rates two major impediments for human health and phar- terpart in patients with corresponding specifi cation of optimal maceutical industries. However time can diff er between treatment delivery profi les. individuals as a result of genetic polymorphism and lifestyle diff erences. These determinants can then result in distinct Primary emphasis will be put on the applications of TEMPO optimal delivery patterns of cancer medication. fi ndings to colorectal cancer. This disease aff ects 300 000 new persons in Europe each year and constitutes the second cause of deaths from cancer in both sexes.

TREATMENT 217 Dedicated experimental models addressing circadian clock, Project number cell cycle and drug pharmacology issues will allow to dis- LSHG-CT-2006-037543 sect the molecular and signalling mechanisms that underlie optimal therapeutic schedules for both agents. Dedicated EC contribution mathematical and computational methods will address € 2 086 720 complex dynamic issues in chronotherapeutics delivery modelling, based on already existing computational mod- Duration els for the mammalian circadian clock, the cell division 36 months cycle and anticancer drug pharmacology. Starting date 01/10/2006 Expected results Instrument TEMPO combines functional genomics, proteomics, cell STREP signalling, systems biology and pharmacokinetics to opti- mize therapeutic index in patients. TEMPO will determine Project website chronotherapeutics schedules with distinct temporal deliv- www.chrono-tempo.org ery patterns of the same anticancer drug. Each schedule is adjusted to a diff erent dynamic class of temporal genom- ics and phenomics parameters related to interwoven Coordinator circadian and cell division cycles and drug metabolism. In vivo, in vitro and in silico approaches are integrated Francis Lévi Stefano Iacobelli through the multidisciplinary excellence in the consortium. Institut National de La Santé CINBO et de la Recherche Médicale Consorzio Interuniversitario Nazionale TEMPO will off er a proof of principle of tailored chrono- INSERM U776 – Rythmes per la Bio-oncologia therapeutics in mouse models for an active drugs against biologiques et cancers Laboratory of Molecular Oncology colorectal cancers. Hôpital Paul Brousse Center of Excellence on Aging Ce.S.I. Avenue Paul-Vaillant Couturier 14 C.E.S.I. via Colle Dell’Ara’ In silico dynamic models of coordinated clock, cell cycle and 94807 Villejuif, France 66100 Chieti, Italy pharmacology pathways will identify new therapeutic tar- [email protected] [email protected] gets and delivery schedules of active molecules. TEMPO will provide tools to reduce both therapeutic variability and Marco Pirovano attrition rates. New tools will enable personalized medicine Partners H.S. Hospital Services S.p.A to integrate the time dimension in routine implementation. Villa delle Vallis snc Franck Delaunay Therapeutic delivery CNRS 04011 Aprilia (Latina), Italy Potential applications Université de Nice – CNRS UMR 6348 [email protected] Bâtiment de Sciences Naturelles TEMPO will give the clues to implement research results into 28 avenue Valrose Jean-Baptiste Dumas clinical applications. Through the identifi cation of nodal 06 108 Nice cedex 2, France Milne Edwards points in the interplay between the circadian timing system, [email protected] Helios Biosciences SARL the cell division cycle and drug pharmacology determinants, 8 Avenue du Général Sarrail TEMPO will provide key information for potential targeted Laurent Meijer 94010 Créteil, France drug developments. Station Biologique – Amyloïds and Cell [email protected] Division Cycle (ACDC) – CNRS TEMPO allows foreseeing a new opportunity for cost- Place Georges Teissier, B.P.74 Christophe Chassagnole eff ective medical progress through the real development 29682 Roscoff cedex, France Physiomics PLC of ambulatory medicine with direct relevance to the quality [email protected] The Magdalen Centre of life of cancer patients. The Oxford Science Park Jean Clairambault OX4 4GA Oxford, United Kingdom The reduction of side eff ects and the improvement of anti- INRIA [email protected] tumour activity is particularly important in women and in INRIA Rocquencourt Research Unit elderly patients who experience nearly 20% more side Teams Bang and Contraintes Isabelle Geahel eff ects from chemotherapy than men or younger adults. Domaine de Voluceau – Rocquencourt Inserm Transfert 78153 – PO Box 105 – Le Chesnay, France 7 rue Watt [email protected] 75013 Paris, France [email protected]

218 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Anticancer therapy | oncology | health sciences | virotherapy | pox- | myxoma- | adenovirus | colorectal | pancreatic | ovarian cancer | tumour-specifi c targeting | spreading | replication | arming | molecular chemotherapy | non-invasive imaging |

THERADPOX Problem

Optimised and novel oncolytic Cancer still remains the second leading cause of death in Europe and in the world. THERADPOX, by providing new adenoviruses and pox viruses in treatments for three major (colorectal, pancreatic and ovarian) cancers, will contribute to addressing and pursuing central the treatment of cancer: Virotherapy directions of the European policy against cancer. combined with molecular chemotherapy Virotherapy exploits the use of natural or engineered Oncolytic Viruses (oncolytic vectors, OVs) to selectively kill tumour cells. To date, many types of OVs have been developed and have entered clinical trials. These trials dem- Summary onstrated a high safety profi le of OVs, but showed limited therapeutic eff ect when used as a monotherapy. Improved Today, cancer is the second cause of disease-induced mor- effi cacy was noted when OVs were used in combination tality worldwide. Among the innovative treatments for with traditional therapies (chemotherapy or radiation). How- cancer, virotherapy holds great promise. Virotherapy exploits ever, the effi cacy and safety of virotherapy is limited by the an intrinsic feature of the life cycle of oncolytic viruses (OVs): low effi ciency of tumour cell infection, the low level of repli- replicating and spreading exclusively in tumour cells leading cation in some tumour cells and the ineffi cient spreading to their destruction, while not aff ecting normal cells. Clinical capacity within the tumour mass. studies have demonstrated the safety and feasibility of this approach, but have shown only minimal therapeutic effi cacy. Synergistic eff ects of combination treatments of OVs with chemo- and radiation therapy have been observed. Never- theless, this approach still leaves patients subjected to the toxic adverse eff ects of chemotherapy and radiation. Thus, an unmet need exists for the improvement of current and the development of new treatment platforms, leading to a sig- nifi cant increase in cure rates.

Owing to their inherent strong oncolytic potency and safety record, poxvirus and adenovirus-based vectors have been chosen to pursue the goal of the THERADPOX project: to improve the safety and therapeutic effi cacy of OVs in vivo. Novel and improved OVs will be engineered which, in vivo: • specifi cally target colorectal, pancreatic and ovarian cancer cells; • replicate exclusively in cancer cells; • are armed with therapeutic genes rendering only tumour cells sensitive to chemotherapy; • widely spread within the tumour to permit total tumour eradication.

Through the multidisciplinary work plan proposed and the strong and complementary expertise of the ten European part- ners from fi ve European countries involved, the THERADPOX project will: • generate advanced knowledge which could be trans- lated towards a safer cancer treatment with an increased therapeutic index; • contribute to improve the quality of life of cancer patients by fewer treatments with no toxic side eff ects; • lead to the proposal of new guidelines and standards for THERADPOX approach. the development of OVs; • strengthen the competitiveness of Europe in the war against cancer.

TREATMENT 219 Aim Expected results

The THERADPOX project aims at engineering novel and THERADPOX OVs will be engineered to: optimised oncolytic pox- and adenoviruses for cancer ther- • selectively target cancer cells in vivo (up to a 100-fold apy, specifi cally targeting colorectal, pancreatic and ovarian increase of tumour cell infection can be expected: 100 can- cancers. The innovative strategy of THERADPOX relies on cer cells infected for 1 normal cell infected) (M30); the original engineering of OVs to render them safe, specifi c • selectively replicate and propagate in tumour cells in vivo and effi cient for infection (binding and replication) and for (expectations are a 100-fold increase of viral yield in the destruction of cancer cells through a combination of tumour cells versus normal cells) (M32); virotherapy with non-toxic chemotherapy in vivo. To achieve • widely spread within tumours in vivo (a statistically signif- an enhancement of tumour cell infectivity of THERADPOX icant increase of the therapeutic index is expected) vectors, tumour-specifi c ligands, for which particular mem- (M30); brane proteins of cancer cells show high affi nity, will be • specifi cally render cancer cells sensitive to chemotherapy incorporated in viral surface proteins and will be optimised. in vivo: OVs will be engineered to express in the infected In addition, by modifying or exchanging ligand expression of cancer cells prodrug- converting enzymes, enabling the THERADPOX OVs, one can imagine targeting other tumour conversion of a non-toxic molecule (given orally or intra- types. The viral genome will also be engineered to ensure venously) to toxic compounds (a statistically signifi cant that viruses selectively replicate and express therapeutic increase of the therapeutic index is expected) (M36); proteins in tumour cells and that they spread widely through • overcome the pre-existing immunity and to delay the the tumour mass. Furthermore, capsid modifi ed oncolytic induced adenoviral immune response, concerning onco- Ad vectors will be explored to overcome pre-existing immunity lytic Ad (M36). and delay an induced immune response.

The oncolytic vectors (OVs) will be derived from the viral Potential applications platforms described below: • vaccinia virus (VV): the advantages of VV as OV are a The THERADPOX project contributes to supporting the quick and effi cient life cycle, strong lytic activity and Programme of Community action in the fi eld of public health rapid cell-to-cell spreading. The virus can infect a wide (2003-2008) (1786/2002/EC) by: variety of human tissues but does not cause any known • promoting and improving health, with a view to reduc- human disease. VV was the fi rst widely used vaccine ing avoidable morbidity: THERADPOX will develop new which resulted in the eradication of smallpox. As a result, OVs to cure patients aff ected with colorectal, pancreatic the responses, safety profi le and adverse reactions have and ovarian cancers; been extensively studied and documented; • reacting rapidly to health threats: THERADPOX vectors • myxoma virus (MV): MV causes myxomatosis in European are designed to eradicate tumours. Their selectivity for rabbits but is non-pathogenic in man. However, myxoma one tumour type relies on the tumour cell selectivity of virus productively infects a variety of human tumour specifi c ligands. Thus, by only changing the ligand in cells (Sypula et al., 2004), suggesting a signifi cant THERADPOX OVs, one can imagine targeting and effi - potential for exploiting MV as a novel OV platform; ciently and rapidly eradicating other tumour types that • adenovirus (Ad): one of the most extensively studied may be a threat to human health in the future; viruses which have been engineered for gene therapy • promoting better knowledge and communication fl ows, and for virotherapy of cancer, particularly serotypes 2 thus allowing a greater involvement of individuals in deci- (Ad2) and 5 (Ad5). The virus is endemic in the human sions that concern their health. THERADPOX includes population and its natural pathogenicity is associated specifi c tasks for: with mild respiratory infections (common cold). It can be • communicating about the knowledge, impacts and grown easily and to high titres, and the methodology to benefi ts of the project; generate recombinant viruses is well established. • disseminating results and information, in a simple, clear and sound way about the work undertaken within THERADPOX to the scientifi c community as well as to the community population, with the ulti- mate goal to improve the quality of life.

220 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHB-CT-2004-018700 Monika Lusky Akseli Hemminki Transgene SA University of Helsinki EC contribution Strasbourg, France Helsinki, Finland € 2 411 006 [email protected] [email protected] Duration Mohammed Benbouchaib 36 months Partners Newlab Nancy, France Starting date Ramon Alemany [email protected] 02/11/2005 Institut Català d’Oncologia L’Hospitalet de Llobregat Gerd Sutter Project website Barcelona, Spain Paul-Ehrlich Institute (PEI) www.theradpox.org [email protected] Langen, Germany [email protected] Stéphane Bertagnoli École nationale vétérinaire de Toulouse Victoria Smith UMR1225 IHAP/ENVT (INRA) Niko Bausch Toulouse, France Oncotest GmbH [email protected] Freiburg, Germany [email protected] Richard Iggo University Court of St. Andrews David Koubi St. Andrews, United Kingdom ACIES SAS [email protected] Lyon, France [email protected] Harry Jalonen Delsitech Ltd Turku, Finland [email protected]

TREATMENT 221 Keywords | Breast cancer | clinical trials | molecular signature |

TRANSBIG Problem

Translating molecular knowledge Breast cancer is the most common cancer among women in developed countries, with one out of eight to ten women into early breast cancer management: developing the disease in her lifetime. While incidence has steadily increased over the past decades, a slight decrease in building on the Breast International deaths from breast cancer has only recently been noted, and that only in a few countries. Breast cancer is curable in about Group (BIG) network for improved 70% of cases if diagnosed and treated early enough. But because of uncertainty over the best treatment in individual treatment tailoring cases, many women receive chemotherapy or hormonal treat- ment after surgery, based on the assumption that there is a high risk of their breast cancer recurring. Some women ben- Summary efi t signifi cantly from such treatment, others only very little or not at all. The reason for this is because breast cancer is a dis- The key to individualising treatment for cancer lies in fi nd- ease that develops very diff erently in each woman. If individual ing a way to quickly ‘translate’ the discoveries about human tumours were better understood, physicians would be able to genetics made by laboratory scientists in recent years into make more enhanced decisions about which treatments are tools that physicians can use to help make decisions about best for individual patients and which patients need no further the way they treat patients. This area of medicine that links treatment after surgery. Presently it is estimated that about 12 basic laboratory studies to the treatment of patients is to 20% of patients are over-treated, resulting in avoidable costs called translational research. TRANSBIG has been created to both health services (fi nancial) and patients (side-eff ects). as a multidisciplinary network of excellence, devoted spe- cifi cally to this type of research in breast cancer. Aim TRANSBIG is a research network of 40 world-class institu- tions in 21 countries. Each participating organisation brings The aims of this network are: with it expertise that ranges from being specialised in cut- • to develop ways of individualising breast cancer treatment, ting-edge biomedical technologies and cancer treatment so that treatment is tailored to the person receiving it; programmes to lobbying governments on behalf of patient • to integrate, strengthen and facilitate translational clinical groups and supporting cancer societies. As a network, breast cancer research in Europe and internationally by TRANSBIG will be dedicated to high-level collaboration linking it to an existing network for clinical breast cancer that will contribute dramatically to advancing individual- trials (BIG); ised treatment for breast cancer patients. Among its many • to develop and run a major clinical trial aimed at validating strengths is the fact that it is linked to an already existing the hypothesis that understanding the genetic make- network of groups around the world that conduct clinical up (signature) of a tumour can lead to better targeted breast cancer research together – the Breast International treatment. Group (BIG). BIG’s 44 member organisations are active in 40 countries. Although TRANSBIG will ultimately develop many projects, it will start with a clinical trial called MINDACT (Microarray The headquarters is located in Brussels, and it coordinates for Node Negative Disease may Avoid Chemotherapy). This the activities of both TRANSBIG and BIG. By linking the two trial will compare two diff erent ways of assessing the proba- networks and by benefi ting from a central coordinating bility or risk that a woman’s breast cancer will come back. body, the fragmentation currently existing in the fi eld will The traditional method is based on international guidelines be reduced, and translational research in Europe will be and looks at specifi c characteristics such as the size of a pa- strengthened and accelerated. New technologies will only tient’s tumour and whether the disease has spread to the gain acceptance by physicians and patients after fi rst being lymph glands (nodes).The new method uses microarrays as validated in large, independent clinical trials. Microarray a way of analysing the genetic components of a tumour. technology has enabled scientists to determine the signa- Specifi cally, traditional methods of assessing risk will be ture of individual tumours, but it must be proven that this compared to a 70-gene tumour ‘signature’ identifi ed by information is more reliable than existing methods for a group of scientists at the Netherlands Cancer Institute determining how best to treat individual patients. that appears to predict very accurately whether a particular woman’s breast cancer will come back. MINDACT will involve

222 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME 6 000 women over a three-year period. Other cutting-edge Coordinator techniques and technologies will be used in the project over time, and tumour and blood samples donated by patients Martine Piccart Lubos Petruzelka will create an invaluable resource for further research that Breast International Group (BIG-aisbl) Dept. of Oncology of the 1st Faculty of Medicine will help us to better understand and treat breast cancer. Brussels, Belgium Charles University and General [email protected] Teaching Hospital Prague, Czech Republic Expected results Partners Henning Mouridsen The TRANSBIG partners believe that the results of MIND- Finsen Centre – Rigshopitalet ACT will show that using the new technology to assess risk Christos Sotiriou Copenhagen, Denmark will result in fewer women being treated unnecessarily. This, Institut Jules Bordet in turn, will mean that fewer women will suff er from the Brussels, Belgium Mahasti Saghatchian-d’Assignies unpleasant side-eff ects of chemotherapy. Not only will the Suzette Delaloge overall quality of life of breast cancer patients be improved, Harry Bartelink Institut Gustave Roussy but the healthcare costs associated with such cancer treat- The Netherlands Cancer Institute Villejuif, France ment will be reduced as well, thus providing a signifi cant Amsterdam, The Netherlands benefi t to society. As the fi rst project in TRANSBIG, MIND- Frank Wermer ACT will also establish valuable resources for future research Giuseppe Viale West German Study Group and establish links between research and biotechnology IEO – European Institute of Oncology Frauenklinik der Heinrich-Heine-Universität enterprises in order to develop further diagnostic tools that Milan, Italy Düsseldorf, Germany can be widely disseminated and easily used by scientists and physicians alike. Jonas Bergh Gunter von Minckwitz Karolinska Institute & Hospital Universitätsfrauenklinik Stockholm, Sweden Frankfurt, Germany Potential applications Robert C.F. Leonard Nadia Harbeck The long-term aim is to develop TRANSBIG into a permanent Géraldine A. Thomas Technische Universitaet München network for translational research that is complementary to Imperial College Munich, Germany the clinical work done by BIG. This guarantees a connection London, United Kingdom between what scientists learn in the laboratory and what Christoph Thomssen physicians and patients decide together about treatments Denis Lacombe Martin Luther Universität Halle Wittenberg in the clinic. But TRANSBIG’s reach will be wider than simply The European Organization for the Halle, Germany research. It will also be concerned with education through Research and Treatment of Cancer (EORTC) the provision of traineeships for young scientists and physi- Brussels, Belgium Christos Markopoulos cians, and public education on the issues involved with National and Kapodistrian University genomics by working closely together with cancer societies John Bartlett of Athens and patient advocacy groups. By bringing together scien- The University of Edinburgh Athens Medical School tists, clinicians, and representatives from patient groups, Edinburgh, United Kingdom Athens, Greece cancer societies and industry, TRANSBIG will bring a coher- ence and synergy to breast cancer research that has Michael Gnant Arnold Hill previously not existed in Europe. Vienna General Hospital St. Vincent’s Hospital Vienna, Austria Dublin, Ireland

Alejandro Corvalan Rodolfo Passalacqua Chilean Cooperative Group Gruppo Oncologico Italiano for Oncologic Research di Ricerca Clinica Santiago, Chile Parma, Italy

Adamos Adamou Caroline Duhem The Bank of Cyprus Oncology Centre Centre Hospitalier de Luxembourg Nicosia, Cyprus Luxembourg

TREATMENT 223 Project number LSHC-CT-2004-503426 Pierre Hupperets Michael Atkinson University Hospital German Research Center for EC contribution Maastricht, The Netherlands Environmental Health € 7 000 000 Munich, Germany Jacek Jassem Duration Medical University of Gdansk Laura van ’t Veer 84 months Gdansk, Poland Agendia BV Amsterdam, The Netherlands Starting date Jose Manuel Leal da Silva 01/03/2004 Portuguese Institute of Oncology Marc Buyse Porto Centre International Institute for Instrument Porto, Portugal Drug Development NoE Brussels, Belgium Mikhail Lichinister Project website N. N. Blokhin Cancer Research Centre Josep Baselga www.breastinternational Moscow, Russian Federation Fundacion Institut per la Recerca group.org Vall d’Hebron Tanja Cufer Barcelona, Spain Institute of Oncology Ljubljana, Slovenia Jose Vasquez Grupo Español de Estudio, Tratamiento Olivia Pagani y otras Estrategias Expirementales en Institute of Oncology of Southern Tumores Sólidos (SOLTI) Switzerland Madrid, Spain Mendrisio, Switzerland Mauro Delorenzi Gul Basaran Swiss Institute of Bioinformatics Marmara University Medical School Hospital Lausanne, Switzerland Istanbul, Turkey Adrian Harris Michel Ballieu The Chancellors Masters and Scholars European CanCer Organisation (ECCO) of the University of Oxford Brussels, Belgium Oxford, United Kingdom

Susan Knox Alistair Thomson Mary Buchanan The University of Dundee Europa Donna – The European Breast Dundee, United Kingdom Cancer Coalition Milan, Italy

Fernando Schmitt Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto, Portugal

224 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Solid tumours | apoptosis | tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) | receptor-selective TRAIL mutants | TNF ligand-mimicking peptides | intracellular peptide inhibitors | computational rational protein design | directed evolution | tailor-made therapy | primary tumour culture | cell-based delivery systems of anti-cancer genes | GLP/GMP procedures |

TRIDENT Problem

Therapeutic molecules for treatment With almost 3 million new cases each year and 1.7 million deaths, cancer is an important public health problem in Europe. of solid tumours by modulating death The ageing of the European population will cause these num- bers to continue to increase. The most common cancers are receptor-mediated apoptosis lung, colorectal and breast cancers. The available treatments for these solid cancers and the outcome of the treatments are not satisfactory. New therapeutic strategies and novel tumour- Summary selective anti-cancer agents are necessary in order to improve the treatment of these and other solid tumours. The effi cacy of current treatments for some types of solid tumours is disappointingly poor. New therapies using novel tumour-selective anti-cancer agents are necessary. A major Aim aim of anti-tumour therapies is to inhibit proliferation and induce death of tumour cells without aff ecting normal cells. The ultimate aim of the TRIDENT project is to develop novel In this regard, members of TNF ligand/receptor family are molecules that target critical apoptotic signalling pathways of interest since they regulate both apoptosis (programmed important in the formation of various solid tumours. cell death) and cell proliferation. One TNF family member, TRAIL, is of particular interest since it selectively induces The specifi c objectives are: death of tumour cells without aff ecting normal cells. Cur- • to develop of novel apoptosis-inducing agonists and pro- rently, TRAIL and TRAIL-specifi c antibodies are being liferation antagonists using state-of-the art, computer investigated as anti-cancer agents. However, a major draw- based rational design and directed evolution techniques; back to TRAIL’s effi cacy is that it binds to multiple receptors, • to gain in-depth knowledge on the role of the TNF lig- not all of which transduce an apoptotic signal. Previously, and-receptor family interactions in the carcinogenesis of we developed receptor-selective TRAIL variants which are solid tumours, both at a molecular and structural level; potent inducers of apoptosis in various tumour cells, are more effi cacious than native TRAIL, and display synergistic eff ect in combination with other chemotherapy treatments or radiotherapy.

This proposal will investigate and characterise TRAIL vari- ants pre-clinically in solid tumour models and defi ne new treatment protocols in combination with already proven treatments. Furthermore, we will elucidate the role of other TNF receptor family members in signalling in tumour cell survival/death. Biochemical and structural characterisation will identify new targets for molecular cancer therapy while computational design and molecular evolution techniques will be used to develop novel receptor-selective apoptosis- inducing agonists. We will also develop intracellular acting agents (intracellular-acting peptides inhibiting pro-survival signals; intracellular peptide inhibitors), which will block the unwanted proliferative/anti-apoptotic signals activated by some TNF members. The tumoricidal activity of these lead molecules will be tested using conventional, viral and cell based delivery strategies which will utilise peptide sequences to specifi cally target them to tumour cells. The objective of TRIDENT is to channel death receptor activation towards tumour cell apoptosis. Activation of cell surface death receptors do not only induce apoptosis of the receptor carrying cell but can simultaneously activate compensatory, pro-survival pathways, which limits the use of this pathway to kill cancerous cells. The TRIDENT project aims to generate TNF ligand variants that only bind to the death-inducing members of the TNF receptor family, not to decoy TNF receptors (selective ligand) and design cell permeable peptide inhibitors (intracellular inhibitors; IC inh) against anti-apoptotic molecules. These novel molecules used in combination can maximize tumour cell killing.

TREATMENT 225 • identify high effi ciency combinations of the novel lead Project number molecules with chemotherapy and/or radiation and con- LSHC-CT-2006-037686 duct pre-clinical studies; • develop a prediction model and high-throughput primary EC contribution tumour characterisation to identify patient-specifi c (tailor- € 2 069 000 made) targeted treatments; • devise new tumour targeting techniques by exploiting Duration gene and cell therapy-based approaches; 36 months • development of new computational and experimental methods in order to advance potential protein therapeutics Starting date faster from pre-clinical to clinical stage; 01/10/2006 • development of an exploitation strategy involving a start- up SME. Instrument STREP

Expected results Project website www.trident- The anticipated deliverables include the development of biotech.com novel diagnosis technologies and novel therapeutics for intervention in cancer progression through activation of apoptosis as well as technologies to advance a more Coordinator rational approach to the design of ‘tailor-made’ therapeu- tic drugs. This proposal takes a multi-disciplinary approach Afshin Samali Steven de Jong to develop new methodologies and will specifi cally gener- National University of Ireland University Medical Center Groningen ate unique scientifi c knowledge and industrial technologies Galway, Ireland Groningen, The Netherlands that could not be created on a national level by individual [email protected] partners. The participants involved are from both industrial Guillermo Montoya and academic backgrounds and are experienced with Fundación Centro Nacional working in research networks at a European level. Our Partners de Investigaciones application of state-of-the-art technologies will facilitate Oncológicas Carlos III and accelerate the development of new tools and process- Ralf Zwacka Madrid, Spain es in general, for development and production of novel National University of Ireland protein/peptide therapeutics. Galway, Ireland Ian Hayes Triskel Therapeutics Ltd. TRIDENT will assist in the advancement of genetic and pro- Luis Serrano Galway, Ireland tein engineering, in silico protein design, molecular evolution, Centre de Regulació Genòmica protein microarray technology and lab-on-a-chip formats in Barcelona, Spain the development and production of lead therapeutic mole- cules. A greater understanding of molecular mechanisms Wim Quax involved in the control of apoptotic signal transduction in University of Groningen tumour cells will be also gained. The integration of this Groningen, The Netherlands derived knowledge will ultimately be useful in the context of post-genomic research for human health activities. Our focus will be on the market need for alternative, more eff ec- tive therapies in the treatment of solid tumours, and more particularly for therapeutics with minimal toxic-side eff ects.

Potential applications

Treatment of solid tumours and possibly leukemias, identifi - cation of most effi cient treatments for individual patients, high effi ciency design of protein mutants and specialised- variants (e.g. receptor selective ligands, agonistic, antagonistic ligands).

226 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Keywords | Lymphoma | leukaemia | vaccine | idiotype | immunotherapy |

VITAL Problem

Development of optimised recombinant Non-Hodgkin’s lymphomas (NHL) constitute a heterogene- ous group of malignancies whose incidence has signifi cantly idiotypic vaccines for subset-specifi c increased in recent decades. In the year 2000, more than 145 000 cases of NHL were diagnosed in developed coun- immunotherapy of B cell lymphomas tries, representing the sixth most common cancer occurring among men and the eighth among women. Low-grade B cell NHLs, in particular, are incurable diseases characterised by relatively slow growth and excellent initial responsiveness to Summary chemotherapy but also by continuous relapses. In particular, for patients with follicular lymphoma, median overall survival Therapeutic vaccines targeting B cell non-Hodgkin lympho- (7-10 years) has not improved over the past 30 years. ma (NHL) idiotype (Id) represent a promising approach against these malignancies. A broad use of Id-based vaccina- Although in the vast majority of patients complete or partial tion, however, is hampered by the complexity and costs due remissions can be obtained with either single agents or to the individualised production of these vaccines. Recent combination chemotherapy, the clinical course is character- evidence indicates that these limitations may be overcome. ised by a high relapse rate. After relapse, both the response In fact, distinct sets of stereotyped immunoglobulins have rate and relapse-free survival after subsequent salvage been identifi ed in various B-NHL, suggesting that patients treatment regimens steadily decrease, resulting in a median share Id with a higher frequency than appreciated previously. survival of only 4-5 years after the fi rst relapse. These clinical fi ndings, coupled with the substantial toxicities of Through the complementary and synergistic work of academic standard treatments, have stimulated the search for novel partners and three SMEs, we plan to exploit the molecular fea- and more tumour-selective therapies. Therapeutic vaccines tures of Id proteins of distinct B cell lymphomas/leukemias, targeting B cell lymphoma idiotype (Id) represent a promis- particularly those pathogenically associated with antigen stim- ing immunotherapeutic approach for a better clinical control ulation and/or selection, to develop pre-made, recombinant of these malignancies. This strategy is based on the obser- Id proteins to vaccinate subgroups of lympho-proliferative vation that immunoglobulins (Ig) expressed by neoplastic disorders expressing molecularly correlated idiotypes. B lymphocytes carry unique determinants in their variable regions (idiotypes), which can be recognised as tumour- A database of Id sequences expressed by diff erent B-NHL specifi c antigens. will be constructed to identify subgroups of tumours express- ing molecularly correlated Id proteins. Selected Id proteins Indeed, both protein- and dendritic cell-based vaccines that will be characterised for their immunogenicity and, particu- use the patient-specifi c Id have resulted in clinically signifi - larly, for the ability to induce cross-reactive immune responses cant tumour-specifi c cellular responses with very little toxicity. against related Id proteins. B and T cell epitopes will be iden- A broad use of Id-based vaccination for B cell lymphomas, tifi ed using innovative approaches, and dedicated assays for however, is hampered by the fact that these approaches are immunomonitoring will be developed. Optimised versions of patient-specifi c, so that the vaccine must be individually pro- selected Id vaccines will be produced using new strategies duced for each patient. On these grounds, new strategies and validated in animal models. New adjuvants and delivery obviating the need to produce customised vaccines would systems for improved Id vaccine formulations and admin- further simplify clinical applications of idiotypic vaccines. istration will be also evaluated and validated. The most promising Id proteins will be produced and purifi ed accord- ing to GMP standards and included in new vaccine formulations Aim for innovative trials of ‘cross-reactive’ immunotherapy. The objective of VITAL is the development and production of optimised recombinant idiotypic vaccines for the treatment of subgroups of lymphoproliferative disorders expressing molec- ularly correlated idiotypes. These vaccines will be included in new formulations for innovative trials of immunotherapy potentially targeting a large fraction of lymphoma/leukemia patients.

TREATMENT 227 Expected results

• Establishment of a large database including sequences of idiotypic VH and VL genes expressed by a variety of lympho-proliferative disorders, including low grade B-NHL, autoimmunity-associated lympho-proliferations, and chronic lymphocytic leukemia. This will allow the identifi cation of candidate Id proteins for ‘cross-reactive’ immunotherapy. • Pre-clinical characterisation of the immunogenicity of selected natural Id proteins, with particular regard to their ability to induce immune responses against lymphoma cells expressing molecularly correlated Id proteins. The characterisation will include the iden- tification of B cell epitopes and HLA Class I-restricted cytotoxic T cell epitopes using innovative approaches and will allow the development of dedicated assays for immunomonitoring. • Design and validation of optimised Id vaccines. • Evaluation and validation of new adjuvants and innova- tive delivery systems for improved Id vaccine formulations and administration. • ‘Clinical-grade’ production and purifi cation of optimised Id proteins for patient vaccination.

The SMEs are an integral part in the project in making the new diagnostic and therapeutic tools available, not only for Europe but also for the world market. The close integration between clinical and research activities at several university hospitals and cancer centres with the SMEs will form new centres of excellence where European SMEs will benefi t from close collaboration, at the same time as new diagnos- tic and therapeutic products will be developed to the benefi t of patients with lymphoid malignancies.

Potential applications

The results obtained in the present project will allow the Flow chart, outlining the main expected results, leading from identifi cation of shared idiotypes design and activation of phase I/II clinical trials aimed at to the development of optimized vaccines for the treatment of B-cell lymphoproliferations. validating the use of optimised, pre-made vaccines for the treatment of a relatively broad spectrum of lymphoid malig- nancies. The proposed Id vaccination may be benefi cial also for patients with pre-neoplastic B-cell lymphoproliferations, such as mixed cryoglobulinaemia. These vaccines, in fact, may be used with the purpose of alleviating symptoms and, ultimately, preventing a possible evolution towards an overt B cell malignancy. Once validated as drugs, the vaccines will have the advantage of being easily distributed to all hema- tology and oncology departments, including those of peripheral hospitals/universities. Thus, results obtained in the present project will have an important strategic impact in solving, at least in part, the dramatic social and health problem represented by NHL.

228 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Coordinator Project number LSHC-CT-2006-037874 Riccardo Dolcetti Antonio Rosato Centro di Riferimento University of Padova EC contribution Oncologico – IRCCS Padova, Italy € 2 050 000 National Cancer Institute Aviano, Italy Hans Petrus Duration [email protected] Maria Langedijk 36 months Pepscan Systems BV Lelystad, The Netherlands Starting date Partners 01/01/2007 Nikolai Schwabe Bjarne Bogen ProImmune Limited Instrument University of Oslo Oxford, United Kingdom STREP – SME and Rikshospitalet University Hospital Maria Luisa Nolli Project website Oslo, Norway Areta International Srl www.cro.sanita.fvg.it/ Gerenzano, Italy progetti/vital/index.htm Maria Masucci Karolinska Institutet Stockholm, Sweden

TREATMENT 229

Cancer control, Survivorship and outcomes research

The projects included in this part of the catalogue have a particular importance in controlling cancer and although they belong to diff erent scientifi c areas, their contribution to the portfolio is important. The fi rst group of projects belongs to what could be called analysis of funding provision in research, proposals to enhance quality of the funders and surveillance. The CCRB project aims to improve cancer control by linking biobanks and cancer registries through integration activities; EUROCAN +PLUS, a coordination activity of the European research area (ERA), is trying to identify research where national coordination is lacking and whether there is a possibility to achieve better coordination. EUSTIR, although a smaller scale project than the ones previously mentioned, has an equally impor- tant objective to propose harmonisation activities in breast cancer research funding bodies in order to achieve better research results and to be able to control breast cancer research more eff ectively. Quality of life, pain control and management and psychological impact of cancer patients – in short palliative medicine and care – incorporates in a complex disease such as cancer, which is often incur- able, a continous input from the start of the disease to the end of life care for the patients, their family and care givers. This area of research of growing importance receives special attention among funding and policy makers in cancer research. There are two projects representing this area of research: NORMOLIFE which is aiming to synthesise new compounds alternative to opioids, to fi ght pain and reduce side eff ects; EPCRC is an ambitious project aiming to identify the genetic variation to opioid responses and cachexia, to improve the classifi cation of pain, depression and cachexia and most importantly to develop guidelines for the above symptoms.

Elengo Manoussaki Keywords | Biobank | registries | population-based | standards | harmonisation | quality assurance | genetic epidemiology | infections |

CCPRB Expected results

Cancer Control using Population-based • Provide the study base for uniquely large population- based prospective studies on cancer. Registries and Biobanks • Defi ne and implement a European Quality Standard for Biobanking. • Defi ne and promote the implementation of integrity-proof methods for biobank-based research involving well- Summary defi ned and secure thirdparty code-keeping systems. • Establish a Europe-wide network for spreading the aware- This Network of Excellence project is aimed at improved ness of possibilities and best practice quality standards control of cancer by facilitating research linking bio banks for biobank-based research. and cancer registries. The project involves a systematic quality assurance of European bio banks, as well as improved integrity-protection in the handling of sensitive information Potential applications in connection with bio bank-based research. The samples in the biobanks will be used in large-scale cancer research Large-scale, population-based research will be enabled on: searching for genetic and infectious causes to cancer, par- • evaluation of cancer treatment and role of molecular ticularly in the areas of breast and colorectal cancer, and markers in treatment selection; childhood leukaemias. • identifi cation and evaluation of genetic markers associ- ated with increased cancer risk using over-generation linkages; Problem • exploration and evaluation of intrauterine exposures asso- ciated with increased cancer risk using over-generation Longitudinal studies nested in biobanks enable more reliable linkages; and effi cient study designs, for both design and evaluation • design of optimal strategies for cancer prevention and of cancer treatment and cancer prevention, as well as for its evaluation. exploring and evaluating etiologic hypotheses. However, several prerequisites apply: • there must be very large-scale biobanks in place that should already have information dating back several decades; • it must be possible to link biobanks with quality-assured, population-based cancer registries to enable population- representative studies with minimal case ascertainment bias; • important problems regarding overview, accessibility, quality control, phenotypic characterisation, effi ciency and avoiding risks for violation of personal integrity must be addressed.

Aim

The objective is to achieve improved control of cancer by The samples in the prospective research biobanks are allocated into colour-coded tubes facilitating research that links biobanks and cancer (buff y coat, EDTA-plasma, heparin-plasma, etc.). registries.

232 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2004-503465

EC contribution € 6 050 000

Duration 60 months

Starting date 01/06/2004

Instrument NoE

Project website www.cancerbiobank.org

Work in the -80˚ facility in the Malmö Biobank Consortium.

Coordinator

Joakim Dillner Egil Jellum Geoffrey Garnett Marc Arbyn Lund University Norwegian Cancer Society Imperial College of Science, Technology Scientific Institute of Public Health Dept. of Medical Microbiology Institute of Clinical Biochemistry and Medicine Unit of Epidemiology – I.P.H. Malmö University Hospital Oslo, Norway Dept. of Infectious Disease Epidemiology Brussels, Belgium Malmö, Sweden [email protected] Faculty of Medicine [email protected] [email protected] London, United Kingdom Kari Hemminki [email protected] Frank Buntinx Karolinska Institutet Limburg Cancer Registry (LIKAR) Partners Dept. of BioSciences Matti Lehtinen Hasselt, Belgium Huddinge, Sweden University of Tampere [email protected] Timo Hakulinen [email protected] Public Health School and Medical School Finnish Cancer Registry Tampere, Finland Arthur Löve Helsinki, Finland Helga M. Ögmundsdóttir [email protected] Landspitali-University Hospital [email protected] Icelandic Cancer Society Dept. of Medical Virology Armuli 1a Molecular and Cell Biology Research Paolo De Paoli Reykjavik, Iceland Steinar Thoresen Laboratory Centro di Riferimento Oncologico [email protected] Kreftregisteret/Cancer Registry of Norway Reykjavik, Iceland Dept. of Laboratory Medicine Oslo, Norway [email protected] Laboratory of Microbiology Mats G. Hansson [email protected] Aviano (PN), Italy Uppsala University Pentti Koskela [email protected] [email protected] Dept. of Public Health Ethel-Michele de Villiers National Public Health Institute and Caring Sciences Deutsches Krebsforschungszentrum Dept. of Microbiology Laboratory Richard Houlston Uppsala, Sweden Angewandte Tumourvirologie/ of Prenatal Serology Section of Cancer Genetics [email protected] Tumourvirus-Charakterisierung Finnish Maternity Cohort serum bank Institute of Cancer Research Heidelberg, Germany Oulu, Finland Sutton, United Kingdom [email protected] [email protected] [email protected]

Per Lenner Claus R. Bartram Ewa Grzybowska Umeå Universitet University Hospital Heidelberg Centre of Oncology – M. Sklodowska-Curie Institutionen för Strålningsvetenskaper Institute of Human Genetics Memorial Institute, Branch Gliwice Onkologi Heidelberg, Germany Dept. of Tumour Biology Umeå, Sweden [email protected] Cancer Genetics Laboratory [email protected] Gliwice, Poland [email protected]

CANCER CONTROL, SURVIVORSHIP AND OUTCOMES RESEARCH 233 Keywords | Cancer | palliative care | pain | depression | fatigue | cachexia | opioid response | genetic marker | classifi cation | assessment | guidelines |

EPCRC Problem

The European Palliative Care Research Even though pain, fatigue and depressive symptoms are the most common symptoms in advanced cancer, there is still Collaborative: improved treatment of inadequate understanding of the inter-individual variability of these problems. Cachexia is a major reason for fatigue in pain, depression and fatigue through palliative care patients, but there is no internationally agreed assessment tool or classifi cation system for either cachexia translation research or depression in this patient group. Although there are sev- eral publications and agreements on the classifi cation of pain, there is still no consensus on how to assess or measure it. In addition, there is a lack of internationally developed Summary and updated clinical guidelines for the treatment of these conditions and symptoms. Pain, depression and fatigue are subjective clinical manifes- tations of advanced cancer. Control of these symptoms is pivotal for the quality of life of millions of palliative care Aim patients. Pain is the most feared symptom for many patients. The prevalence of depression varies from 6-58% in pallia- The overall objectives are to develop novel genetic methods tive care patients, refl ecting lack of a standardised validated for prediction of opioid responses and individual variation of methodology for its assessment in these patients. fatigue (cachexia), and methods for assessment and classi- fi cation of pain, fatigue (cachexia), and depression. Cachexia is likely to be the most important contributor to fatigue in palliative care. The plethora of other symptoms, • To identify genes and genetic variation relevant for inter- co-morbidities, and the advanced age of most palliative individual variation in opioid responses and genetic patients support the need for evidence-based management variation that may identify patients at particular risk for strategies. To improve management of pain, depression and developing cachexia. cachexia in cancer patients demands new knowledge through research in several areas. • To improve classifi cation and assessment of pain, depres- sion and cachexia by computer-assisted approaches. The research plan of the EPCRC will be based upon ques- tions raised in a clinical setting, with focus on palliative care • To combine the new knowledge of symptoms, genomics cancer patients, thus a ‘true’ translational approach is cho- and assessment in an Internet-based system for imple- sen. The research will focus both on diagnosis and mentation of European evidence-based guidelines, which classifi cation of these symptoms and on an understanding will include standardised assessment and individualised of the underlying mechanisms. To reach the aims of EPCRC treatment plans for pain, depression and cachexia. requires a multidisciplinary approach, including basic scien- tists and clinicians who will translate human genome data • To develop a long lasting European Collaborative in into practical applications for these patients. palliative care cancer research.

Assessment and classifi cation of pain, depression and cachexia (fatigue) are the basis for diagnosis and subse- quent treatment. By use of modern molecular biology methods in this project, we will increase the understanding of the role of genetic variability for pain and cachexia. Euro- pean evidence-based Internet guidelines will be developed by members of the EPCRC, supported by an international advisory board. By recruiting a pan-European panel, cultural, social and language barriers will be taken into consideration in the early phase of guideline development.

234 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2006-037777

EC contribution € 2 799 910

Duration 36 months

Starting date 01/11/2006

Instrument STREP

Project website www.EPCRC.org

Identifi cation of profi les of genetic markers that best predict pain treatment responses.

Expected results Coordinator

• Identifi cation of profi les of genetic markers that best Stein Kaasa Lukas Radbruch predict pain treatment responses, with specifi c emphasis Norwegian University of Science Rheinisch-Westfälische Technische on opioids. and Technology Hochschule Aachen • Increased understanding of the molecular basis for Trondheim, Norway Aachen, Germany cachexia and identifi cation of genetic factors that may [email protected] predict patients at particular risk. Kenneth Fearon • Increased understanding of the value of serum param- University of Edinburgh eters as an indicator of pain response. Partners Edinburgh, United Kingdom • Better methods for classifi cation and assessment of pain, depression and cachexia in palliative care. Geoffrey Hanks Hellmut Samonigg • International European-adopted and agreed clinical University of Bristol Medical University of Graz guidelines for classifi cation, assessment and treatment Bristol, United Kingdom Graz, Austria of pain, depression and cachexia in palliative care. • Guidelines available and regularly updated on the EPCRC Franco De Conno Ketil Bø website, the EAPC (European Association for Palliative Fondazione IRCCS Istituto Nazionale Trollhetta AS Care) website, and other relevant websites. dei Tumori Trondheim, Norway • Guidelines translated and disseminated in relevant Milan, Italy European languages. Michael Schaude Irene Higginson Bender MedSystems King’s College London Vienna, Austria Potential applications London, United Kingdom Odd Erik Gundersen The aim of the EPCRC is to have the guidelines dissemi- Florian Strasser Volve AS nated and universally accepted within the palliative care Spitalregion St. Gallen Rorschach Trondeim, Norway community in Europe, both in clinical work and research. Kantonsspital [email protected] St. Gallen, Switzerland

CANCER CONTROL, SURVIVORSHIP AND OUTCOMES RESEARCH 235 Keywords | Collaboration | article 169 | research priorities | quality control | survival | prevention | clinical trials | translational research |

EUROCAN+PLUS context. As a consequence, Europe is unable to fully benefi t from the advantage of scale aff orded by its 500 million Feasibility Study for Coordination population.

of National Cancer Research Activities Europe is at present, and has been for many years, unable to retain many of its most talented scientists and is unable to provide a scientifi c environment capable of attracting top young scientists from outwith the continent. In addition, Summary there is no national incentive to promote mobility within the Member States. Consequently, the development of transna- A key issue remains how eff ective coordination of Cancer tional research activities is impeded by the obstacles to the Research in Europe can see the European Union (EU) benefi t mobility of researchers. from the advantage of scale, which its population provides. Cancer research in EU is fragmented and frequently duplica- A further obstacle is the lack of common core elements in the tive. Resources are wasted and implementation of closer curriculum of professionals. Common quality standards in cooperation to develop a strategy for Cancer Research by training are needed to facilitate the collaboration at European the Member States would clearly be cost-effi cient and has- level as well as the mutual recognition of the qualifi cations ten the development of major advances and their delivery to between European countries and therefore the mobility of the population. Barriers to collaboration in cancer research researchers and physicians. The situation is particularly exem- need to be identifi ed and ways sought to encourage the plifi ed by the absence of recognition of Oncology as a Medical development of collaborations in the Member States. discipline by many European countries and its variable status in most Member States.

Problem Consequently, although a large amount of fi nancial resources is involved, and a substantial portfolio of initiatives is carried Cancer remains a major Public Health problem worldwide out, cancer research eff orts are not currently benefi ting from with Europe hit hard and the situation set to worsen in abso- the advantages that a coherent and more co-ordinated lute terms as the population ages. Around one half of cancer framework would bring about. patients still die from their disease. On the other hand, there are currently great expectations that we are on the brink of making huge progress against the disease. Elucidation of Aim the human genome and rapid advances in understanding details of its function allied to rapid progress in technology, On the basis of an overview as complete as possible of gives great hope of rapid advances taking place. The current Cancer research in Europe, objectives of the project are to: era off ers more real hope than any previous. • identify the fi elds, topics and research subjects where the lack of co-ordination of national activities is particu- Cancer remains the subject of signifi cant research eff ort at larly detrimental for the progress of knowledge and the both the European level and in the Member States. Between quality of care; 2002 and 2006, the European Union will be devoting more • identify those specifi c fi elds, topics and research subjects than €435 million to this fi eld of research. This is in addition where the awareness of the need, as well as the willing- to national funding in Member States. ness and readiness to achieve a better co-ordination, are established enough as to make such an achievement An important aim for the Commission is to achieve a better likely; framework for collaboration in cancer research in Europe, and • explore the suitability, for this purpose, of the various sup- there is a recognition that coordination of national cancer port schemes available in the Sixth Framework Programme research eff orts at the European level is far from being (Coordination actions; ERA-NET schemes; article 169); achieved. Among the key elements proposed to explain this • explore, in particular, the interest and feasibility of an ini- situation are the barriers between disciplines and fi elds of tiative based on article 169 (participation of the EU into research; the fragmentation of research activities dedicated national research programmes jointly implemented); to the diff erent types of cancer and the resultant sub-optimal • help determine the means by which further exploring the critical mass; the weakness of the links between basic, applied possibilities and ways to progress in the direction of a better and clinical research, leading to a rather limited integration of coordination (study, workshop, conference, survey); basic and clinical research; and the implementation of all • give orientation on all the issues above raised and practical these activities mainly in a national framework and a national recommendations on the last points.

236 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Expected results Project number LSSC-CT-2005-015197 The project shall provide key answers to the following ques- tions through the exploration of barriers to Research EC contribution Collaboration in the EU in specifi c fi elds as well as by dealing € 3 000 000 with some of the key issues including mobility of cancer research workers throughout the European Union: Duration • irrespective of the prospects generated by considerations 24 months of alternative legal, governance and fi nancial matters, including article 169, what can be done to facilitate Starting date Cancer Research in the European Research Area? 01/10/2005 • what could be done to enhance Cancer Research in the European Research Area by new application(s) of available Instrument legal, governance and fi nancial considerations, including SSA article 169?

Potential applications

The project is certainly going to have a major impact on the structure of Cancer Research, basic and clinical, throughout the EU. Furthermore, the EU will dispose of concrete and practical recommendations for the defi nition of priorities in research programmes.

Coordinator

Peter Boyle Diana Dunstan David Kerr Ulrik Ringborg International Agency for MRC Research Management Dept. of Clinical Pharmacology Radiumhemmet-Dept. of Oncology Research on Cancer – IARC UK Medical Research Council The Chancellor, Masters and Scholars Karolinska University Hospital Solna Lyon, France London, United Kingdom of the University of Oxford Stockholm, Sweden [email protected] [email protected] Radcliffe Infirmary [email protected] Oxford, United Kingdom Alexander M.M. Eggermont [email protected] Dimitrios Trichopoulos Partners Erasmus University Medical Center Dept. of Hygiene and Epidemiology Dept. of Surgical Oncology Peter Lange School of Medicine Harry Bartelink Erasmusc MC – Daniel Den Hoed Unterabteilung 61: Gesundheit, National and Kapodistrian University The Netherlands Cancer Institute Cancer Center Biowissenschaften of Athens Dept. of Radiotherapy Rotterdam, The Netherlands Bundesministerium für Bildung Athens, Greece The Netherlands Cancer Institute/ [email protected] und Forschung [email protected] Antoni van Leeuwenhoek ziekenhuis Berlin, Germany Amsterdam, The Netherlands John M. Fitzpatrick [email protected] Thomas Tursz Surgical Unit Direction Générale Filippo Belardelli Mater Misericordiae Hospital Jose Martin Martin-Moreno Institut Gustave Roussy Dept. of Cell Biology University College Dublin Professor of Medicine and Public Health Villejuif, France and Neurosciences Dublin, Ireland Medical School, University of Valencia [email protected] Istituto Superiore di Sanita’ [email protected] Valencia, Spain Rome, Italy [email protected] Jan-Willem Hartgerink Herbert Michael Pinedo International Affairs Department VUMC Cancer Center Amsterdam Julio Celis Ministerie van Volksgezondheild, Amsterdam, The Netherlands Institute of Cancer Biology Welzijn en Sport [email protected] Danish Cancer Society The Hague, The Netherlands Copenhagen, Denmark [email protected] [email protected]

CANCER CONTROL, SURVIVORSHIP AND OUTCOMES RESEARCH 237 Keywords | Breast cancer | funding | harmonisation |

EUSTIR Problem

A European strategy for the integration The present methods of awarding research grants in cancer suff er from many defects and appear to result in repetitive of research on breast cancer research, often with no clear result and no clinical relevance. There is no agreement as to which areas are the most impor- tant, there is no attempt to ensure claims are validated, there is no audit process for success/failure and no ranking of abil- Summary ity of individual units to complete projects and their value. This means that monies for research are often spent poorly. The overall objective is to create a permanent European overview process for the award, audit and recording of all Aim research on breast cancer. 1. Long-term aims The project aims to create: • To harmonise breast cancer research through individual • a European overview process for project proposals funding organisations operating within Europe. received by all funding bodies. This will: • To encourage research to be focused on that which will • prevent research from being funded for similar work have ultimate clinical application. in multiple projects; • To ensure that validation is a part of the design of all • result in a few large, rather than multiple small series, applications. which are much more likely to yield defi nite results; • To establish an audit system backed by a database that • a body of the leading researchers in breast cancer which allows assessment of the success rate of individual agree the areas most likely to give results of clinical rele- research groups. vance and agree certain issues that must be included in all proposals (such as validation of the results); 2. Project-specifi c aims • an audit process of research work. This addresses the • To bring together all organisations involved in develop- problem that many projects do not address their aims. ing, supporting and undertaking breast cancer research The audit outcomes will be accessible to research funders, in Europe to design a strategy for the pan-European so that institutes most likely to complete valuable projects harmonisation of breast cancer research. are identifi ed (and the converse!). • To develop a process of audit of completed research whereby research projects will also be judged as to This project will be divided into three parts: whether they have advanced the science and to what • a workshop of leading European research workers in degree they are relevant to clinical practice. breast cancer to defi ne the most important areas for • To maintain a database of projects and of the audit of research and to make suggestions on an overview completed projects. process; • Audit of past projects and production of a policy paper • a workshop of the funding organisations and other for implementation. interested parties to discuss and agree a strategy for • To infl uence journal editors, to ensure higher standards harmonising research in the identifi ed areas; are set for acceptances for publication of results; valida- • validation of projects funded to date against criteria tion and clinical relevance will be the most important established within the project. issues.

238 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Expected results Project number LSSC-CT-2005-517659 • A European overview process for project proposals received by all funding bodies. This will: EC contribution • prevent research from being funded for similar work € 198 640 in multiple projects; • result in a few large, rather than multiple small data Duration sets, which are much more likely to yield defi nitive 30 months results. • Agreement and ranking of the areas most likely to give Starting date results of clinical relevance. 01/01/2006 • Agreement on certain issues that must be included in all proposals (such as validation of the results). Instrument • An audit process of the results of funded research. This SSA will initially show if the contentions expressed above with regard to funded research are in fact correct. The audit outcomes will be accessible to research funders, in that institutes most likely to complete valuable projects will be identifi ed (and the converse!).

Potential applications

Aside from the obvious and intended application in breast cancer funding across Europe, the model created by the project can be applied to many funding areas where multi- ple sources of funding create the same problems as seen in breast cancer.

Coordinator

Roger Blamey Breast Institute Nottingham City Hospital NHS Trust Nottingham, United Kingdom [email protected]

CANCER CONTROL, SURVIVORSHIP AND OUTCOMES RESEARCH 239 Keywords | Cancer pain | analgesic medicines | pain pharmacology |

NORMOLIFE Problem

Development of new therapeutic The approach in which compounds are designed to interact with a wide spectrum of targets involved in pain signal for- substances and strategies mation and transmission is a new and original therapeutic strategy, opposite to current strategies that use drugs which for treatment of pain in patients are as receptor-selective as possible. The project’s major goal is chemical design of new multitarget molecules and with advanced stages of cancer analysis of their pharmacological properties that will result in the selection of several new compounds for further clini- cal evaluation as a new generation of potent analgesics for multicomponent cancer pain treatment. Summary

Prolonging the life expectation of patients with advanced Aim cancer could be done by modern medicine. However, pro- gressive pain that is associated with progression of the The project will involve three general complementary sci- disease is the major factor that destructs the last moments entifi c objectives: chemistry, in vitro biopharmacology and of life. Severe progressive and uncontrolled pain is a major in vivo pharmacology that will be accomplished by multi- reason of requesting euthanasia. The applications of oral disciplinary teams integrated in the project. (morphine) pills or transdermal patches with lipophilic analgesic drugs are the most common treatments of cancer Synthesis of new compounds, designed by theoretical pain. These compounds penetrating into central nervous (SAR) analysis, will be synthesized in chemical laborato- system produce side eff ects (respiratory depression, con- ries. Hundred new compounds will be designed and stipation, tolerance, sedation, etc.) to such extent that pain synthesized on initial stages of the project. These com- treatment is reduced by doctors or refused by the patients. pounds will be preselected in in vitro tests. The in vitro The discoveries of the last years indicated the changes in tests comprise receptor affi nity evaluation and functional expressions of pro- and antinociceptive receptors in patho- cell-based assays. The selected (expected 6) compounds logically changed peripheral tissues as well as in the central will be fi nally characterized in vivo in an animal model of nervous system. The concerted modulation of these recep- cancer pain. tors in combination with designed receptor ligands may block nociceptive signal formation and transmission more eff ectively than traditional monotherapies. The objective Expected results of this project is to focus on the development of new mul- titarget compounds and methods which will interact with The application of a new generation of medicines designed opioid receptors expressed in infl amed and/or pathologi- under the NORMOLIFE project will reduce side eff ects gen- cally modifi ed tissues. Partial penetration into the central erated by traditional opioids in central nervous system, nervous system will result in synergistic pain suppression including tolerance, dependence, constipation, euphoria, via interaction between the peripheral and central nervous etc. The major prospective application of the results will be system. Alternatively, newly developed compounds could a more eff ective treatment of acute as well as chronic, neu- be applied directly into central nervous system to interact ropathic and infl ammatory cancer pain of patients with with the specifi c, pathological set of receptors. The devel- advanced stages of the disease. We predict that the project oped compounds will be screened in vitro in a cell silicon will be able also to defi ne the diff erences between the spec- hybrid biosensor and selected compounds, in vivo in trum of pain symptoms and pain progression in progressive rodent’s cancer pain models. The project will yield new cancer typical for female (ovarian) and male (prostate) basic data on structural requirements of analgesics for patients. The establishment of such diff erences will help to treatment of persistent cancer pain in advanced stages propose diff erent pain treatment for women and men. and will develop new compounds characterized to the stage that will allow to promote them for further clinical phase testing. Potential applications

The experimental preclinical data of the newly-developed compounds will allow for selection and proposition of new medicines for further clinical evaluation.

240 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number LSHC-CT-2006-037733

EC contribution € 2 182 325

Duration 36 months

Starting date 01/12/2006

Instrument STREP

Project website www.normolife.eu Nerve cells cultured on a micro-electrode chip for testing analgetics. (Foto C. and M. Kage)

Coordinator

Andrzej W. Lipkowski Zofia Lipkowska Medical Research Centre Institute of Organic Chemistry Polish Academy of Sciences Polish Academy of Sciences Warsaw, Poland Warsaw, Poland [email protected] Wieslawa Walisiewicz-Niedbalska Industrial Chemistry Partners Research Institute Warsaw, Poland Giuseppe Ronsisvalle Faculty of Pharmacy Dieter G. Weiss University of Catania University of Rostock Catania, Italy Rostock, Germany

Dirk Tourwe Olaf Schroeder Free University of Brussels Pattern Expert Brussels, Belgium Borsdorf, Germany

Aleksandra Misicka-Kesik Frank Graage Warsaw University Steinbeis-Forschungs- und Warsaw, Poland Entwicklungs-zentrum GmbH Rostock, Germany Geza Toth Biological Research Centre Hungarian Academy of Sciences Szeged, Hungary

Zafiroula-Iro Georgoussi Institute of Biology National Centre of Scientific Research ‘Demokritos’ Athens, Greece

CANCER CONTROL, SURVIVORSHIP AND OUTCOMES RESEARCH 241

Scientifi c Model Systems

The complexity of cancer initiation and progression combined with heterogeneity of diff erent cancers presents a big challenge to researchers studying this disease. In order to overcome these diffi culties cancer research often has to rely on model systems that can be used as examples of other systems that are more diffi cult to study directly. Good model systems have to be suffi ciently simple to be studied, but at the same time suffi ciently complex to allow for generalisation of the study results. The model systems have to mimic the problem under investigation and to be reproducible. Advantages of their use in cancer research include time and cost effi ciency and relative ease to control for the factors involved. Develop- ment and characterization of new model systems – be it living organisms or computer software capable of reproducing some processes involved in cancer biology or investigating potential treatments – and technologies that facilitate their use is of the utmost importance in current cancer research. This area of research is represented by two projects that answer to the need for better cancer models in very diff erent ways. ESBIC-D is a Coordination Action that aims to establish a framework for a sys- tems biology approach to combat cancer by creating a network of partners with diff erent expertise on the European level. ZF-Tools is a STREP project aiming to develop and characterize a zebrafi sh model system that could be used as a high-throughput screening tool in drug discovery research.

Dominika Trzaska Keywords | Systems biology | computational biology | cancer research | modelling | signalling pathways | bioinformatics and patient information |

ESBIC-D This goal will be achieved via a series of steps: • designing the protocols needed for rapid data and infor- European Systems Biology Initiative mation exchange for the diff erent levels of cellular information; combating complex diseases • connecting leading European research groups in a con- sortium that contributes existing data and computational resources and links clinical and experimental groups with computational groups; Summary • providing standards and protocols to combine the data resources with theoretical models; It is the goal of this coordination action (CA) to establish • providing documentation and a series of workshops to a European framework for a systems biology approach to achieve the largest possible benefi t for European cancer combat complex diseases using cancer as a prototypical research. problem. The coordination action will be fundamentally based on existing resources of leading research groups in These interaction points between the diff erent expertises Europe. It unites groups with a strong clinical focus, with build the basis for measurable and verifi able targets of experience in high throughput functional genomics as well the project that will have a high impact on future planning as with computational and systems biology resources. More- and design of systems biology approaches for all complex over, it brings together groups from some of the largest genetic diseases. European cancer research organisations and centres. Aim Problem Exchange and dissemination of information – combining Primary targets of the Sixth Framework programme are leading EU wide resources. A particular goal of this CA will activities for the combat of multigenic complex diseases be the agglomeration and integration of relevant informa- such as cancer, diabetes, obesity, heart diseases and diseases tion from all three components. Existing resources of the of the nervous system. In particular, cancer is, after decades partners/partner institutions will be incorporated and an of research, still a devastating disease, responsible for immediate added-value is achieved on the European level roughly one quarter of the death in Europe. by the correlation and integration of those components.

Essentially, the three main causes for cancer are infection, Performance of joined studies and analyses – bridging environmental infl uence and genetic predisposition. However, experiment and model. There is a fundamental discrepancy on a more analytical and molecular level the ontogeny of in current cancer research. Much of the analysis carried out cancer is less evident and both clinical as well as basic up to now has been focussed on the eff ect of single genes, research suggests that cancer is the result of an accumula- resulting in models that are far too simple to explain the tion of many factors that promote tumour growth and complex biological processes acting in cancer develop- metastasis. Consequently, it is not clear, if much of current ment. Thus, modelling at the state of the art is in most cancer research, typically focussed on analysing subproc- cases not very helpful for e.g. prediction of the response of esses involving at most a few genes or gene products at patients to diff erent types of treatment or the develop- a time, will ever be able to ‘understand’ such a complex phe- ment of new drugs. On the other hand there is the tendency nomenon, and to form the basis for dramatic improvements to generate more and more data in an uncoordinated and in cancer treatment. It is also clear, that the current research non-standardized fashion. This not only increases costs but approaches, in spite of all successes in some areas, have not also leads to heterogeneous and often confl icting results resulted in any dramatic increase in the rates of cure for for the relevant biological processes. Thus, experimental most common cancers. data generation at the state of the art is not very helpful to guide the development of theoretical models. With this CA With this CA we expect to improve this situation by we aim at identifying critical parameters in the course of addressing the problem with a systems biology approach. such model development and the identifi cation of experi- In particular, the strong interaction of clinical and experi- mental protocols and strategies to measure these critical mental data with theoretical computer modelling will be parameters in coordinated experiments that target diff erent applied in an interdisciplinary and international approach. levels of cellular information.

244 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Project number Performance of benchmarking exercises – defi ning test cases LSHG-CT-2005-518192 for systems biology approaches in cancer. There are many promises for health care: models of regulatory networks are EC contribution necessary to understand their alterations in case of a dis- € 350 000 ease and to develop methods to cure the disease. Furthermore, since there is an observable trend in health Duration care towards an individualized and predictive medicine 24 months there will be an increasing need for the exact formulation of cellular networks and the prediction of systems behaviour in Starting date the areas of drug development, drug validation, diagnostics, 01/11/2005 and therapy monitoring. In this project we will defi ne several test cases that will show for example the performance of Instrument models for signalling pathways in the light of the experimental CA data resources. Project website Organisation and management – setting up an expert group http://pybios.molgen. for a European wide systems approach towards the combat mpg.de/ESBIC-D of cancer. So far, on the European level, there are some excellent groups and networks that focused their work in particular fi elds of genomics, proteomics, clinical research and bioinformatics. While on the one hand theses areas will need additional strengthening to remain competitive on an Coordinator international level, we are still lacking an initiative that brings together these groups to fi nd common and effi cient ways to Hans Lehrach Crispin Miller integrate and to utilise the data produced. This will be a fi rst Max Planck Institute for Molecular Genetics University Manchester necessary step to create a European platform for systems Dept. Vertebrate Genomics Paterson Institute for Cancer Research biology of complex diseases/cancer. Consequently a coher- Berlin, Germany Christie Hospital NHS Trust ent structure for data acquisition and data integration for [email protected] Manchester, United Kingdom modelling has to be built. For this purpose we need to: [email protected] • defi ne cancer related clinical, genomic and proteomic data sets in the context of systems biology; Partners Emmanuel Barillot • improve ways of data acquisition, storage and communi- Institut Curie cation procedures; Annemarie Poustka Paris, France • set standards for quality data integration; German Cancer Research Centre (DKFZ) [email protected] • defi ne common targets of systems biology modelling in Dept. Molecular Genome Analysis cancer. Heidelberg, Germany Kurt Zatloukal [email protected] Medical University of Graz Dept. of Pathology Expected results Jean-Philippe Vert Graz, Austria Association pour la recherche [email protected] A coordinated action for the systems biology of cancer will et le développement des méthodes create an expandable network of partners that develop effi - et processus industriels cient tools for data collection, integration and modelling. Paris, France In the future, this will improve our understanding and in par- [email protected] ticular our prognostic and therapeutic abilities for the complex genetic disease cancer. Ron Shamir Tel Aviv University School of Computer Science Potential applications Tel Aviv, Israel [email protected] Not applicable.

SCIENTIFIC MODEL SYSTEMS 245 Keywords | Zebrafi sh embryo model | functional genomics | tumor markers | defence response | cell transplantation |

ZF-TOOLS more effi cient methods in the anti-tumor drug discovery process. Acceleration of drug lead time benefi ts economy High-throughput Tools for as well as quality of life of cancer patients.

Biomedical Screens in Zebrafi sh The lack of basic knowledge of disease marker genes is the current bottleneck for biomedical research in zebrafi sh and for genomics-based compound screens in this model organism. The ZF-TOOLS project uses multidisciplinary Summary functional genomics approaches to discover novel disease markers. The expected identifi cation of factors important The zebrafi sh embryo model has rapidly gained ground for tumor growth and metastasis and organismal defence in biomedical research based on functional genomics responses will contribute fundamental knowledge rele- approaches. As a result it shows great potential to be incor- vant to human health and will open the door to the porated into preclinical drug screening pipelines. ZF-TOOLS establishment of zebrafi sh-based biomedical research aims to develop a case study for an anti-tumor drug screen- and screening tools. ing system, based on implantation of fl uorescently labeled tumor cells into zebrafi sh embryos. The optically transpar- ent embryos provide a highly useful in vivo system to Aim monitor growth and metastasis of implanted tumor cells. This system will allow for the powerful combination of vis- The ZF-TOOLS project is a coordinated eff ort of three ual monitoring with high-throughput analysis of expression research laboratories and three SMEs aimed at the following of marker genes with a predictive value for tumor progres- objectives: sion or for defence responses towards developing tumors. • genomic-based marker discovery for biomedical screens However, the bottleneck for application of this approach is in zebrafi sh; insuffi cient knowledge of relevant disease marker genes in • use of high-throughput marker analysis and tumor cell zebrafi sh. Therefore, the fi rst objective of ZF-TOOLS is implants for the identifi cation of tumor growth and marker discovery. To achieve this objective fl uorescent metastasis factors and organismal defence factors. zebrafi sh cell lines expressing selected oncogenes will be generated and a multidisciplinary functional genomics The project aims to develop a case study for an anti-tumor approach, integrating diff erent genomics techniques and drug screening system, based on the implantation of fl uores- bioinformatics, will be undertaken to compare expres- cently labeled tumor cells into zebrafi sh embryos. This sion profi les before and after implantation into zebrafi sh innovative tumor cell implantation system is currently being embryos. The experimental design of our genomics strate- developed by one of the SME partners in the project and has gy will enable distinction between tumor cell markers and the major advantage that it does not involve the use of trans- markers for immune or general defence responses of the genic animals. Growth and metastasis properties of implanted organism. After marker validation, high-throughput tools tumor cells can be effi ciently monitored by fl uorescence for large scale expression screens will be developed. The microscopy during development of the transparent zebrafi sh second objective of ZF-TOOLS is to exploit the combina- embryos. The system resembles the natural situation of tion of high-throughput markers and implant system to tumor growth, as the tumor cells are derived from zebrafi sh study diff erent oncogenic implants and eff ects of a test cell cultures of embryonic origin and implanted back into panel of drugs used in human cancer therapy. This case zebrafi sh embryos. We envisage that a powerful screening study should result in identifi cation of important tumor system can arise from the combination of high-throughput growth and metastasis factors as well as defence factors. marker analysis with the possibility to visualize tumor growth Fundamental knowledge, tools and technical expertise and metastasis in an optically transparent vertebrate model gained from ZF-TOOLS will be commercially exploited by organism. However, for realization of such a screening three high-tech SMEs. system, the identifi cation of relevant disease marker genes in zebrafi sh forms a crucial step. In the ZF-TOOLS project diff erent genomics approaches will be used to discover Problem novel markers, which will be suitable for application in the ZF-TOOLS tumor screening system and also will have The ZF-TOOLS objectives are focussed on the incorporation a broader utility for disease research in the zebrafi sh model. of the zebrafi sh embryo model into the preclinical drug screening pipelines. The use of mice for in vivo monitoring of The experimental design of our genomics approach is disease processes such as tumorigenesis, metastasis and expected to result in the identifi cation of two classes of immune response to tumors is limited by costs and through- markers: put level. Introducing a high-throughput zebrafi sh embryo • markers correlating with growth and metastasis of tumor model could potentially contribute to cost-eff ective and cells;

246 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Two-day-old zebrafi sh embryo.

• markers correlating with the immune or other defence disease processes in a transparent vertebrate model responses of the organism towards tumor cells. organism; • it has the potential for high-throughput application due The reason for concentrating on both classes of markers is to the small size of zebrafi sh embryos, the high numbers that interactions between developing tumors and the tumor with which embryos can be obtained and the choice of microenvironment are decisive for tumor survival or rejec- high-throughput molecular screening tools that will be tion. Strategies to boost anti-tumor immunity have been developed within the project. explored for many years. Therefore, knowledge of tumor markers as well as defence response markers will increase In order to establish the zebrafi sh screening tools, the ZF- the versatility of the anti-tumor drug screening system to be TOOLS project will undertake a multidisciplinary functional developed in the project. genomics approach integrating diff erent global expression profi ling techniques and bioinformatics. High-throughput Based on the genomic analyses in the project, tools will be tests for expression screening of defi ned sets of newly iden- developed for high-throughput simultaneous quantifi ca- tifi ed disease marker genes and disease-associated small tion of defi ned subsets of relevant marker genes. Next, the regulatory RNAs will be developed. In addition, based on combination of high-throughput marker analysis and the genomic data resulting from the project, a collection of nov- tumor cell implantation system will be applied to investi- el oncogenic and fl uorescent reporter cell lines will be gate diff erent oncogenic cell implants and to carry out developed, suitable for implantation into zebrafi sh embryos a case study with a test panel of drugs used in human and in-vivo monitoring of tumor growth and metastasis cancer therapy. This will allow assessment of which mark- processes. These cell lines also off er the attractive possibili- ers represent important factors with roles in tumor growth ty to perform complementary, in vitro cell culture based and/or metastasis or roles in defence responses. Knowl- screens. With this approach the ZF-TOOLS project is expected edge of these factors is expected to form a solid basis for to result in: further development of a powerful screening system that • knowledge of tumor growth and metastasis factors and can be off ered to the pharmaceutical industry after the organismal defence factors; project. Furthermore, technical expertise in development • high-throughput tools for quantitative analysis of disease and application of high-throughput analysis tools will be marker sets; used to expand the service activities of SMEs involved in • a collection of constitutive and inducible, oncogenic and the project and strengthen their position. Finally, basic non-oncogenic reporter cell lines useful for basic disease knowledge of disease markers, an expected achievement research and for application in screening systems; of the project, is indispensable to advance biomedical • case study results of a novel anti-tumor drug screening research in the zebrafi sh model. system, based on the implantation of fl uorescently labeled tumor cells into zebrafi sh embryos. Expected results Potential applications The strategic aim of the ZF-TOOLS project is the develop- ment of a zebrafi sh embryo screening system as an The ZF-TOOLS project aims to make an impact on reinforcing innovative genomics tool. This system will be employed for European competitiveness by generating strategic know- high-throughput eff ectiveness testing of pharmaceutical ledge in a multidisciplinary research approach. The studies to compounds that have the potential to infl uence disease be carried out within the ZF-TOOLS project will result in the processes including tumor growth, metastasis and immune development of novel tools for biomedical research and defence responses. This zebrafi sh screening tool off ers some pharmaceutical screenings as well as in technical expertise unique features that make it very attractive in comparison that will be valuable to a broad range of research topics. with existing tools: These tools and technology will be exploited for basic research • it combines the power of genomic analysis of disease of vertebrate disease as well as for strategic research and marker genes with the power of in-vivo monitoring of service activities of three high-tech SMEs.

SCIENTIFIC MODEL SYSTEMS 247 Coordinator Project number LSHG-CT-2006-037220 Annemarie H. Meijer Bas Reichert Institute of Biology BaseClear B.V. EC contribution Leiden University Leiden, The Netherlands € 1 739 000 Leiden, The Netherlands [email protected] [email protected] Duration Tamás Forrai 36 months Zenon Bio Ltd. Partners Szeged, Hungary Starting date [email protected] 01/01/2007 Herman P. Spaink ZF-screens B.V. Mátyás Mink Instrument Leiden, The Netherlands Szeged University STREP [email protected] Szeged, Hungary [email protected] Project website Nicholas Foulkes http://biology. Forschungszentrum Karlsruhe GmbH leidenuniv.nl/ibl/S1/ Institute for Toxicology and Genetics research/ZF-TOOLS Eggenstein-Leopoldshafen, Germany [email protected]

248 CANCER RESEARCH PROJECT FUNDED UNDR THE SIXTH FRAMEWORK PROGRAMME Indices – Keywords Indices – Partners Indices – Organisations

249 Indices – Keywords

accurate patient positioning 215 blood vessels 13 chondrosarcoma 36 activators 10 blood/brain 188 chronic disease 98 adeno-associated virus (AAV) 172 bone metastasis 66 chronobiology 217 adenovirus 207, 219 bone tumour 36 chronotherapeutics 217 adjuvants 184 brain tumour diagnosis 129 circadian 217 adult stem cell therapy 205 BRCA1 86 circulating nucleic acids 119 adults 23 BRCA2 86 classification 234 Ag processing 175 breast 17, 95 clinical analysis 123 ageing 70 breast cancer 38, 49, 62, 116, 121, 135, clinical diagnosis 118 age-related macular 137, 222, 238 clinical outcome 57 degeneration (AMD) 170 breast cancer diagnosis 102 clinical pharmacology 23 alcohol 100 breast imaging 135 clinical trials 13, 180, 222, 236 ALL 196 cachexia 234 clinical validation 215 AML 196 cancer 30, 38, 70, 118, 142, 164, CLL 196 analgesic medicines 240 166, 179, 217, 234 clocks 217 androgen receptor 66 cancer and infectious diseases 184 clonal disease progression 55 angiogenesis 13, 47, 83, 155, 162, 164 cancer biology 42 CML 196 animal models 82 cancer chemotherapy 177 CMPD 196 antiangiogenesis 164 cancer incidence 100 collaboration 236 antibody 155 cancer metastasis 157 colon cancer 116, 137 antibody-photosensitiser conjugates 211 cancer pain 240 colorectal 219 anticancer drugs 217 cancer pre-disposition 28 colorectal cancer 62 anticancer therapy 23, 123, 219 cancer research 246 combination therapy 155 apoptosis 34, 40, 81, 108, 166, 209, 225 cancer screening 142 computational biology 244 aptamers 108 cancer stem cell 55 computational rational protein design 225 arming 219 cancer therapy 75, 108, 111, 205 contrast mammography 135 arthritis 166 cancer treatment 162 coronary heart disease (CHD) 98 article 169 236 capsule endoscopy 142 CRC-colorectal cancer 64 assessment 234 caspase-2 64 creation of virtual libraries 172 associate candidate countries 86 CD4 175 crypt 62 association studies 95 CD40 166 CTL 175 autophagy 81 CD99 153 cyclin dependent kinases 217 bacteria 93 cell cycle 217 data mining 116 baculovirus 170 cell death 40, 70, 81 DC 175 beta catenin 137 cell imaging 40 defence response 246 bifunctional 111 cell transplantation 246 dendritic cells 184 biobank 232 cell-based assays 157 dependence receptors 209 biobanking 119 cell-based delivery systems depression 234 bioinformatical synopsis 119 of anti-cancer genes 225 dermatology 162 bioinformatics 172 cellular senescence 70 detection 150 bioinformatics and patient information 244 CGH 144 developmental biology 72 bioluminescence 150 chemical inhibitors 51 diagnosis 53, 146 biomarkers 30, 82, 116, 194 chemotherapy 102, 144 diagnostic treatment unit 108 biomedical engineering 162 children 23, 179 diagnostics 113, 131 biosensing 142 chimaeric T-cell receptor 179 diet 98 bispecific 111 chimeric immune receptor (CIR) 168 differentiation 34 blood 131 choline kinase 64 directed evolution 225 blood separation 148 chondrogenesis 36 DISC 64

250 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME disease markers 131 gene regulation 75 immunosurveillance 70 DNA damage 28, 70 gene therapy 47, 162, 166, 207 immunotherapy 180, 227 DNA electrotransfer 162 genetic engineering 111 IMRT 215 DNA-methylation 121 genetic epidemiology 232 in situ analysis 30 drosophila 62 genetic marker 234 in vivo dosimeters 215 drug 203 genetic microarrays 129 in vivo imaging of gene expression 190 drug delivery 217 genetics 91 infections 232 drug design 82 genome 53 inflammatory diseases 47 drug development 190, 217 genome (in)stability 28 infrared imaging 118 drug resistance 177 genomic profiling 119 infrared microscopy 118 drugs 53 genomics 28, 68, 116, 157, 182 infrared spectroscopy 118 DSS 129 giant cell tumour of bone 36 inhibition of protein-protein interactions 19 dual-energy 135 GIST 23 inhibitors 10 dynamic models 217 GLP/GMP procedures 225 insect cells 170 dynamical modelling 26 glycan 131 in-silico prediction of early diagnosis 140 glycome 131 drug-like properties 172 EBV 93 grid technology 172 insulin like growth factor 153 EEC-related syndromes 32 guided therapies 190 intracellular peptide inhibitors 225 electric pulses 162 guidelines 234 ion mobility spectrometry 106 electropermeabilisation 162 harmonisation 232, 238 keratinocyte differentiation 32 electroporation 162 HCV 93 kinase inhibitors 40 endothelial cells 13 health sciences 133, 219 kinases 45 engineered T-cell 168 helicobacter pylori 93 kinome 137 epigenetic 34 hepatocellular carcinomas 79 knowledge driven drug design 188 epigenetics 75, 137 hereditary 77 knowledge-based cancer therapy 42 epithelial stem cell 32 HHV8 93 KSHV 93 Ewing 127 HIF 203 larval neuroblast 62 Ewing’s sarcoma 36, 153 high-throughput screening 19, 42 laser spectrometry 106 EWS/FLI1 153 high-throughput low molecular leiomyoma 77 exhaled breath analysis 106 weight compound screening 66 lentivirus 83 expert system 148 high-throughput target leukaemia 38, 111, 179, 196, 227 familial gastric cancer 139 identification and validation 66 library design 172 fatigue 234 histone modification 75 Life Sciences, Genomics and flash lamp 148 HIV 182 Biotechnology for Health 88 fluorescence 148 HNPCC 139 lifestyle 98 follow-up diagnostics 116 homing 168 luminescent tags 148 fruit and vegetables 100 host 83 lung cancer 106, 148, 177 fumarase 77 HPV 93 lymphangiogenesis 47 functional genomics 21, 26, 246 HR-MAS 129 lymphedema 47 funding 238 HSV-1 79 lymphoma 111, 227 gain-of-function 57 HTLV 93 mammography 135 gas chromatography 106 human 203 mammospheres 62 gene 95 human glandular kallikrein 2 150 mantle cell lymphoma 201 gene delivery 170 hypoxia 203 markers 146 gene expression 72, 146, 157 identification of novel compounds 19 mass spectrometry 51, 106, 131, 146 gene expression profiling 17 idiotype 227 MDS 196 gene profiling 49 immuno-diagnosis 148 medical diagnosis 106 gene promoters 207 immunomonitoring 175 medical imaging 133

INDICES 251 medical instrumentation 162 naked DNA 162 personalized medicine 217 medulloblastoma 127 nanoparticles 111 PET mammography 102 MegaFasL 150 nanosciences 60 PET-based treatment planning 108 melanoma 91, 175, 194 nanotechnology 150 PET-CT simulation 108 metabolomics 116 natural products 19 PET-CT-RT 108 metalloproteinase 113 necrosis 81 pharmacogenomics 201 metastase 82 neoplasm 155 pharmacology 172, 217 metastasis 17, 49, 113, 166 nephroblastoma 127 pharmacophore inhibitors 40 methylation 144 neuroblastoma 127 phenome 217 microarray 13, 123, 153 new drugs 45 phosphatome 137 microarray analysis 119 new therapies 162 phosphoinositide 3-kinase 166 micrometastases 119 non-invasive imaging 219 phosphorylation 51 micrometastasis 150 non-viral gene therapy 162 photodynamic therapy 211 microRNA 72 non-viral vectors 207 photon counting 135 migrating cancer stem cells 137 novel cancer therapy 57 physical activity 98, 100 minimal disease 119, 144 ocular disease 162 physical sciences 133 minimal residual disease 150, 201 oesophageal cancer 106 PI3K 64 miRNA 137 oncofetal antigens 155 PlGF 162 mismatch repair 139 oncology 23, 219 point of care 148 mitochondria 64 oncolytic vectors 79 population-based 232 mitosis 51 opioid response 234 pox- 219 modelling 21, 242 optoacoustic technology 150 pre-clinical studies 182 molecular biology 72 organ-specific metastasis 49 prediction of ADME parameters 172 molecular cell biology 182 osteochondroma 36 predictive toxicology 172 molecular chemotherapy 219 osteogenesis 36 prevention 100, 236 molecular diagnosis 144 osteosarcoma 36 primary tumour culture 225 molecular diagnostics 140 ovarian cancer 144, 194, 213, 219 prognosis 121, 123, 146 molecular genetics 68 overweight 100 programmed 81 molecular imaging 102, 140, 190 p53 10 prostate 95 molecular risk factors 201 p53 status 57 prostate cancer 66, 86, 146, 150, 170, 194, 207 molecular signature 222 p53 tumour suppressor 57 protease 113 molecular tumour imaging 108 p63 10 protein-based drugs 60 molecule coupling 148 p63 and family members 32 Protein-Protein interactions 188 monoclonal antibodies 111 p73 10 proteome 217 Monte Carlo dose calculation TPS 215 padlock probing 30 proteomics 28, 116, 144, 146, 182, 201 mouse 217 paget disease of bone 36 proteomics molecular targets 13 mouse models 28, 64, 137 pain 234 protontherapy 215 MRS 129 pain pharmacology 240 proximity ligation 30 multimodality image registration 215 palliative care 234 PTR-MS 106 multiparameter 148 pancreatic cancer 140 quality assurance 213, 232 multiphoton microscopy 150 PanINs 140 quality control 236 multiple myeloma 55 paraganglioma 77 quantum dots 148 muscular disorders (MD) 170 patients 217 radiation-induced complications 205 mutant p53-reactivating drugs 57 pattern recognition receptors 184 ras 64 mutation 144 pediatric cancers 45 receptor-selective TRAIL mutants 225 mutations 57 PEMT 102 recombinant TCR 168 myxoma- 219 pericellular 203 registries 232 naevi 91 persistence 168 regulatory networks 26

252 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME renal 77 targeted therapy 144 vaccine 227 replication 219 targeting 79 vaccine dendritic cells 186 research priorities 236 technological sciences 133 vasculogenesis 13 re-targeting 207 technology development 30 vector 60 retinoblastoma 127 telomerase 53, 70 vertebrate cells 170 rhabdoid 127 therapeutic monitoring 106 virotherapy 219 risk assessment 215 therapeutic vaccine 175 virtual simulation software 215 risk factors 100 therapy 53, 201 virus 93 RNA array profi ling 201 therapy prediction 121 xenografts 82 RNA interference 72, 157 thymidylate synthase inhibitor 213 zebrafish embryo model 246 RNA interference screening 42 tissue array 62 RNA silencing 72 tissue ischemia 47 RNAi 51 TNF ligand-mimicking peptides 225 safety 168 tomosynthesis 135 sarcomas 23 topoisomerase 217 scaff old inhibitors 40 toxicity 177 screening 116 TRAIL 64 selective targeting 155 transcription factors 68 sensory organ precursor 62 transcriptome 217 serum 146 transcriptomics 116 short interfering RNA 72 translational research 127, 236 SIFT-MS 106 treatment 150 signalling 83, 166 treg 175 signalling pathways 244 tricarboxylic acid cycle 77 signature 144 tumor markers 246 simulation 21 tumour 13, 83 single-cell analysis 137 tumour cell dissemination 119 siRNA 82 tumour diagnosis 190 skin diseases 162 tumour escape 175, 194 small molecule inhibitor design 211 tumour hypoxia 108 small molecule inhibitors 75, 188 tumour imaging 113 small molecules 155 tumour models 40 smoking 100 tumour necrosis factor (TNF)-related solid tumours 225 apoptosis-inducing ligand (TRAIL) 225 spreading 219 tumour neovasculature 155, 211 standards 232 tumour penetrant 188 stealthing 207 tumour profiling 82 stem cell 38, 83 tumour progression 194 stroke 98 tumour suppression 10 stroma 155 tumour suppressor 209 succinate dehydrogenase 77 tumour targeting 15 sun exposure 91 tumour-host interactions 15 survival 236 tumour-specific targeting 219 synchrotron radiation 118 tyrosine kinases 82 systems biology 21, 26, 217, 244 uncommon cancer 23 T lymphocytes 179 urine 146 tailor-made therapy 225 urology 123 targeted screening 86 UV light source 148

INDICES 253 Indices – Partners

Aaltonen, Lauri A. 78, 139 Bágyi, István 174 Bernasconi, P. 199 Aberdam, Daniel 33 Bahler, Jurg 27 Berns, Anton 44 Abrieu, Ariane 52 Baker, Andrew 115 Berns, Els 145 Acilu, Marta 27 Ball, Graham 195 Berrino, Franco 99 Ackermann, M. 200 Ballieu, Michel 224 Bertagnoli, Stéphane 221 Adamou, Adamos 223 Bangham, Charles 94 Berthou, Christian 112 Adema, Gosse 182 Bangma, Chris H. 147, 208 Bertolini, Francesco 14 Agami, Reuven 59 Barbacid, Mariano 159, 178 Betsholtz, Christer 48 Aguet, Michel 44 Barbet, Jacques 192 Beuthien-Baumann, Bettina 110 Aharinejad, Seyedhossein 16 Barbui, T. 199 Biagi, Ettore 181 Aigner, Thomas 37 Bardelli, Alberto 138 Bianchi-Scarrà, Giovanna Libera 92 Aime, Silvio 192 Barillot, Emmanuel 245 Bick, Ulrich 136 Airenne, Kari 171 Baroni, Massimo 214 Bicknell, Roy 156 Akan, H. 198 Barosi, G. 199 Bikfalvi, Andreas 156 Alarcon, Balbino 169 Barricarte, Aurelio 99 Binder, Bernd 115 Alderborn, Anders 31 Bartek, Jiri 12, 29, 59 Binley, Katie 169 Alemany, Ramon 221 Bartelink, Harry 110, 237, 223 Biondi, Leonardo 185 Alitalo, Kari 48, 84 Bartholeyns, Jacques 187 Birchmeier, Walter 159 Alix-Panabieres, Catherine 120 Bartlett, John 31, 223 Bischoff, Rainer 147 Alon, Uri 22 Bartram, Claus R. 233 Bizzari, Jean-Pierre 25 Altevogt, Peter 145 Basaran, Gul 224 Bjerkvig, Rolf 14 Altucci, Lucia 35 Baselga, Jose 224 Bjørås, Magnar 29 Alves, Paula 171 Bassi, Claudi 141 Björklund, Peter 110 Amadori, S. 198 Basso, G. 199 Bjorquist, Petter 90 Amann, Anton 107 Batalla, Alain 216 Blamey, Roger 239 Amigorena, Sebastian 176, 183 Baulcombe, David 74 Blandino, Giovanni 12, 59 Amrolia, Persis 181 Baumbach, Jörg Ingo 107 Blankenstein, Thomas 169 Amroune, Carole 94 Bausch, Niko 221 Blasco, Maria 44, 54 Andera, Ladislav 65 Baxevanis, Costas 195 Blasi, Francesco 115 Andreasen, Peter 115 Beckers, Marie-Claire 178 Blay, Jean-Yves 25 Anisimov, Vladimir 71 Behr, Jean-Paul 208 Blondin, Albert 216 Apperley, J. 198 Beier, Markus 69 Bø, Ketil 235 Apweiler, Rolf 159, 199 Belardelli, Filippo 187, 237 Bode, Wolfram 115 Arbyn, Marc 233 Benbouchaib, Mohammed 221 Boeing, Heiner 99 Arthur, Simon 74 Béné, M. 199 Boffetta, Paolo 101 Arús, Carles 130 Bengtsson, Ewert 31 Bogen, Bjarne 229 Athanasou, Nick 37 Benita, Simon 112 Bois, Emmanuel 149 Atkinson, Michael 224 Berdel, W. 198 Bonin-Debs, Angelika 81 Auclair, Christian 25 Berdugo, Elie 143 Bonnet, Dominique 39 Augustin, Hellmut 48 Berger, François 130 Bonneville, Marc 176 Aul, C. 199 Bergh, Jonas 223 Boon, Thierry 176, 183 Austyn, Jonathan 182 Berghold, A. 198 Borg, Jean-Paul 145 Autier, Philippe 101 Berglund, Goran 99 Borlak, Jürgen 112 Avenard, Gilles 163 Berlin, Kurt 35 Borras, Josép 101 Aymami, Juan 189 Bernabeu, Angels 103 Börresen-Dale, Anne-Lise 59 Azizi, Esther 92 Bernard, Alain 154 Borsi, Balazs 174 Baccarini, Manuela 41, 44, 198 Bernards, René 44, 159 Borst, Piet 178 Badet, Bernard 192 Bernasconi, C. 199 Bos, Johannes L. 159

254 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Bos, Nico A. 56 Calvar, Jorge 130 Comuzio, Sergio 154 Boskovic, Darinka 200 Campbell, John 169 Coombes, Raoul Charles 120 Boudou, JP 61 Campo, Elias 202 Coppes, Rob P. 206 Boukamp, Petra 54 Canet, Daniel 192 Corrales, Fernando 80 Bourhis, Jean 110 Cao, Yihai 14 Corvalan, Alejandro 223 Boyle, Peter 237 Capdevila, Antoni 130 Corvi, Raffaella 90 Boyle, Ross 212 Caristan, Yves 149 Costa, Giuseppe 101 Bozzoni, Irene 74 Carmeliet, Peter 48, 165 Costeas, Paul 200 Brabletz, Thomas 138 Carmichael, Paul 90 Costi, Maria Paola 214 Bracke, Marc 50 Carnero, Amancio 22 Coulie, Pierre 183 Braguer, Diane 61 Caron, Huib 46 Crabtree, Jean 94 Brahme, Anders 103, 110 Carotti, Angelo 174 Craddock, Charles 200 Brakenhoff, Ruud 120 Castell, Jose 90 Crawford, Dorothy 169 Branco, Pedro 103 Castelli, Chiara 176 Crespo Baraja, Piero 41 Brand, Karsten 115 Castronovo, Vincent 50, 156 Crespo, Andres 80 Brandstetter, Hans 115 Cataudella, Tiziana 35 Cross, N. 199 Brandt, Burkhard 145 Catena, Raffaella 210 Cruciani, Gabriele 189 Brazma, Alvis 27 Cato, Andrew 67 Cseh, Sándor 174 Bremer, C. 141 Caux, Christophe 181 Cucinelli, Bruno 94, 117 Brenner, Hermann 101 Cavalieri, Duccio 183 Cuevas, Carmen 20 Bressac-de Paillerets, Brigitte 92 Cecchini, Marco G. 193 Cufer, Tanja 122, 224 Brindle, Kevin 193 Celda, Bernardo 130 Culig, Zoran 67 Brisson, Bruno 192 Celis, Julio 237 Curmi, Patrick A. 61 Brocker, Thomas 80 Cerovic, Gordana 126 Cussenot, Olivier 67 Broggini, Massimo 167 Cerundolo, Vincenzo 176, 182, 185 Cuthill, Scott 76 Broxterman, Henk 14 Cerutti, Martine 112 Czernilofsky, Armin Peter 41 Brucher, Ernö 192 Charbord, Pierre 206 D’Incalci, Maurizio 54 Brug, J. 101 Chassagnole, Christophe 218 D’Incerti, Gilda 130 Brunak, Søren 27 Chesne, Christophe 90 D’Oro, Ugo 182 Brune, M. 199 Christofori, Gerhard 18, 48 Dalmay, Tamas 74 Brünner, Nils 122 Ciminale, Vincenzo 94 Daly, S. 199 Bucciolini, Marta 216 Claesson-Welsh, Lena 14, 48 Damholt, Anders 204 Buccione, Roberto 50 Clairambault, Jean 218 Danielsson, Mats 136 Buchanan, Mary 224 Clark, Richard 200 Dano, Keld 115 Buelens, Eric 192 Clavé, Corinne 81 Dastugue, N. 199 Bueno, Gloria 216 Clavel-Chapelon, Françoise 99 Daugaard, Søren 37 Bueno-de-Mesquita, H.B. 99 Clement-Lacroix, Philippe 50 Day, Nicholas 99 Bulfone, Alessandro 128 Clevers, Hans 63 de Alava, Enrique 37 Buntinx, Frank 233 Clezardin, Philippe 50, 152 de Castro, Arcadio Garcia 25 Bürger, Horst 37 Clifford, Steve 46 De Conno, Franco 235 Burgyán, József 74 Cochlovius, Björn 128 de Fiore, Pier Paolo 63 Burnett, A. 198 Coffin, Robert 182 de Giacomoni, Anne-Cécile 187 Buszewski, Boguslaw 107 Cohen, Stephen 74 De Greef, Catherine 182, 185 Buydens, Lutgarde 130 Coindre, J.-M. 25 De Haan, Gerald 206 Buyse, Marc 224 Colita, N. 198 de Jong, Steven 226 Cadossi, Ruggero 163 Collard, John 18 De Laurenzi, Vincenzo 33 Caligaris-Cappio, F. 199 Colombatti, Marco 118 De Lera, Angel 35 Callet-Bauchu, Evelyne 202 Colombel, Marc 152 De Paoli, Paolo 233

INDICES 255 de The, Hugues 35 Dunstan, Diana 237 Fesus, Laszlo 117 de Villiers, Ethel-Michele 233 Durbin, Richard 52 Fiedler, W. 200 de Wind, Niels 139 Dürst, Matthias 94 Figdor, Carl 176, 182, 185 de Witte, T. 198 DuSautoy, Alan 216 Filipowicz, Witold 74 Dean, Caroline 74 Dusek, L. 200 Fiorini, Carlo 134 Debets, Reno 169 Duyster, J. 200 Fischer, Christian 165 Degrand, Olivier 46 Dzeroski, Saso 128 Fisher, Kerry 208 Delaloge, Suzette 223 Ebbesen, Peter 204 Fisher, Mark 216 Dei Tos, Angelo Paolo 37 Eccles, Suzanne 50 Fisher, Sheila 118 Dejana, Elisabetta 48 Eckardt, Kai-Uwe 204 Fitzpatrick, John M. 237 Dejean, Anne 44 Edwards, Dylan 115 Flanagan, Adrienne 37 Dekker , Adriaan W. 200 Edwards, Milne 218 Fleming, Ian 141 del Conte, Rebecca 61 Eeles, Rosalind 87 Foà, R. 198 Del Guerra, Alberto 193 Eggermont, Alexander 176, 178, 237 Fodde, Riccardo 138 Del Sal, Gianni 12, 59 Eggert, Angelika 128 Foekens, John A. 122 Delattre, Olivier 25, 46, 128 Egly, Jean-Marc 29 Foged, Niels 31 Delaunay, Franck 218 Ehninger, G. 198 Fogel, Mina 145 Delorenzi, Mauro 224 Ehrmann, Jiri 167 Foiani, Marco 29 Demenais, Florence 92 Eichmann, Anne 48 Foidart, Jean-Michel 115 Den Boer, Monique 46 Eidefors, Anna 178 Fonatsch, C. 198 Deonarain, Mahendra 212 Eilers, Martin 41, 44 Fontbonne, Jean-Marc 216 Deperthes, David 152 Eils, Roland 52, 120, 128 Forrai, Tamás 248 Deppert, Wolfgang 12, 59, 120 Einaste, Taavi 141 Forsyth, Ramses 37 Desreux, Jean F. 192 Einsele, H. 200 Foulkes, Nicholas 248 Detmar, Michael 16 Eisenhut, Michael 192 Fragai, Marco 61 Devilee, Peter 78 Ekström, Björn 31 Franceschi, Silvia 94 Di Lauro, Roberto 74 Elder, David 92 Frassoni, F. 199 Diaz, Jean-Jacques 80 Eliopoulos, Aristides 167 Fregonese, Cristina 12 Dieplinger, Hans 145 Ellenberg, Jan 52 Frew, M. 200 Dighiero, G. 199 Enk, Alexander H. 16 Friedl, Peter 193 Dillner, Joakim 233 Enver, Tariq 39 Friess, Helmut 141 Dinkelborg, Ludger 156 Eppenberger, Urs 122 Fröhlich, Kai-Uwe 81 Dobbelstein, Matthias 12 Eppenberger-Castori, Serenella 122 Fuchs, R. 200 Dodi, Italo 195 Epstein, Alberto L. 80 Gabert, Jean 200 Doetsch, Volker 33 Erbacher, Patrick 208 Gajewicz, Witold 130 Döhner, H. 198 Esteller, Manel 76, 138 Galapagos NV 63 Dolcetti, Riccardo 229 Estivill, Xavier 74 Gambacorti-Passerini, C. 200 Domany, Eytan 59 Fabre, Myriam 90 Garbay, Jean Rémi 163 Dombret, H. 199 Fais, Stefano 178 Garnett, Geoffrey 233 Donze, Olivier 210 Falasca, Marco 167 Garrido, Federico 176, 195 Dörr, Wolfgang 206 Falciani, Chiara 212 Garthoff, Bernward 90 Dorronsoro, Miren 99 Farrell, Paul 94 Gassmann, Max 204 Dotto, Gian Paolo 33 Fearon, Kenneth 235 Gassmann, W. 199 Dreno, Brigitte 176 Fechina, Larisa 200 Gattermann, N. 199 Dreyling, Martin 202 Felzmann, Thomas 187 Gaudernack, Gustav 181, 195 Duffy, Joe 122 Fenaux, P. 198 Geahel, Isabelle 61, 218 Duhem, Caroline 223 Ferrari, S. 199 Gehl, Julie 163 Dumas, Jean-Baptiste 218 Fersht, Alan 59 Geisler, C. 199

256 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Geley, Stephan 159 Hagemeijer, A. 198 Hiddemann, Wolfgang 202 Georgopoulos, Lindsay 171 Hahn, Stephan 141 Higginson, Irene 235 Georgoussi, Zafiroula-Iro 241 Hahn, Ulrich 110 Hilanio, Melanie 126 Geraldes, Carlos 192 Hainaut, Pierre 59 Hill, Arnold 223 Gessani, Sandra 183 Haisma, Hidde 16 Hinrich, Abken 169 Giavazzi, Raffaella 156 Hakulinen, Timo 233 Hjorth-Hansen, Henrik 200 Glaichenhaus, Nicolas 183 Hallek, M. 199 Hocevar, Marko 92 Glöckler, Jörn 204 Hallmans, Goran 99 Hochstatter, Julia 76 Gluckman, E. 199 Hamdy, Freddie 67, 147, 152 Hoeben, Rob 208 Glueck, Reinhard 187 Hämmerling, Günter 176 Hoehn, Mathias 192 Gnant, Michael 223 Hanks, Geoffrey 235 Hoeijmakers, H.J. 29 Golay, Josée 112 Hansel, Armin 107 Hofer, Erhard 16 Goldblum, Amiram 174 Hansson, Johan 92, 178 Hoffmann, Hans Falk 110 Goldstein, Pierre 81 Hansson, Mats G. 233 Hofstra, Leo 14 Gomis-Rüth, F. Xavier 115 Harbeck, Nadia 122, 223 Hofstra, Robert M.W. 139 Gonçalves, Anthony 145 Harbott, J. 199 Hogenbirk, Alfred 216 Gonzalez, Carlos 99 Harel-Bellan, Annick 74 Hogendoorn, Pancras CW 37 Gonzalez, Cayetano 63 Harris, Abbie 35 Hoheisel, Jörg 69, 126, 141 Gonzalez, Reinerio 212 Harris, Adrian 14, 204, 224 Hohenberger, Peter 25 Gonzalez-Gaitan, Marcos 63 Hartgerink, Jan-Willem 237 Hokland, P. 198 Görlach, Agnes 204 Hasselbalch, H. 199 Hollo, Zsolt 37 Gorochov, Guy 169 Hauer, Johann 103 Holowiecki, J. 198 Gottik, Marina 154 Haupt, Ygal 12 Holtkamp, U. 198 Graage, Frank 241 Haustermans, Karin 110 Hölzer, D. 198 Granucci, Francesca 182 Hawkins, Robert 169 Hopfner, Karl-Peter 29 Grassmann, Ralph 94 Hayes, Ian 226 Hose, Dirk 56 Gratwohl, A. 198 Hayward, Nicholas Kim 92 Houlston, Richard 78, 233 Greco, Carlo 216 Hedlund, Erik 110 Hovig, Eivind 27 Greco, Simona 12 Heerschap, Arend 130, 193 Howe, Franklyn Arron 130 Gregoire, Vincent 110 Hehlmann, Rüdiger 198 Huber, Christoph 59 Gress, Thomas 141 Hein, Jotun 96 Huber, Lukas 41 Griffioen, Arjan W. 14 Heindel, Walter 136 Hunt, Nick 171 Grimm, Stefan 210 Heisele, Olita 92 Hunt, Tim 52 Griskevicius, Laimonas 200 Heldin, Carl-Henrik 159 Hupperets, Pierre 224 Gronemeyer, Hinrich 35 Helin, Kristian 27, 44 Huret, J. 198 Grotzer, Michael 128 Hellmann, A. 198 Hutvagner, Gyorgy 74 Gruis, Nelkele 92 Hemminki, Akseli 167, 221 Huynen, Martijn 33 Grundy, Richard 130 Hemminki, Kari 233 Hyman, Tony 52 Grzybowska, Ewa 233 Henderson, Blair 41 Hynes, Nancy 159 Guergova-Kuras, Mariana 117 Hennecke, Manfred 152 Iacobelli, Stefano 218 Gulisano, M. 33 Henno, Patrick 112 Ifrah, N. 199 Gullberg, Mats 31 Hentsch, Bernd 18 Iftner, Thomas 94 Gundersen, Odd Erik 235 Hermitte, Fabienne 25, 117, 200 Iggo, Richard 12, 221 Gunnar, Norberg 103 Hernandez Alcoceba, Ruben 80 Illiano, Stephane 204 Guttman, Andras 117 Hernández, J. 199 Imhof, Axel 76 Haas, Olivier 216 Herwig, Ralf 90 Indrák, K. 200 Haase, D. 200 Hess-Stumpp, Holger 35 Jackson, Stephen 29 Haferlach, T. 200 Hickman, John 210 Jacobs, Andreas 192

INDICES 257 Jacobsen, Sten Eirik W. 39 Kerr, David 237 Kyewski, Bruno 176 Jalkanen, Markku 48 Ketting, René 74 La Thangue, Nicholas B. 12 Jalonen, Harry 221 Keun, Hector 90 Labar, B. 199 Janoki, Gyözö 192 Key, Timothy 99 Labigne, Agnès 94 Janos Szollosi 169 Kiemeney, L.A.L.M. 96 Lacal, Juan Carlos 65 Januszewicz, Andrzej 78 Kiessling, Rolf 183, 195 Lacombe, Denis 223 Jasmin, Didi 156 Kimchi, Adi 81 Lah Turnsek, Tamara 115 Jassem, Jacek 224 Kindblom, Lars-Gunnar 37 Laidler, Piotr 195 Jedrzejczak, W. 199 Kjems, Jørgen 74 Lain, Sonia 12 Jelezko, Fedor 61 Klaassen, Arno 130 Lambin, Phillippe 110, 204 Jellum, Egil 233 Klapper, Wolfram 202 Landegren, Ulf 31 Jennings, Paul 90 Klein, Bernhard 56 Lane, David 12 Jensen, Sanne 20 Klein, Christoph 138 Lange, Peter 237 Jiang, Wen 165 Kleinjans, Jos 90 Langedijk, Maria 229 Jiricny, Josef 29 Klener, P. 200 Langer, Thierry 20 Jobst, Gerhard 204 Klepp, Knut-Inge 101 Lanvers-kaminsky, Claudia 46 Jochemsen, Aart Gerrit 12 Kless, Hader 126 Lanzavechia, Antonio 183 Johanness, Ludger 176 Klöppel, G. 141 Lapôtre, Laurence 181 Johannsen, Bernd 110 Kluin, Philip M. 202 Larson, Sten 216 Johansson, B. 199 Kneba, M. 199 Larsson, Anders 31 Johnsen, Hans E. 56 Knoblich, Jürgen 63 Lavielle, Solange 61 Jonassen, Inge 14 Knox, Susan 224 Le Bousse-Kerdilès, M. 199 Jones, Jonathan 81 Knuutila, Sakari 37, 154, 199 Leachman, Sancy 92 Jones, Terry 193 Koch, Troels 46 Leal da Silva, Jose Manuel 224 Joore, Jos 37 Kochanek, Stefan 208 Lecesne, Axel 25 Jotereau, Francine 195 Koenig, Jochen 90, 94 Leconte, Agnès 154 Jotterand, M. 198 Koensgen, Dominique 145 Lefkopoulos, Dimitri 216 Judson, Ian 25 Kolch, Walter 41 Legastellois, Stéphane 61 Juntunen, Mikko 136 Kombi, David 171 Lehmann, Alan 29 Kaaks, Rudolf 99 Kos, Janko 115 Lehrach, Hans 245 Kaasa, Stein 235 Koskela, Pentti 233 Lehtinen, Matti 233 Kacsuk, Peter 174 Kosmehl, Hartwig 156 Leifland, Karin 136 Kadouche, Jean 112 Koubi, David 221 Lemoine, Nicholas 141 Kafrouni, Hanna 216 Kousparou, Christina 212 Lenner, Per 233 Kalén, Mattias 48 Kouzarides, Tony 35, 76 Leonard, Robert C.F. 223 Kalland, Karl-Henning 14 Kovar, Heinrich 128, 154 Leroux, Thierry 216 Kallioniemi, Olli 31, 35, 67, 115 Kreipe, H. 198 Lévi, Francis 218 Kälvesten, Edvard 136 Kreisler, Peter 130 Levitzki, A. 200 Kanopka, Arvydas 204 Krivan, G. 199 Levrero, Massimo 12 Kanz, L. 200 Kroemer, Guido 12, 81, 178 Lichinister, Mikhail 224 Karssemeijer, Nico 136 Krokan, Hans 29 Lidereau, Rosette 50 Katz, Emil 143 Krueger, Anke 61 Lilige, Hans 147 Kaufman, Marcelline 22 Krug, Alfons 204 Lillington, D. 199 Keidiing, Susanne 110 Krüger, Achim 115 Linardopoulos, Spiros 65 Keilholz, Ulrich 176 Kruger-Kjaer, Susanne 94 Lindahl, Per 48 Keller, Jutta 143 Kubbutat, Michael 14 Lindberg Møller, Birger 20 Kéri, György 41, 44, 94 Kunst, A. 101 Lindholm, Leif 208 Kerjaschki, Dontscho 48 Kury, Fritz 145 Line, Aija 195

258 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Lingner, Joachim 54 Mähönen, Anssi 171 Meister, Gunter 74 Linial, Michal 27 Maier, Sabine 122 Meitinger, Thomas 202 Link, H. 200 Mainil, Pierre 37 Melief, C.J.M. 183 Linseisen, Jakob 99 Maitland, Norman James 67, 208 Melief, Cornelis 176 Lion, Thomas 199, 200 Malandain, Grégoire 216 Melino, Gerry 12, 33 Lipkowska, Zofia 241 Malats, Nuria 126, 141 Mellstedt, Hakan 183 Lipkowski, Andrzej W. 241 Malka, David 117 Merbach, André E. 192 List, Heinz Jochim 143 Malvy, Claude 154 Mercey, T. 115 Little, Melvyn 16 Mandelboim, Ofer 16 Mergny, Jean-Louis 54 Ljungmann, P. 198 Mann, Graham 92 Merten, Otto-Wilhelm 171 Llombart-Bosch, Antonio 37, 154 Mann, John 54 Mertens, Fredrik 37 Lluch, Magí 130 Mann, Matthias 183 Meyer, Thomas 74, 94 Locasciulli, A. 200 Manservigi, Roberto 80 Micheli, Andrea 101 Lock, Edward 90 Mansmann, U. 198 Middleton, Mark 178 Löf, Johan 110 Mantovani, Alberto 169, 183 Migneco, Emilio 216 Löhmannsröben, Hans-Gerd 149 Mantovani, Roberto 12, 33 Miklavcic, Damijan 163 Loiseau, Alexandre 192 Manz, Markus 183 Miller, Crispin 245 Lombardi, Paolo 214 Marcelli, Augusto 118 Mills, John 216 Lopez-Otin, Carlos 115 Marczin, Nandor 107 Mills, K. 200 Lorenzi, Luca 33 Margesin, Rosa 107 Mink, Mátyás 248 Loskog, Angelica 167 Margison, Geoff 178 Minn, Heikki 110 Löve, Arthur 233 Marie, J. 198 Minucci, Saverio 35, 174 Lowik, Clemens 192 Markopoulos, Christos 223 Mir, Lluis M. 163 Lowndes, Noel 29 Marsoni, Silvia 156 Mischak, Harald 94 Lu, Xin 12 Martens, John W.M. 122 Misicka-Kesik, Aleksandra 241 Lubinski, Jan 69, 87, 92 Martens, Uwe 54 Miska, Eric 74 Ludwig, W. 199 Martiat, P. 200 Mittelman, M. 200 Lui, Alberto 143 Martin, Michèle 206 Molina, Rafael 149 Lukanidin, Eugene 18 Martinez, Carmen 99 Mondiano, Anna 169 Lukes, Ivan 192 Martinez-Climent, Jose Angel 202 Montoya, Guillermo 226 Luleci, Guven 87 Martin-Moreno, Jose Martin 237 Montserrat, E. 198 Lund, Eiliv 99 Martinou, Jean-Claude 65 Mooï, Wolter 82 Lundeberg, Joakim 178 Martinsson-Niskanen, Titti 165 Moresco, Rosa Maria 193 Luppi, Mario 94 Marty, Michel 25 Moser, Muriel 176, 182, 185 Lusky, Monika 221 Masszi, T. 200 Mosialos, George 94 Lyng, Fiona 118 Masucci, Maria 94, 229 Moss, David 118 Lzaurralde, Elisa 74 Matutes, E. 199 Moszynski, Marek 110 Ma Benlloch, Jose 103 Mavromara, Penelope 80 Mouridsen, Henning 223 Mach, Jean-Pierre 112 Maxwell, Patrick 204 Mouritzen, Peter 74 Machado, Jose 94 Mayer, Bernd 145 Mueller, Margareta M. 115 Macino, Giuseppe 74 Mayer, J. 198 Mufti, G. 199 Mackenbach, Johan 101 McGrath, John 33 Mullenders, Leon 29, 90 Mackensen, Andreas 187 Mecucci, C. 199 Muller, Robert 192 MacPherson, Gordon G. 182 Medico, Enzo 159 Mundy, John 81 Madsen, Lise 20 Megraud, Francis 94 Murphy, Gillian 115 Maecke, Helmut 192 Mehlen, Patrick 210 Mürtz, Manfred 107 Maggi, Adriana 35, 192 Meijer, Annemarie H. 248 Musacchio, Andrea 52 Mahon, F. 198 Meijer, Laurent 218 Mustea, Alexander 145

INDICES 259 Myklebost, Ola 37 Olsson, Håkan 92 Petruzelka, Lubos 223 Myllykallio, Hannu 214 Oren, Moshe 12, 59 Pettersen, Erik 204 Naafs-Wilstra, Marianne C. 181 Orfao, A. 199 Pettersson, Kim S. 147 Naldini, Luigi 84 Orfao, Alberto 56 Piccart, Martine 223 Nasioulas, Georgios 65 Ørntoft, Torben 69 Picci, Piero 37, 154 Naume, Björn 120 Oscier, D. 199 Pieri, Philippe 149 Naumova, Elissaveta 195 Ossenkoppele, G. 198 Pierotti, Marco 159, 178 Navarro, Carmen 99 Ott, German 202 Pierre, Philippe 183 Naylor, Stuart 204 Oultram, John 141 Pietsch, Torsten 46 Neal, David 67 Overvad, Kim 99 Pihlajaniemi, Taina 14 Neidle, Stephen 54 Ozbek, U. 200 Pinedo, Herbert Michael 237 Neoptolemos, John 141 P. Ryan, Michael 90 Pintzas, Alexander 65 Neri, Dario 156, 212 Pagani, Olivia 224 Piotto, Martial 130 Nerlov, Claus 39 Palecek, Emil 59 Pirovano, Marco 218 Neubauer, A. 199 Palli, Domenico 99 Pisa, Pavel 183 Neuhaus, Eckhardt 141 Panayotou, George 159 Pisani, Paola 101 Neumann, Hartmut P.H. 78 Pane, F. 199 Plevani, Paolo 29 Newbold, Robert 54 Panes, Juliàn 193 Plumas, Joël 181 Newell, Herbie 189 Panico, Salvatore 99 Poellinger, Lorenz 204 Newton Bishop, Julia A. 92 Pantel, Klaus 120 Pohlenz, Hans-Dieter 141 Ng, Tony 41 Panzner, Steffen 167 Pongsak, Angkasith 33 Niclou, Simone 14 Papon, Eric 25 Popov, Zivko 126 Nicol, Keith 54 Paridaens, Robert 115 Poremba, Chris 37 Nicolaï, Jean-Philippe 216 Parker, David 192 Porgador, Angel 132 Nicolette, Charles 183 Parkinson, Kenneth 54 Post, Claes 59 Niederhauser, Joel J. 152 Parwaresch, Reza 202 Pott, Christiane 202 Niederwieser, D. 198 Passalacqua, Rodolfo 223 Poustka, Annemarie 159, 245 Nielsen, Peter Egil 192 Passioukov, Alexandre 178 Préat, Véronique 163 Niklas, Zojer 56 Pastorekova, Silvia 204 Preisegger, Karl-Heinz 16 Nilsson, Olle 147, 149 Patient, Roger 39 Preudhomme, C. 199 Nilsson, Sten 59 Pawelec, Graham 71, 195 Price, Patricia 110 Noël, Agnès 18 Pawlita, Michael 94 Prince, Miles 187 Nolli, Maria Luisa 229 Pedley, Barbara 156 Prix, Lothar 145 Norberg, Gunnar 110 Pedone, Carlo 192 Probst, Jochen 176 Normark, Staffan 94 Peeper, Daniel 82 Protti, Maria Pia 183 Novak, Bela 22 Peeters, Petra 99 Puig Sarda, Susana 92 O’Brien, S. 198 Pelicci, Pier Giuseppe 44 Pukkala, Eero 101 O’Dwyer, M. 198 Pellicciari, Roberto 189 Pule, Martin 181 O’Garra, Anne 182, 185 Perbal, Bernard 154 Pyerin, Walter 152 O’Kelly, Paddy 120 Permert, Johan 141 Quax, Wim 226 O’Sullivan, Gerald 25 Peter-Katalinic, Jasna 132 Questier, Benjamin 112 Ochoa, Gorka 126 Peters, Christoph 115 Raap, Anton 31 Ögmundsdóttir, Helga M. 233 Peters, Jan-Michael 52 Rabinovitz, Elisha 143 Ogur, Gönül 200 Peters, Joop A. 192 Radbruch, Andreas 183 Ojala, Paivi 94 Petersen, Ole W. 39 Radbruch, Lukas 235 Olaiz, Javier 25 Peterson, Curt 178 Rademacher, Bernd 193 Olko, Pavel 216 Petralia, Filippo 183 Rademann, Jörg 141 Ollivier, Sophie 189 Petrus, Hans 229 Radvanyi, Francois 126

260 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Ragno, Pia 115 Rotter, Varda 12, 59, 67 Schmitt-Verhulst, Anne-Marie 176 Rainford, Martyn 92 Rousseau, Raphaël F. 181 Schneider, Claudio 159 Rammensee, Hans-Georg 176 Rowe, J. 198 Schöffski, Patrick 25 Ranghetti, Anna 185 Rubinstein, Avraham 143 Schön, Michael P. 163 Rasmussen, Lene Juel 139 Rudd, Pauline 132 Schouten, Jan 37 Ratcliffe, Peter 204 Ruiz i Altaba, Ariel 20 Schroeder, Olaf 241 Raymond, Alan 208 Russo, Vincenzo 176 Schubert, Jochen 107 Real, Francisco X. 141 Ruutu, T. 198 Schuebeler, Dirk 76 Rees, Robert 195 Saarma, Mart 174 Schueler, Julia 82 Reichert, Bas 248 Sacchi, Ada 59 Schuetz, Andreas 145 Reilly, J. 199 Saghatchian-d’Assignies, Mahasti 223 Schuler, Gerold 176, 182, 185 Reimann-Zawadzki, Meike 143 Saglio, G. 198 Schulz, Thomas F. 94 Reis e Sousa, Caetano 183 Sahin, Ugur 176 Schumacher, Ton 169 Reiter, Yoram 169 Sahota, Surinder S. 56 Schwab, Manfred 128 Reske, Sven 141 Salles, Gilles 202 Schwabe, Nikolai 229 Ribera, J. 199 Sallusto, Federica 183 Sciot, Raf 37 Riboli, Elio 99 Salvat, Francesc 216 Scozzafava, Andea 204 Ribrag, Vincent 202 Salven, Petri 84 Sedman, Juhan 20 Ricciardi Castagnoli, Paola 183, 185 Samali, Afshin 226 Segebarth, Christoph 130 Richter, Wiltrud 37 Sambani, C. 200 Seger, Rony 41 Ridley, Anne 159 Samonigg, Hellmut 235 Sehouli, Jalid 145 Ried, Martin 41 Sandro, Onori 216 Selivanova, Galina 12, 59 Riegman, Peter 37 Sansone, Susanna-Assunta 90 Séradour, Brigitte 136 Ringborg, Ulrik 237 Santos, Andrès 193 Serakinci, Nedime 54 Ringwald, Annette 94 Sanz, Ferran 174 Serra, Massimo 46 Rio, Marie-Christine 115 Sanz, M. 198 Serrano, Luis 22, 226 Robak, T. 199 Sastre-Garau, Xavier 117 Serrano, Manuel 44 Robert, Caroline 163 Sauerwein, Wolfgang 216 Seruca, Raquel 139 Robertson, Graeme 189 Sauter, Guido 115 Seymour, Leonard 208 Robine, Sylvie 65 Savchenko, V. 198 Shacked, Zippora 59 Robles, Montserrat 130 Savva, N. 200 Shamir, Ron 245 Robson, Craig 67 Scarpa, Aldo 141 Sharp, Linda 141 Rocchi, M. 199 Schadendorf, Dirk 92, 176, 195 Sheng-Wu, Xie 33 Rocha, Benedita 183 Schaftenaar, Gijs 33 Shipley, Janet 46 Roesch, Frank 192 Schalken, J. A. 67 Sibilia, Maria 41 Roggen, Erwin 90 Schalken, Jack 147 Sicard, Hélène 176 Rogiers, Vera 90 Schaude, Michael 235 Siebert, Reiner 202 Roman, E. 200 Schauser, Leif 96 Sieckmann, Frank 52 Romeo, Giovanni 210 Scheffold, Alexander 183 Sierra, Angels 50 Romero, Pedro 176 Schiewe, Hajo 20 Sierra, J. 198 Ronsisvalle, Giuseppe 241 Schild, Hansjoerg 176 Sikora, Ewa 71 Roos, Goran 54 Schlag, Peter 18 Simonsson, B. 198 Rosato, Antonio 229 Schlegelberger, Brigitte 202 Sivard, Ake 143 Rosenberg, Ivan 192 Schmitt, Clemens 44 Sixt, Bernhard 44, 120, 159 Rosenfeld, Rakefet 132 Schmitt, Fernando 224 Skotnicki, A. 198 Rosenwald, Andreas 202 Schmitt, Manfred 122 Skov, Lone 163 Rossi, Carlo Ricardo 25 Schmitt, Manfred 178 Sleeman, Jonathan 18 Rossig, Claudia 181 Schmitt-Gräff, A. 199 Slegers, Guido 115

INDICES 261 Slijper, Monique 120 Szendröi, Miklös 37 Tryggvason, Karl 14, 115 Sliwka, Ireneusz 107 Taieb, Julien 132 Tschopp, Jurg 210 Smedegaard, Niels 202 Taipale, Jussi 69 Tschurtschenthaler, Gertraud 200 Smith, Desmond 149 Takalo, Harri 147 Tumino, Rosario 99 Smith, Edvard 159 Tanke, Hans 120 Tursz, Thomas 237 Smith, Graeme 29 Taraboletti, Giulia 115 Uggeri, Fulvio 192 Smith, Victoria 221 Tartour, Eric 176 Ugorski, Maciej 50 Sockalingum, Ganesh 118 Tatusyan, Alexander 192 Uguccioni, Mariagrazia 183 Sokoloff, Pierre 82 Tavernarakis, Nektarios 81 Uhl, Rainer 120 Sonneveld, Pieter 56 Tavitian, Bertrand 115, 192 Ulbrich, Karel 208 Sotiriou, Christos 223 Taylor, Naomi 169 Ullmann, A. 198 Spaink, Herman P. 248 Te Riele, Hein 59 Umaña, Pablo 156 Spanel, Patrick 107 ten Dijke, Peter 14, 18, 84 Unterkofler, Karl 107 Spatz, Alan 178 Testi, Roberto 81 Urban, Gerald 204 Speicher, Michael 120 Teti, Anna Maria 50 Vainchenker, William 200 Speleman, Frank 128 Thaler, J. 198 Vajkoczy, Peter 14, 16, 156, 212 Splendiani, Andrea 183 Thalmann, George 67, 152 Valdes Olmos, Renato A. 103 Spolders, H. 115 Theillet, Charles 145 Valencia, Alfonso 22, 27 Spyratos, Frédérique 122 Theobald, Matthias 59 Valoti, Massimo 189 Stanislawski, Thomas 59 Thieblemont, Catherine 202 van ’t Veer, Laura 120, 224 Stassen, Jean-Marie 165 Thieffry, Denis 27 van Bokhoven, Hans 33 Stauber, Roland 18 Thiel, Andreas 183 Van Cutsem, Eric 165 Stauss, Hans 169 Thielemans, Kris 176, 183 van Dam, Hans 31 Steegmann, J. 198 Thierry, Dominique 206 van den Oord, Joost 178 Steingrimsson, Eirikur 96 Thiéry, Jean-Paul 18 van der Burght, Roeland 136 Steinkasserer, Alexander 182 Thomas, Géraldine A. 223 van der Kogel, Albert 110 Stenman, Ulf-Hakan 147 Thomson, Alistair 224 van der Linden, Annemie 192 Stevens, Gary 52 Thomssen, Christoph 223 van der Pluijm, Gabri 50, 67, 152 Stieber, Petra 149 Thorel, Alain 61 van Dongen, Guus 156 Stierum, Rob 90 Thoresen, Steinar 233 van Dongen, J. 202 Stoeber, Kai 52 Thybo, Tanja 20 van Engen, Ruben 136 Stoppelli, Maria Patrizia 115 Tijhuis, Johan 67 van Gorp, Toon 145 Storm, Hans 101 Tinsley, Jon 39 van Huffel, Sabine 130 Storme, Guy 159 Tjonneland, Anne 99, 101 van Krieken, Johannes H.J.M. 202 Strand, Ulf 136 Tobler, A. 198 van Lohuizen, Maarten 44 Strasser, Florian 235 Tomlinson, Ian 78 van Oers, Monique M 171, 199 Stratford, Ian 204 Tommasino, Massimo 94 Van Roy, Frans 18 Stroud, Robert 214 Tönisson, Neeme 59 Van Valen, Frans 154 Stuart Naylor 169 Toth, Geza 241 van Weerden, Wytske 208 Stubenrauch, Frank 94 Totterman, Thomas 208 Vandenabeele, Peter 33 Stunnenberg, Henk 35 Tourwe, Dirk 241 Vanderkerken, Karin 56 Suerbaum, Sebastian 94 Trapman, Jan 67 Vannucchi, Alessandro M. 200 Suter, Mark 183 Treussart, François 61 Vasquez, Jose 224 Sutter, Gerd 221 Trichopoulos, Dimitrios 237 Vassal, Gilles 46 Svensson, Roger 110 Trichopoulou, Antonia 99, 101 Vendrell, Jean-Pierre 120 Swain, Paul 143 Trnény, Marek 202 Venkitaraman, Ashok 20 Sweep, Fred C.G.J. 122 Troussard, X. 199 Verfaille, Christine 110 Sykova, Eva 14 Trumpp, Andreas 44 Vergote, Ignace B. 145

262 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Vernos, Isabelle 22 Wingender, Edgar 22 Veronesi, Umberto 63 Winther, Henrik 31 Vert, Jean-Philippe 245 Witkovsky, Viktor 107 Verweij, Jaap 25 Wodak, Shoshana 22 Viale, Giuseppe 223 Wölfel, Thomas 176 Vikkula, Miikka 48 Wolfhard, Semmler 130 Villadsen, Jan 204 Wondergem, Jan 206 Vilo, Jaak 117 Workman, Paul 65 Vineis, Paolo 99 Wouters, Brad 204 Visakorpi, Tapio 67 Wuyts, Wim 37 Visani, Luigi 130 Yahioglu, Gokhan 212 Viscoli, C. 200 Yarden, Yosef 159 Vitti, Francisca 156 Ye, Shu 115 Vladareanu, Ana-Maria 200 Yiotakis, Athanasios 115 Voinnet, Olivier 74 Ylä-Herttuala, Seppo 48 von Kries, Jens 141 Yoram Reiter 169 von Minckwitz, Gunter 223 Young, Antony 92 Voudsen, Karen 12, 44 Young, Kenneth 136 Wade, Rebecca 214 Young, Lawrence 94 Wagner, Ernst 208 Zaffaroni, Nadia 25, 54 Wagner, Hermann 183 Zalud, Petra 152 Walewski, Jan 199, 202 Zanda, Matteo 156 Waligorski, Michael 216 Zardi, Luciano 156, 212 Walisiewicz-Niedbalska, Wieslawa 241 Zaritskey, A. 200 Walker, Anthony 195 Zatloukal, Kurt 245 Wallis, Matthew 136 Zatonski, Witold 101 Waltenberger, Johannes 14 Zeillinger, Robert 145 Ward, K. 200 Zelig, Eshhar 169 Wareham, Nick 99 Zhivotovsky, Boris 65 Wassenegger, Michael 74 Ziegler, Sibylle 103 Wasylyk, Bohdan 67 Zini, G. 198 Weber, Simone 193 Zitvogel, Laurence 183 Weber, Viktoria 145 Zoetelief, Johannes 216 Weigel, Detlef 74 Zollo, Massimo 18, 128 Weinberger, Klaus 117 Zvonimir, Rudolph 25 Weiss, Dieter G. 241 Zwacka, Ralf 226 Weltmann, Klaus-Dieter 149 Zwerschke, Werner 94 Wenger, Roland 204 Zwierzina, H. 200 Wermer, Frank 223 West, Stephen 29 Wester, Hans-Jürgen 193 Wex, Kerstin 107 Wiig, Helge 14 Wijfjes, Andre 92 Willems, Luc 94 Willemze, R. 198 Williger, Ben-Tsion 50 Wiman, Klas 33, 59

INDICES 263 Indices – Organisations

Aalborg Hospital 56, 99 Association pour la Recherche sur Breast International Group (BIG-aisbl) 223 Aalborg University 204 les Transplantations Médullaires 199 Brucells 182, 185 Aarhus University Hospital 56, 69, 110, 198 Associazione Iblea per Bruker Biospin SA. 130 Abcam 35 la Ricerca Epidemiologica 99 Brunel University 54 Academic Hospital Groningen 202 Aureus Pharma 189 Budapest University of Academisch Medisch Centrum 46 Austrian Academy of Sciences 63, 94 Technology Economics 22 Academisch Ziekenhuis bij Avalon Product Development 136 Bundesministerium für Bildung de Universiteit van Amsterdam 199 Azienda Ospedaliera und Forschung 237 ACIES 171, 181, 221 San Camillo-Forlanini 199, 200 Cancer Coalition 224 ACN L’accessorio Nucleare S.R.L. 134 Azienda Ospedaliera – Ospedali Cancer Research UK 29, 39, 52, 65, 78, Addenbrooke’s Hospital 136 Riuniti di Bergamo 112, 134, 199 99, 141, 156, 183 Adolf-Butenandt-Institut 76 Azienda Sanitaria Locale 101 CancerTek Pharmaceuticals Ltd 50 Advalytix AG 141 Bank of Cyprus Oncology Centre 223 Capio Diagnostics Radiology Sweden 136 ADVANCELL 90 BaseClear B.V. 248 Cardiff University 165, 198 Affimed Therapeutics AG 16 Bayerische Julius-Maximilian- Catalan Institute of Oncology 99 Affitech AS 128 Universität Würzburg 200 CEA, Département d’Ingenierie Agendia 44, 120, 159, 224 BCHM/Christian de Duve Institute et d’Études des Protéines 115 Agricultural Biotechnology Centre 74 of Cellular Pathology 48, 183 CEA – SHFJ 192 Akademia Medyczna w Warszawie, Beatson Institute for CEINGE Biotecnologie Medical University of Warsaw 199 Cancer Research 12, 41, 44 avanzate s.c.a.r.l. 128, 199 Akdeniz University 84 Belarusion Research Center for Cellartis 90 Albert Ludwigs University Freiburg 204 Pediatric Oncology and Hematology 200 Center for Genomic Regulation 74 ALMA Consulting Group 112, 210 Belozersky Institute of Center of Excellence in Medicine AlPlanta-Institute for Plant Research 74 Physico-Chemical Biology 154 & IT GmBh 41 Altonabiotec 171 Bender MedSystems 235 Center of Serbia 44 AMRI Hungary 174 Ben-Gurion University of the Negev 132 Central Manchester and Manchester, AnalytiCon Discovery GmbH 20 Berthold GmbH & Co. KG 152 Children’s University Hospitals Andalusian School of Public Health 99 BioAlliance Pharma SA 163 NHS Trust 199 AngioGenetics AB Medicinaregatan 48 BioBase 22 Centre d’Immunologie de Ankara University 198 Biocrates Life Sciences GmbH 117 Marseille-Luminy 183 Apotech Corporation 210 Bioflag Srl 128 Centre de la recherche public Apoxis S.A. 152 Biofocus GmbH 145 de la santé 14 Applied Imaging 120 BIOGEM Biotecnologie Avanzate 74 Centre de Recherche pour Aprea AB 59 Bioinformatics ApS 96 les pathologies prostatiques 67 Areta International Srl 229 BioInvent International AB 165 Centre de Regulació Genòmica 226 Argos Therapeutics, Inc 183 BioLigands ApS 18 Centre for Biotechnology 22 Aristotle University of Thessaloniki 94 Biological Research Centre 241 Centre for Blood Cell Therapies 187 Ark Therapeutics Oy 171 Biomedical Sciences Research Centre for Drug Research 208 Artinis 136 Centre ‘Alexander Fleming’ 159 Centre for Genomic Regulation 22 Arttic SA 25, 94, 117 Biopolo Scrl - c/o IFOM 185 Centre for Medical Genetics 128 Asper Biotech 59, 141 Biopredic International 90 Centre for the Validation Assistance Publique – Biospace Mesures 192 of Alternative Methods 90 Hôpitaux de Paris 199, 202 BioSystems International 117 Centre Hospitalier de Luxembourg 223 Association pour la recherche Biotecgen s.r.l. 12 Centre Hospitalier Universitaire d’Angers 199 et le développement des méthodes Biotech Research and Innovation Centre 44 Centre Hospitalier Universitaire de Caen 199 et processus industriels 245 Biovex 182 Centre Hospitalier Universitaire de Nantes 176 Association pour la Recherche sur BRACCO Imaging S.P.A. 192 Centre Hospitalier Universitaire le dépistage des Cancers du Sein 136 Breast Institute 237 de Saint-Louis 25

264 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME Centre Hospitalier Universitaire Chiron 182 de Duve Institute 176 de Toulouse, Hôtel-Dieu Saint-Jaques 199 Christian de Duve Institute of Delft University of Technology Centre Hospitalier-Régional, Cellular Pathology 48, 183 and Radiation Technology 216 Universitaire de Lille 199 Christian-Albrechts-University of Kiel 61 Delsitech Ltd 221 Centre Léon Bérard 181, 210 Chroma Therapeutics 76 Deutsche Leukämie und Centre National de la Recherche Clare Hall Laboratories 29 Lymphom-Hilfe e.V. 198 Scientifique 35, 52, 74, 112, 149, 154, 169, 216 CNIO – Centro Nacional de Deutsches Herzzentrum München 204 Centre National François Baclesse 216 Investigaciones Oncologicas 54, 76, 138, 159 Deutsches Institut für Centre of Excellence in Molecular/ CNRS – ICSN 192 Ernährungsforschung 99 Cancer Biology 48 CNRS – CIML 81 Deutsches Centre of Molecular Biology CNRS – INSERM – Univ. Med. 183 Krebsforschungszentrum 54, 66, 69, 92, and Neuroscience 29 CNRS – UMR 144 18 94, 99, 115, 126, 130, 141, 152, Centre of Oncology 233 CNRS – UMR 5095 81 159, 176, 192, 195, 233, 245 Centre Régional de Lutte contre CNRS – UMR 8125 81 Deutsches Rheuma-Forschungszentrum 183 le Cancer de Montpellier 145 Commissariat à l’Énergie Deutsches Zentrum für Alternforschung 101 Centre René Huguenin 50, 122 Atomique 149, 206, 216 Direccion General de Salud Publica Centro Biotecnologie Avanzate 212 COMPOUND Handling BV 67 y Planificacion 99 Centro de Neurociências Congenia 35 Dosisoft S.A. 216 de Coimbra e Biologia Celular 192 Consejeria de Sanidad y Politica DTCA HYGEIA Hospital 65 Centro di Riferimento Oncologico 233 Social de la Region de Murcia 99 Dublin Institute of Technology 117 Centro Nacional de Investigaciones Consejo Superior de Investigaciones Durham University 192 Oncológicas 22, 44, 159 Cientificas (Madrid) 115, 159, 169, 200 Eberhard-Karls-Universität Centro per lo Studio e la Consejo Superior de Investigaciones Tübingen 94, 176, 200 Prevenzione Oncologica 99 Cientificas (Santander) 41 EccoCell Biotechnology and Centrum Onkologii Oddzial w Krakowie 216 Consejo Superior de Investigaciones Stem Cell Therapy GmbH 16 CERBM-GIE/GBMC Centre Européen Cientificas (Valencia) 103 Eckhard Kindel 149 de Recherche en Biologie Consiglio Nazionale delle Ricerche 156 École Normale Supérieure de Cachan 61 et Médecine 29, 35, 67, 115 Consorzio Interuniversitario Biotecnologie 159 École Nationale Supérieure des Cezanne SAS 149 Consorzio Interuniversitario Nazionale Mines de Paris 61 CF consulting Finanziamenti 134 per la Bio-oncologia 218 École nationale vétérinaire de Toulouse 221 Chancellor, Masters and Scholars Consorzio Interuniversitario École Polytechnique Fédérale de Lausanne 192 of the University of Cambridge 193 Risonanze Magnetiche di Edinburgh Instruments 149 Chancellor, Masters and Metalloproteine paramagnetiche 61 Eldim S.A. 216 Scholars of the University Consorzio Mario Negri Sud 50 EMBL 22 of Oxford 204, 206, 224, 237 Copenhagen University Hospital 115 Emergentec biodevelopment GmbH 145 Charité-Universitätsmedizin Coventry University 216 EML Research GmbH 214 Berlin 14, 16, 18, 136, 145, 165, 176, 199 C-Rad Imaging AB 103, 110 Epigenomics 35, 122 Charles University and General C-RAD Innovation AB 110 EPLF 54 Teaching Hospital 223 CRCE – Faculty of Medicine, Erasmus MC Daniel den Hoed 169 Charles University of Prague 202 University of Liège 115 Erasmus Medical Center 29, 37, 46, 67, 101, Chemotherapeutisches Forschungsinstitut 18 CRELUX GmbH 41 122, 138, 145, 147, 169, 176, 178, 208 Chiang Mai University 33 CureVac the RNA people 176 Erasmus University Children’s Cancer Research Cyclacel Ltd 141 Medical Centre 25, 56, 198, 202, 237 Institute 128, 154, 187, 199 DAC 174 Ernst & Young (Israel) LTD. 143 Children’s Hospital 200 Dako Denmark A/S 31 Établissement Français du Sang 181 Children’s Hospital, London 181 Daniel Den Hoed Cancer Center 169, 237 ETH Hönggerberg 156 Chilean Cooperative Group Danish Cancer Society 12, 18, 29, 94, 99, 101, 237 Etnabiotech 187 for Oncologic Research 223 Danube University Krems 145 Eurogentec SA 178

INDICES 265 Europa Donna – The European Breast 224 Fraunhofer Gesellschaft zur Förderung GLYCART biotechnology AG 156 European Bioinformatics Institute 27 der angewandten Forschung e.V. 112, 143 Gotagene AB 208 European CanCer Organisation (ECCO) 224 Fraunhofer-Institut für Göteborg University 199 European Consensus Platform Integrierte Schaltungen 103 Grupo Español de Estudio, Tratamiento for Alternatives 90 Friedrich Miescher Institute y otras Estrategias Expirementales European Institute of Oncology 14 for Biomedical Research 74, 76, 159 en tumores solidos 224 European Molecular Biology Friedrich-Alexander Universität Gurdon Institute 76 Laboratory 39, 52, 90, 159, 199 Erlangen-Nürnberg 94, 176, 182, 204 H.S. Hospital Services S.p.A 218 European Organisation for Nuclear Research 110 Fujirebio Diagnostics (FDAB) 149 Haartman Institute 94, 139, 154 European Organization for the Fundació IMIM 141 Hamburg-Eppendorf 120, 145, 200 Research and Treatment of Cancer 178, 223 Fundación Centro Nacional Hanover Medical School 94 European School of Haematology 156 de Investigaciones 178, 226 Hebrew University European Society for Therapeutic Fundacion de Investigacion del Cancer of Jerusalem 27, 112, 143, 174, 200 Radiology and Oncology 110 de la Universidad de la Salamanca 199 Hebrew University-Hadassah Evolva SA 20 Fundación Hospital Universitario ‘La Fe’ 198 Medical School 12, 16 Exiqon A/S 74 Fundacion Institut per la Recerca 224 Heinrich-Pette-Institut 12, 59, 120 Experimental Biomedicine 193 Fundacion para la investigacion Helios Biosciences SARL 218 Faculté de Pharmacie 208 medica aplicada 80, 202 Helios Klinikum Erfurt GmbH 156 Faculty of Medicine London 233 Fundación para la Lucha contra Hellenic Anticancer Institute 195 Fakultni nemocnice Brno 198 Enfermedades Neurológicas de la Infancia 130 Hellenic Pasteur Institute 80 Febit biotech gmbh 69 Fundació Privada Institut d’Investigació Helsinki University Federal State Institution Centre for Heart, Biomèdica de Bellvitge 50 Central Hospital 48, 147, 198 Blood and Endocrinology 200 Fundacion Vasca de Innovacion Herlev Hospital 163 Finnish Cancer Registry 101, 233 e Investigacion Sanitarias 99 Hopital Avicenne (CHU Paris 13) 198 Finsen Centre – Rigshopitalet 223 Fundacion Virgen de las Nieves 176 Hospices-CHUV 198 Flanders Interuniversity Institute Fundeni Clinical Institute 198 Hospital Clinic Provincial for Biotechnology 33, 165 G. Salvatore, Consiglio Nazionale de Barcelona 92, 149, 193, 198 Fondazione Andrea Cesalpino 12 delle Ricerca 115 Hospital Clinico Universitario 154 Fondazione Bruno Kessler Galapagos NV 63 Hospital of Treviso 37 (Istituto Trentino di Cultura) 143 GanyMed Pharmaceuticals AG 59 Hospital of Zurich 126 Fondazione Centro San Raffaele GEIE-LINC 159 Hospital San Joan de Deu 130 del Monte Tabor 193 Gene Bridges GmbH 52 Hospital Universitario de la Princesa 198 Fondazione Collegio Ghislieri 199 Genedata AG 90, 94 Hospital Universitario, Granada 195 Fondazione IRCCS Istituto Nazionale GeneSpin SrL 12, 33 HS Rigshospitalet 37, 199 dei Tumori 235 Genethon 171 Hubrecht Laboratory 63, 74 Fondazione Istituto Natzionale Tumori 176 Genewave 126 Humanitas Mirasole SPA 169 Fondazione San Raffaele del Monte Tabor 176 Genome Research Limited, Hungarian Academy of Sciences 174 Forschungsinstitut für Molekulare Wellcome Trust Sanger Institute 27, 52 Hybrid Systems Ltd 208 Pathologie Gesellschaft 52 Genopoietic 80 Hyperphar Group SpA. 130 Forschungsverbund Berlin e.V. 141 GENOPOLIS 183 Instituto de Biologica Experimentale Forschungszentrum Jülich GmbH 193 Genoptics SA 115 e Tecnololgica – IBET 171 Forschungszentrum Karlsruhe Gentofte Hospital 163 Iceland Genomics Corporation 96 GmbH 18, 67, 118, 248 German Cancer Research Centre 99, 120, 145, 245 Icelandic Cancer Society 233 Forschungszentrum Rossendorf e.V. 110 German Research Center for IDIBELL 50 Foundation for Research and Technology 81 Environmental Health 224 IDM SA Immuno-Designed Molecules 187 France Europe Innovation 46 GGI-UTOPIKA LTG 103 IEO – European Institute of Frauenklinik der Heinrich-Heine- Given Imaging Ltd 143 Oncology 14, 52, 63, 223 Universität Düsseldorf 37 GKI Economic Research Co 174 IFOM – Institute of Molecular Oncology 115

266 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME IFOM – Fondazione Istituto FIRC Institut National de Recherche en Instituto de Salud Publica de Navarra 99 di Oncologia Molecolare 29, 48, 159 Informatique et Automatique 216 Instituto Nazionale per lo Studio IGEA S.r.l. 163 Institut Paoli-Calmettes 145 e la Cura dei Tumori 25, 99, 101, 178 Imaging S.A. 103 Institut Pasteur 44, 65, 94, 199 Instytut Fizyki Jadrowej PAN 216 Immunsystem I.M.S. AB 31 Institute for Analytical Sciences 107 Inte:Ligand 20, 174 Imperial College London 90, 107, 120, 143, Institute for Cancer Research Interfaculty Reactor Institute 216 204, 212, 223 and Treatment, Candiolo 159 International Affairs Department 237 Imperial College of Science, Technology Institute for Cancer Research, Oslo 59, 195 International Agency for and Medicine 94, 99, 143, 198, 204, 210, 233 Institute for Experimental 82 Research on Cancer – IARC 59, 94, 101, 237 Indicia Biotechnology 61 Institute for Molecular Biology International Confederation Indivumed GmbH 143 and Tumour Research 44 of Childhood 181 Industrial Chemistry Research Institute 241 Institute for Research in Biomedicine, International Hereditary Cancer Centre 84 Innate Pharma SA 176 Bellinzona 183 International Institute for Drug Innotrac Diagnostics OY, Turku 147 Institute for Toxicology and Genetics 248 Develpoment 224 INNOVA spa 12 Institute of Biochemistry and Genetics 18, 48 IOCB-AS of the Czech Republic 192 Innsbruck Medical University 41, 90, 107, 200 Institute of Biological Research Ion Beam Applications SA 216 INRIA 218 and Biotechnology 65 IONIMED Analytik GmbH 107 INSERM 12, 54, 92, 152, 192 Institute of Biology, Athens 241 Ipsogen SAS 25, 117, 200 INSERM Transfert 61, 218 Institute of Biophysics 59 IRCCS Policlinico S. Matteo 199 INSERM U318 130 Institute of Biotechnology, Vilnius 204 Israelitisches Krankenhaus 143 INSERM U463 195 Institute of Cancer Biology, ISREC 44 INSERM U591 Institut Necker 183 Copenhagen 12, 18, 29, 59, 237 Istanbul University 200 INSERM U664 50 Institute of Cancer Research, Istituti Ortopedici Rizzoli 46 Institut Bergonié 25 London 25, 46, 50, 65, 78, 87, 92, 141, 199, 233 Istituto Clinico Humanitas 183 Institut Català d’Oncologia 101, 199, 221 Institute of Cancer Research, Sutton 233 Istituto di Biostrutture e Bioimmagini 192 Institut Català d’Oncologia-Hospital Institute of Cancer Research/ Istituto di Chimica del Riconoscimento 156 Universitari Germans Trias 199 Royal Marsden NHS Trust 87 Istituto di Ricerche Farmacologiche 156 Institut Curie 18, 25, 46, 65, 117, 126, 128, 176, Institute of CarcinoGenesis, Moscow 192 Istituto di Ricerche Mario Negri 154, 115, 156, 167 183, 245 Institute of Clinical Biochemistry 233 Istituto Europeo di Oncologia 35, 44 Institut d’Hématologie et d’Oncologie 181 Institute of Experimental Medicine, Istituto Giannina Gaslini 156 Institut de Chimie Moléculaire Prague 14 Istituto Nazionale di Fisica Nucleare 216 et biologique 192 Institute of Genetics and Biophysics Istituto Nazionale per lo Studio Institut de Radioprotection ‘Adriano Buzzati-Traverso’ 115 e la Cura dei Tumori 25, 178 et de Sûreté Nucléaire 206 Institute of Hematology Clinical 200 Istituto Oncologico del Mediterraneo 33 Institut de Reçerca Biomédica 22, 63 Institute of Macromolecular Chemistry 208 Istituto Ortopedico Rizzoli 37, 46, 154 Institut de Recerca de l’Hospital Institute of Molecular Biotechnology Istituto Superiore de la Santa Creu i Sant Pau 134, 198 of the Austrian Academy of Sciences 63 di Sanità 154, 178, 183, 187, 216, 237 Institut de Recherche Pierre Fabre 82 Institute of Molecular Genetics 65 IT Dr. Gambert GmbH 107 Institut de Recherche Servier 210 Institute of Oncology Ljubljana 25, 92, 122, 224 J.W. Goethe-Universität Frankfurt am Main 33 Institut für Humangenetik Ingolstädter 202 Institute of Oncology of Southern Jagiellonian University, Cracow 195, 198 Institut für Med. Mikrobiologie 183 Switzerland 224 Jena University 94 Institut für Toxikologie und Genetik 18 Institute of Oncology, Warsaw 199, 22 Jobst Technologies GmbH 204 Institut Gustave Roussy 25, 46, 92, 110, 117, Institute of Organic Chemistry 241 Johannes Gutenberg-Universität Mainz 176, 198 163, 178, 183, 200, 202, 216, 223, 237 Institute of Pharmacology Johannes-Gutenberg-University Institut Jules Bordet 223 and Pathobiology 122 Medical School 18, 59 Institut National de la Santé Institute of Virology 204 John Innes Centre 74 et de la Recherche Médicale 33, 48, 99, 154, Instituto de Investigaciones Biomédicas 65 John Moores University 90 156, 176, 178, 199, 218 Instituto de Patologia e Imunologia 224 Josephine Nefkens Institute 122

INDICES 267 Jules Bordet Institute 200 London Research Institute 78 Medical University of Graz 120, 235, 245 Julius-Maximilians-Universität Würzburg 200 London School of Pharmacy 54 Medical University of Silesia 198 Justus-Liebig-Universität 199 Loreus Ltd 195 Medizinische Hochschule Hannover 198 Kaplan Medical Centre 145 Ludwig Institute for Cancer Research 12, 159, 176 Medizinische Universität Graz 198 Karaiskakio Foundation 200 Ludwig-Maximilians-Universität Medizinische Universität Innsbruck 67 Karolinska Institute & Hospital 223 München 80, 198 Medizinische Universität Wien 145, 198 Karolinska Institutet 12, 14, 33, 48, 59, 65, 92, Lund University 233 Medizinische Universitätsklinik Freiburg 78 94, 103, 110, 159, 178, 183, 195, 198, 204, 229, 233 Lunds Universitet 199 Medres Medical Research GmbH iGR 193 Karolinska University Hospital Solna 237 Lymphatix Oy (Lymphatix Ltd) 48 Megapharm GmbH 200 Katholieke Universiteit Lyon I Ingénierie 25 Memorial Institute, Branch Gliwice 233 Leuven 25, 37, 130, 145, 165, 178, 192, 198 Mabgène S.A. 112, 154 MICROART, S.L. 130 Kinderspitalgasse 187 Magnetic Biosolutions AB 178 Miescher Institute for Biomedical Research 159 King’s College London 33, 41, 92, 199, 235 Maria-Slodowska-Curie Cancer Miltenyi Biotec GmbH 169 Klinikum at the University of Cologne 192 Center and Institute of Oncology 101, 202 MLL Münchner Leukämielabor GmbH 200 Klinikum der Universität zu Köln 169 Marmara University Medical Molecular Discovery Pinner 189 Klinikum Kreuzschwestern Wels GmbH 198 School Hospital 224 Molecular Discovery Pinner 189, 214 Klinikum Rechts der Isar der Technischen 103 Martin Luther Universität Halle Mosaiques Diagnostics & Therapeutics AG 94 Kontron Medical S.A.S. 152 Wittenberg 223 MR Solution Ltd 193 Krankenhaus der Barmherzigen Schwestern 200 Masarykova univerzita 200 MRC Molecular Hematology Unit 39 Kreftregisteret/Cancer Registry of Norway 233 MAT BioPharma 112 MRC Research Management 237 Kreftregisteret/Cancer Registry of Norway 233 Mauna Kea Technologies 192 MRC-Holland 37 KRKA d.d., Pharmaceutical Company 115 Max Planck Institute for Biochemistry 74 Muenster University 132, 136 KTB Tumorforschungsgesellschaft mbH 14, 18 Max Planck Institute for N Goormaghtigh Institute KuDOS Pharmaceuticals Ltd 29 Developmental Biology 74 of Pathology 37, 156 Kungliga Tekniska Högskolan 178 Max Planck Institute for Infection Biology 74 N. N. Blokhin Cancer Research Centre 224 LabDia Labordiagnostik GmbH 200 Max Planck Institute for Molecular N.N. Petrov Research Institute 71 Laboratoire de Biologie des Tumeurs Genetics (Berlin) 245 National and Kapodistrian et du Développement 18 Max Planck Institute for Molecular University of Athens 99, 101, 115, 223, 237 Laboratorio Nazionale CIB 59 Genetics (Munchen) 90 National Cancer Institute, Italy 54, 229 Laboratory for Biotechnology Max Planck Society for the Advancement National Center for Scientific Research & Applied Pharmacology 25 of Science (Munchen) 115 (NCSR) ‘Demokritos’ 200 Labordiagnostika GmbH 145 Max Planck Society for the Advancement National Centre of Biotechnology, Spain 27 Landspitali-University Hospital 233 of Science (Berlin) 94 National Fund for Scientific Research Lapeyronie Hospital, Montpellier 120 Max-Delbrück-Center for Molecular at Faculté Universitaire des Sciences Lautenberg Center for General Medicine Berlin 44, 159, 169, 183 Agronomiques 94 and Tumour Immunology 12 Max-Planck-Gesellschaft zur National Hellenic Research Foundation 65, 185 LEA Medizintechnik GmbH 204 Foerderung der Wissenschaften eV 134 National Institute for Medical Research, Leaf Bioscience 183 Max-Planck-Institut für Biochemie 183 United Kingdom 182, 185 Leica Microsystems CMS GmbH 152 Max-Planck-Society MPI of neurological National Institute of Biology, Slovenia 115 Leiden University Medical Center 12, 14, 18, 29, research 192 National Institute of Cardiology, Poland 78 31, 37, 50, 67, 78, 84, 90, 92, 120, 139, 152, 176, Max-Plank-lnstitut für Molekulare National Institute of Public Health 183, 192, 198, 206, 208, 248 Zellbiologie und Genetik 52 and the Environment, The Netherlands 99 Leo Pharma A/S 204 Med Discovery S.A. 152 National Medical Center 200 Leopold-Franzens-Universtität Medical Research Centre, Warsaw 241 National Physical Laboratory, Innsbruck 107 Medical Research Council 12, 99, 182, 185, 237 United Kingdom 216 Limburg Cancer Registry (LIKAR) 233 Medical University Center Freiburg 54 National Public Health Institute, Finland 233 Linköping University 178 Medical University Lodz 130 National Research Centre for Hematology, LMU 76 Medical University of Gdansk 198, 224 Russia 198

268 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME National University Polish Academy of Sciences 71, 107, 241 Schering AG 35, 141, 156 of Ireland 25, 29, 122, 198, 226 Politecnico di Milano 134 School of Medicine 56, 115 Naxospharma srl 214 Polyplus Transfection 208 Scientific Institute of Public Health 233 NCPH-National ‘FJC’ Research Institute Pomeranian Medical University 69, 87, 92 Scientific Instituto San Rafaelle 183 for Radiobiology & Radiohygiene 192 Portuguese Institute of Oncology, Scito S.A. 130 Nederlands Kankerinstituut/Antoni 159 Porto Centre 224 Scuron 208 Nencki Institute of Experimental Biology 71 Procognia Ltd. 132 Seconda Università degli Studi Netherlands Cancer Institute 103, 178, 223, 237 Pro-Cure Therapeutics Ltd 208 di Napoli 35 New Knowledge Directorate 92 Progenika Biopharma, S.A. 126 Sectra Mamea 136 Newlab 221 ProImmune Limited 229 Sekmed 183, 185 NIBRT 132 ProSkelia 50 Semmelweis University Budapest 37 Nicolaus Copernicus University 107 ProtEra s.r.l. 61 SENDO Foundation 156 Noray Bioinformatics, S.L. 27 Proteros Biostructures GmbH 115 ServiceXS B.V. 92 Norwegian Cancer Society 233 PubGene AS 27 Servizio Universitario de Epidemiologia Norwegian Radium Hospital 37, 181, 195 QMUL 54 dei Tumori Universita di Torino 99 Norwegian University of Science Queen Mary University of London 199 Shanghai Jiaotong University 33 and Technology 29, 200, 235 Queens University Belfast 54, 200 Siemens AG 130 Nottingham City Hospital NHS Trust 239 Queensland Institute of Medical Research 92 Siena Biotech SpA 189 Nottingham Trent University 195 Radboud University Nijmegen Silex Microsystems AB 136 Novamed Ltd 143 Medical Centre 33, 67, 96, 110, 136, 182 SkyScan 192 Novosom AG 167 Radiation Oncology UMC St. Radboud 110 Slotervaart Medical Center 9D 159 Novozymes 90 Radiopharmaceuticals Research 156 Slovak Academy of Sciences 107, 204 NTNU 27 Radium Hospital Oslo 37, 120, 181, 195 Soltan Institute for Nuclear Studies 110 NUAce Tecnologies, Ltd 126 Rambam Medical Centre 198 Solvo Biotechnology, Inc. 37 Nuclear Fields International B.V. 134 RayClinic AB (RayEducation) 110 Spitalregion St. Gallen Rorschach 235 Nuclear Research and Consultancy Group 216 RaySearch Medical AB 110 St. Johannes Hospital Duisburg 199 Odense University Hospital 199 Regina Elena Cancer Centre 59 St. Laszlo Hospital 199 Office for National Statistics 101 Regina Elena Cancer Institute 12 St. Marien-Krankenhaus Siegen 199 Olink AB 31 REM Radioterapia SRL 12, 216 St. Vincent’s Hospital 223 OncoMethylome Sciences SA 115 Rheinisch-Westfälische Technische 235 St. Petersburg State Pavlov Medical 200 Oncotest GmbH 221 Rigshopitalet 223 State Institution of Healthcare Ondokuz Mayis University Medical Faculty 200 RiNA-Netzwerk RNA Technologien GmbH 204 ‘Regional Children’s Hospital #1’ 200 Onyvax Ltd 195 RNTech Diagnostics 132 Station Biologique – Amyloïds and Oxford Biomedica PLC 169, 204 Royal Bournemouth and Christchurch Cell Division Cycle (ACDC) – CNRS 218 Parc cientific de Barcelona 22 Hospital NHS Trust 199 Steinbeis-Forschungs- und Pathologisches Institut 202 Royal Liverpool University Hospital 141 Entwicklungs-zentrum GmbH 241 Pattern Expert 241 Royal Orthopaedic Hospital NHS Trust 37 Stichting Katholieke Paul-Ehrlich Institute (PEI) 221 Royal Surrey County Hospital NHS Trust 136 Universiteit 35, 130, 176, 193, 198, 202 Pepscan Systems BV 37, 229 Royal Veterinary & Agricultural Stichting Landelijk Referentie Peter MacCallum Cancer Centre 187 University 20, 122 Centrum voor Bevolkingsonderzoek 136 PEVIVA AB 110 Rudolf Virchow Centre for 193 Stiftung Tumorbank Basel 122 Pharma Quality Europe, s.r.l. 130 Ruprecht-Karls-Universität Heidelberg 198 Swedish Institute for Infectious PharmaMar SA 20, 25 Sainsbury Laboratory 81 Disease Control 94 PharmaTarget BV 14 San Raffaele Telethon Institute Swiss Federal Institute of Philipps-Universität Marburg 41, 44, 199 for Gene Therapy 84 Technology Zurich 16, 156, 212 Philogen s.r.l. 156, 212 Sanofi-Aventis 25, 204 Swiss Institute of Bioinformatics 224 Photobiotics 212 Santaris Pharma A/s 46 Szeged University 248 Physiomics PLC 218 Scanditronix Wellhöfer AB 216 Tallinn University of Technology 174

INDICES 269 TargetEx 174 Università degli Studi di Modena Université de Liège 156, 192 Technical University of Denmark 27 e Reggio Emilia 94 Université de Nice-Sophia Antipolis 183, 218 Technical University Università degli Studi di Padova 25, 94, 199 Université de Poitiers 117, 198 of Munich 115, 122, 178, 183, 193, 200 Università degli Studi di Pavia 199 Université François Rabelais 206 Technion-Israel Institute of Technology 169 Università degli Studi di Perugia 199 Université Henri Poincaré, Nancy 1 192, 199 Technische Universität Dresden 198 Università degli Studi di Roma Université Joseph Fourier 130 Technische Universität München 200, 223 ‘La Sapienza’ 198 Université Libre Technische Universiteit Delft 192 Università degli Studi di Roma de Bruxelles 22, 176, 182, 183, 185, 200, 241 Tecnogenetics srl 154 Tor Vergata 33, 198 Université Louis Pasteur de Strasbourg 208 Tel Aviv University 92, 245 Università degli Studi di Torino 192, 198 Université Paris 7 Denis-Diderot 154 Tel-Aviv Medical Center 200 Università degli Studi di Trieste 12 Université Paris Sud 214 Temasek Life Sciences Laboratory 74 Università di Bologna 198, 210 Université Pierre et Marie Curie 61, 169, 198 Tepnel Life Sciences plc 141 Università di Catania 187 Université René Descartes 176 The Netherlands Institute for Università di Firenze 216 Université Victor Segalen Bordeaux 94, 198 Developmental Biology 63 Università Milano 181 Universiteit Antwerpen 37, 192 The Norwegian Radium Hospital 181 Università Vita-Salute San Raffaele 199 Universiteit Maastricht 204 The University of Liverpool 200 Universitair Ziekenhuis Gasthuisberg 110 University College Dublin 390, 237 ThromboGenics Ltd 165 Universitat Autònoma de Barcelona 130 University College London 37, 52, 134, 156, TIGEM-Telethon 18 Universität Bern 67 159, 167, 169, 181, 200 TILL Photonics 120 Universität Duisburg-Essen 216 University Court of St. Andrews 221 TNO Quality Of Life 90 Universität Köln 199 University Cyril and TopoTarget Germany AG 18 Universität Leipzig 37, 198 Methodius-Faculty of Medecine 126 tp21 GmbH 152 Universitat Pompeu-Fabra 126 University Hospital Centre, Rebro 199 Trans Spectra Limited 107 Universität Rostock 107 University Hospital Copenhagen 202 Transgene SA 221 Universität Ulm 198 University Hospital Gasthuisberg 115 Triskel Therapeutics Ltd. 226 Universitatea de Medicina si Farmacie 200 University Hospital Heidelberg 233 Trojantec 212 Universitätsfrauenklinik 223 University Hospital Maastricht 224 Trollhetta AS 235 Universitätsklinik Kiel Institut University Hospital Malmö 147 UCSF-Genentech Hall, UCSF 214 für Hämatopathologie 200 University Hospital Mannheim 195 UK Medical Research Council 237 Universitätsklinik Münster 181 University Hospital Umeå University 54, 233 Universitätsklinikum Bonn 46 Munich-Grosshadern 149, 202 UMR 8121 CNRS – IGR 163 Universitätsklinikum Düsseldorf 107, 199 University Hospital of Erlangen 185 Unilever 90 Universitätsklinikum Frankfurt 198 University Hospital of Münster 141, 154 Universidad de Barcelona 216 Universitätsklinikum Freiburg 199 University Hospital Schleswig-Holstein 199, 202 Universidad de Castilla-La Mancha 216 Universitätsklinikum University Hospital, Lund 92 Universidad de Navarra 202 Hamburg-Eppendorf 145, 200 University Hospital, Sofia 195 Universidad de Oviedo 115 Universitätsklinikum Heidelberg 37, 115 University Hospital, Valencia 90 Universidad de Salamanca 37 Universitätsklinikum Mannheim 25 University Hospitals Coventry and Universidad de Vigo 35 Universitätsklinikum Münster 198 Warwickshire NHS Trust 216 Universidad Politécnica de Madrid 193 Universitätsklinikum Schleswig-Holstein 141 University Medical Center Amsterdam 120 Universidad Politécnica de Valencia 130 Universitatsklinikum Tübingen 195 University Medical Center Universidade do Porto 224 Universitätsmedizin Göttingen 200 Groningen 56, 139, 206, 226 Università Cattolica del Sacro Cuore 198 Université Catholique de Louvain 110, 163 University Medical Center Hamburg 120, 183 Università degli Studi di Bari 199 Université Claude Bernard Lyon 25, 80, 202 University Medical Università degli Studi di Ferrara 80 Université d’Aix-Marseille 61 Center Nijmegen 122, 130, 185, 193, 198, 202 Università degli Studi di Genova 92, 183 Université de Bretagne Occidentale 112 University Medical Center Utrecht 99, 159, 200 Università degli Studi Université de la Méditerranée 127, 200 University of Aarhus 74, 115 di Milano 29, 33, 35, 134, 183, 192, 200 Université de Lausanne 33, 112, 210 University of Barcelona 202

270 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME University of Bari 174 University of Modena and University of Würzburg 163 University of Basel 18, 48, 115, 192, 198, 212 Reggio Emilia 199, 214 University of York 67, 171, 200, 208 University of Bergen 14 University of Mons-Hainaut 192 University of Zurich 29, 183, 204 University of Bern 37, 152, 193, 198 University of Montpellier 56 University Palacky 200 University of Birmingham 94, 130, 200 University of Munich 29, 78, 115 University Pompeu Fabra 174 University of Bochum 141 University of Newcastle Universtita degli Studi di University of Bristol 235 upon Tyne 46, 67, 189, 198 Napoli Federico II 99 University of Cambridge 20, 35, 59, 67, 74, University of Nijmegen 122, 130, 147, 185, Univerzita Karlova 192, 202 99, 115, 136 193, 198, 202 Univerzita Palackeho v Olomouci 167 University of Catania 241 University of Oslo 29, 37, 101, 107, 204, 229 Uniwersytet Medyczny w Lodzi 199 University of Copenhagen 27, 39, 80, 192 University of Oulu 14, 183 Uppsala Universit 167, 198, 208, 233 University of Crete University of Oxford 12, 14, 37, 94, 101, 156, Ustav hematologie a krevni transfuze 200 Medical School 167 176, 178, 182, 185, 204, 206, 208, 224, 237 van Leeuwenhoek 18, 44, 59, 82, 103, 110, 120, University of Debrecen 117, 169, 192 University of Padova 229 159, 169, 178, 223, 237 University of Dundee 12, 74, 200, 224 University of Pennsylvania 92 Vastox 39 University of East Anglia 74, 115, 216 University of Perugia 189 Vichem Chemie Research Ltd 41, 44, 94 University of Edinburgh 31, 169, 223, 235 University of Pisa 193 Victoria University of Manchester 178, 193, 204 University of Florence 183, 200, 204 University of Porto 94, 139 Vienna General Hospital 223 University of Freiburg 115, 138 University Of Potsdam 149 Vilnius University Hospital 200 University of Geneva 20, 63, 65, 126 University of Regensburg 138, 187 Visiopharm A/S 31 University of Genoa 200 University of Rome ‘La Sapienza’ 74 Vitateq Biotechnology GmbH 145 University of Ghent 18, 50, 115 University of Rome ‘Tor Vergata’ 81 ViVoX ApS 204 University of Glasgow 54, 115 University of Roskilde 139 Vorarlberg University of Applied Sciences 107 University of Göteborg 48, 199 University of Rostock 241 Vrije Universiteit Brussel 56, 90, 176, 183 University of Göttingen 12, 22 University of Salamanca 56 Vrije Universiteit Medical University of Graz 81, 120, 235, 245 University of Sheffield 67, 147, 152, 199 Center Amsterdam 14, 82 University of Groningen 16, 147, 226 University of Siena 189 VTT Technical Research 31 University of Hamburg 12, 110 University of Southampton 115, 199 VU Academic Medical Center, Amsterdam 198 University of Heidelberg 16, 56, 141, 212 University of Southern Denmark 54 VUMC Cancer Center Amsterdam 237 University of Helsinki 37, 48, 69, 78, 84, University of St. Andrews 12 Wageningen University 171 94, 154, 167, 174, 199, 221 University of Stuttgart 61 Warsaw University 241 University of Hull 212 University of Sussex 29 Weizmann Institute University of Innsbruck 117, 159 University of Sydney 92 of Science 12, 22, 41, 59, 67, 81, 159, 169 University of Kuopio 47, 171 University of Tampere 67, 233 Wellcome Trust, Sanger Institute 27 University of L’Aquila 50 University of Tartu 20, 117 Wellcome Trust/Cancer Research University of Latvia 92, 195 University of Technology Dresden 110, 206 UK Gordon Institute 29, 183 University of Leeds 92, 94, 118 University of Torino 138 West German Study Group Fraeunklinik University of Leuven 37, 48 University of Tromso 99 der Heinrich-Heine-Universität 223 University of Liège 50, 115, 156, 192 University of Tübingen 71 Westfalische Wilhelmuniversity University of Ljubljana 163 University of Turku 35, 67, 110, 115, 147 Münster 37, 46 University of London 78 University of Ulm 208 Westpfalz-Klinikum GmbH 200 University of Louvain 183 University of Umeå 99 Wilheminenhospital 56 University of Lund 37, 39, 99, 233 University of Uppsala 14, 31, 167, 198, 208, 233 Wroclaw University of Environmental University of Maastricht 110 University of Utah 92 and Life Sciences 50 University of Mainz 192 University of Utrecht 120 Xanthos Biomedicine AG 81 University of Manchester 110, 169, 178, 193, University of Valencia 37, 130, 237 Zarlink Semiconductor AB 143 204, 245 University of Verona 117, 141 Zenon Bio Ltd. 248 University of Milano-Bicocca 182, 185 University of Vienna 16, 41, 44, 48, 115, 145, 198 ZF-screens B.V. 248

INDICES 271 European Commission

Cancer Research – Projects funded under the Sixth Framework Programme (2002-2006)

Luxembourg: Offi ce for Offi cial Publications of the European Communities

2008 – 272 pp. – 21.0 x 29.7 cm

ISBN 978-92-79-09352-4 Interested in European research?

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European Commisssion Directorate-General for Research Directorate F – Health Unit F.2 – Medical and Public Health Research Area: Cancer

Contact: Dominika Trzaska E-mail: [email protected] European Commission Offi ce CDMA 2/46 B – 1049 Brussels 2002-2006

PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME FRAMEWORK FUNDED UNDER THE SIXTH PROJECTS CANCER RESEARCH

PROJECT SYNOPSES PROJECT

CANCER RESEARCH CANCER CANCER RESEARCH CANCER

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