Oslo University Hospital The Norwegian Radium Hospital INSTITUTE Institute for Cancer Research FORINSTITUTE CANCER Ullernchausseen 70 RESEARCH N–0379 Oslo FOR CANCER Norway P.O. BOX 4953 Nydalen RESEARCH N–0424 Oslo Norway ANNUAL http://ous-research.no/institute/ REPORTAnnual 201Report7 INSTITUTE FOR CANCER RESEARCH ANNUAL REPORT 2017 2018 Contents
4 Introduction by the Director 6 The Institute for Cancer Research into the future 8 Organisation and key figures 12 Oslo University Hospital Comprehensive Cancer Centre
14 Departments and research groups 16 Cancer Genetics 22 Cancer Immunology EDITORIAL STAFF: 30 Molecular Cell Biology Kjetil Taskén Gunhild M. Mælandsmo 36 Molecular Oncology Peter Wiedswang Kari Aalrust Berger 42 Radiation Biology 48 Tumor Biology DESIGN: Espen Liland 54 Core Facilities PHOTOGRAPHY: Terje Heiestad The photographic theme of this year’s Annual Report is Humans at ICR. - The most important part of ICR is 58 Research centres by far its human resources and our collective competence. 60 Centre of Excellence 62 K. G. Jebsen Centres FRONT PAGE: Light, protons and neutrons are utilised 68 Norwegian Cancer Genomics Consortium to activate photosensitizers for cancer therapy. This is funded by two new EU Horizon2020 Future Emerging Technologies (FET-OPEN) grants to 70 International Collaboration Department of Radiation Biology (Theo Theodossiou and Kristian Berg) along 72 Recent Innovations with support from HSØ. Here: Diode 74 Publications laser-based PCI treatment.
PAPER: 150/300 Profimatt CIRCULATION: 800
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 3 Introduction by the Director
The Institute for Cancer Research (ICR) is an Society to Vessela Kristensen, the award of the UiO institution with approximately 350 employees Research Prize to Harald Stenmark, the Ragnar Mørk’s plus students organised in 24 research groups Prize for Outstanding Research to Kaisa Haglund and complemented with cutting-edge core facilities. The the election of Johanna Olweus to the Norwegian ICR is a premier institution in basic and translational Academy of Science and Letters. Also, OUH awarded cancer research on a national and international arena prizes in their bi-annual assessment of best papers to and has a strong prior track record in translation ICR researchers Fergal O’Farrell and Tor-Erik Rusten and innovation. It was therefore with a great deal of (May 2018) and Tord Hompland and Heidi Lyng (Nov humility and respect that I came to the position as 2018). Head and Director of the Institute of Cancer Research 2018 marked the end of the Norwegian Cancer (ICR) at Oslo University Hospital (OUH) from January Genomics Consortium project (NCGC, headed by 2018. Ola Myklebust) where numerous patients with From the start of 2018 we set out as a long-term nine different cancers have been sequenced and goal, in agreement between the ICR Leadership group mutational analysis conducted. A special report has and the Head of the Division for Cancer Medicine, now been published that summarizes the extent of the that rather than increasing the scientific output in accomplishments made and shows how this may form terms of number of papers, we would like to see a a solid research fundament for future development further increase in quality of the output. Against this of precision cancer medicine in Norway.1In addition backdrop, it is interesting to see that already now, to the above highlights, numerous other research the median impact factor of the papers produced is discoveries and clinical trials report on major up from 4.1 in 2017 to 5 in 2018. The fact that we have scientific advances at ICR and represent good news still produced 186 papers (and more than 50 in the for future cancer patients, as exemplified elsewhere in two first months of 2019) is also excellent, particularly this report. as almost half of the production also has first and/or In the Department of Cancer Immunology, June senior authors from ICR. Myklebust has been appointed Group Leader for More than 2/3rds of the total ICR funding in 2018 the Lymphoma Biology Group and succeeds Erlend (310 MNOK) came from extramural grants. ICR Smeland who continues to support the group as scientists have also been able to obtain substantial a senior member and co-lead in addition to his new funding and secured major new grants from job as OUH Director of Research and Innovation. the Norwegian Cancer Society, the Research Council ICR’s strong standing in Norwegian research is also of Norway, and the South-Eastern Norway Regional illustrated by the fact that members of the institute Health Authority as well as private and international lead a Centre of Excellence (CoE) Centre for Cancer sources. Cell Reprogramming (CanCell, Director Harald We celebrate our victories at the ICR, and in Stenmark) and the three K.G. Jebsen centres for 2018 we have marked the fact that both Karl-Johan Cancer Immunotherapy (Director Johanna Olweus), Malmberg and Tor Erik Rusten won very prestigious Colorectal Cancer Research (Director Ragnhild A. 5-year “Toppforsk” grants from the Research Council Lothe), both in the extension phase, and for B Cell and the University of Oslo. We have also had the Malignancies (new, Deputy Director June Myklebust), official opening of a new KG Jebsen Centre for B Cell all with strong participation from ICR groups. Malignancies where ICR scientists participate (and The ICR sets out to maintain the excellent science with June Myklebust as Deputy Director). In the and outstanding production and to further build fall, we celebrated the award of a highly prestigious excellence by organising more collaborative efforts ERC Advanced Grant to Harald Stenmark (one of at all levels to deal with grand challenges in cancer very few that has been granted an ERC AdG for the medicine and to position the ICR in national and second time!). We have marked the fact that Kristian international alliances and consortia (see following Berg and Theo Theodossis have won two prestigious section on ICR into the future). We aim to be a Horizon2020 Future Emerging Technologies (FET- significant partner for the clinical activities in the “Research and OPEN) grants for research on how light, neutrons and Division of Cancer Medicine and the OUS OECI- innovation with protons can be combined with photosensitizers for accredited Comprehensive Cancer Centre (CCC). We drug delivery and cancer therapy and that Guro Lind continue feeding results into a translational research patient benefit won a large KLINBEFORSK grant for a multi-centre path and to have patient benefit in mind in all aspects trial to document a biomarker for bladder cancer of research and innovation. in mind” recurrence. Newly appointed Assoc. Prof. Anita Sveen won a Young talent grant from the RCN. And we March, 2019, have celebrated internally the award of King Olav Vs Kjetil Taskén, Head of the ICR Prize for Cancer Research by the Norwegian Cancer
1 The NCGC Report can be downloaded at: https://kreftgenomikk.no/files/2019/01/NCGC-Rapport.pdf
4 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 5 The Institute for Cancer Research Into the future!
In 2018 the new ICR leadership team consisting of b) Find collaborators and partners internally and externally ■ Objectives Q Department Heads Therese Sørlie, Johanna Olweus, Harald that enables a); ■ Ambition U N A A. Stenmark, Ragnhild A. Lothe, Kristian Berg, Gunhild c) Increase number of applications, specifically targeting IO ■ Global influence L M. Mælandsmo and Leonardo A. Meza-Zepeda, ICR Chief unexplored grant opportunities. IS ■ Cutting-edge IT Administrative Officer Kari Aalrust Berger and ICR Director V ■ Passion Y
Kjetil Taskén have worked to find our complementarities 4. Establish a new SAB for ICR, recruit members, and
and create basis for future collaboration and cohesion. organise a SAB-visit and evaluation in 2020, to follow up
on the SAB visit in 2018 (to CCC). ■ Respect VISION, VALUES AND OBJECTIVES ■ Excellence In a leadership development programme with the 5. Increase internationalisation and technology ■ Synergy in research assistance of Tone Ringstad in Culturengine, we have development: Increase mobility (particularly outgoing EXCELLENCE ■ Diversity ■ Trust
mapped our individual values and work culture. We have shorter research stays) to develop new networks, new ■ Generosity IN FIGHTING ■ Competence
worked on how we want the ICR as a whole to stand out competencies and find new project ideas.
■ Partnerships
with its vision, objectives and values. We have analysed ■ Solidarity CANCER
what work culture we need and where the gaps are that WHAT VALUES AND WHICH CULTURE DO WE NEED AT THE
■ Openness
we need to fill. The draft ICR Objectives for 2019-20 and ICR IN ORDER TO REACH OUR GOALS? (see figure, right) T
the ICR vision and values have next been discussed in an • INTEGRITY for us means: We all take responsibility. We E
A
ICR leadership meeting in February 2019 and at an all-day have high ethical standards in all our research. We show ICR Group Leader meeting on March 4, 2019. The finalized integrity in what we do and how we act, we stand for M ■ Ethics ICR vision, values and objectives 2019-2020 were then what we report in our research. Our demands are high W ■ Responsibility Y approved by the ICR Leadership in a meeting on March 20, and we show loyalty to objectives and team. T O ■ Loyalty I 2019 and represent our joint view on where the ICR as a • QUALITY for us means: We have high standards scientif- R R K ■ Demands G whole is going. ically in everything that we do and all that we produce TE and deliver, this is the basis of our excellence. All cate- IN OBJECTIVES 2019-2020 gories of staff with different backgrounds and training With basis in the research goals of the Division for Cancer are equally important and form the basis for an overall Medicine and OUH and our internal ambitions, the ICR quality that goes through the entire project portfolio. We shall: set demands to our collaborators, and in return we offer and expect trust in the scientific quality of the data we 1. Strengthen translational research. Hereunder: produce jointly. a) Establish an advisory board or team for translational • TEAMWORK for us means: We accomplish more if we research projects drawing on our internal competencies work together as a team, we work to elicit synergy in to help projects forward; our research and between our projects. We need differ- b) Define and inform the Division for Cancer Medicine ent competencies to achieve our goals and we appreci- (DCM) what we aim to accomplish and where we are ate diversity and differences in scientific and cultural heading with ICR (translational) research, our strengths background. We show respect for all categories of staff. and needs; and We exercise generosity in collaboration, education and c) Find the opportunity space in DCM and OUH for development. We work as teams at the level of projects, developing projects. in research groups, at the level of the departments and at the ICR as a whole. We aim for synergy in the whole or- 2. Strengthen contact, coordination and collaboration with ganisation to reach our most ambitious goals. We cheer clinicians and diagnostic staff in OUH CCC. Hereunder: each other along and celebrate our successes jointly. a) Take forward and make an overview of basic, • VISION for us means: We draw on our integrity and qual- translational and clinical studies that ICR groups ity and our abilities for teamwork to raise our expecta- conduct or are involved in *; tion of what we can accomplish and fulfill our vision. We b) Invite and meet N4-leaders on the clinical /diagnostic exercise courage, dare to think big and set our ambitions side in CCC (DCM and other divisions) for discussion on high. We go for passion, support visionary thinking and coordination and collaboration (ICR group- and project work for international visibility and global influencein leaders); and cancer research. c) Use this as a starting point to implement ICR knowledge, research and competencies into OUH practise*. With basis in these values and culture, our vision is: «Excellence in Fighting Cancer» 3. Build further excellence in research. Hereunder: a) Develop and document more projects, focus on ICR Leadership, March 2019 originality, depth, quality and international value; ICR leadership: Harald A. Stenmark, Therese Sørlie. Kristian Berg, Gunhild M. Mælandsmo, Leonardo A. Meza-Zepeda, Kjetil Taskén, Johanna Olweus, Ragnhild A. Lothe, Kari Aalrust Berger.
*Start with use of the DCM research administrative system being developed.
6 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 7 Organisation
The Institute for Cancer Research Head ofHead Institute of Institute Institute for Cancer Kjetil TaskénKjetil Taskén Research is organized in 6 research departments AdministrationAdministration Manager Manager with 24 research groups, Kari AalrustKari AalrustBerger Berger and one Department of
Core Facilities.
AdministrationAdministration ServiceService Lab Lab
CancerCancer Genetics Genetics CancerCancer Immunology Immunology Molecular Molecular Cell Biology Cell Biology MolecularMolecular Oncology OncologyRadiationRadiation Biology Biology TumorTumor Biology Biology Core FacilitiesCore Facilities ThereseTherese Sørlie Sørlie JohannaJohanna Olweus Olweus Harald A.Harald Stenmark A. Stenmark RagnhildRagnhild A. Lothe A. Lothe KristianKristian Berg Berg GunhildGunhild M. Mælandsmo M. Mælandsmo LeonardoLeonardo A. Meza-Zepeda A. Meza-Zepeda
Gry AarumGry GeitvikAarum Geitvik ThereseTherese Sørlie Sørlie JohannaJohanna Olweus Olweus Harald StenmarkHarald Stenmark RagnhildRagnhild A. Lothe A. Lothe KristianKristian Berg Berg GunhildGunhild M. Mælandsmo M. Mælandsmo Trond StokkeTrond Stokke Lab TechnologyLab Technology Breast TumorBreast InitiationTumor Initiation ExperimentalExperimental CellularCellular Membrane Membrane GeneticsGenetics PhotochemicalPhotochemical MetastasisMetastasis Biology Biology Flow-CytometryFlow-Cytometry and and ImmunotherapyImmunotherapy DynamicsDynamics Internalization Internalization and Experimentaland Experimental Pre-ClinicalPre-Clinical Imaging Imaging TherapeuticsTherapeutics Guro ElisabethGuro Elisabeth Lind Lind Heidi LyngHeidi Lyng Åslaug ÅslaugHelland Helland Karl-JohanKarl-Johan Malmberg Malmberg Jorrit EnserinkJorrit Enserink EpigeneticsEpigenetics SusanneSusanne Lorenz Lorenz ClinicalClinical Radiation Radiation TranslationalTranslational Studies Studies NK CellNK Biology Cell Biology and and CancerCancer Molecular Molecular Medicine Medicine Kjersti FlatmarkKjersti Flatmark GenomicsGenomics and and in Solidin Tumors Solid Tumors Cell TherapyCell Therapy BiologyBiology TranslationalTranslational Cancer Cancer BioinformaticsBioinformatics Rolf I. SkotheimRolf I. Skotheim TherapyTherapy Tor ErikTor Rusten Erik Rusten GenomeGenome Biology Biology Einar RofstadEinar Rofstad Ellen SkarpenEllen Skarpen VesselaVessela N. Kristensen N. Kristensen June HelenJune Myklebust Helen Myklebust Tumor-hostTumor-host Biology Biology RadiationRadiation Biology Biology AdvancedAdvanced Microscopy Microscopy CancerCancer Genome Genome LymphomaLymphoma Biology Biology Eivind HovigEivind Hovig and Tumorand Tumor VariationVariation ComputationalComputational Kirsten KirstenSandvig Sandvig PhysiologyPhysiology Cancer Cancer Genomics Genomics IntracellularIntracellular Transport Transport Hege E.Hege G. Russnes E. G. Russnes MouldyMouldy Sioud Sioud Randi SyljuåsenRandi Syljuåsen Jørgen JørgenWesche Wesche Genomic Genomic Alterations Alterations ImmunomodulationImmunomodulation RadiationRadiation Biology Biology MolecularMolecular biology biology in Breastin CancerBreast Cancer and Targetedand Targeted and DNAand Damage DNA Damage of Sarcomaof Sarcoma TherapiesTherapies SignalingSignaling
Kjetil TaskénKjetil Taskén Cell SignallingCell Signalling and and ImmuneImmune Regulation Regulation
8 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 9 Key figures 2018
1.8% 1.8% FundingFunding ExternalExternal funding funding by sourceby source 6.5% 6.5% Percent Percent 4.4% 4.4% Percent Percent 31.4% 31.4%
Actual InstituteActual expenditure Institute expenditure for 1 forby 1 by 7.5% 7.5% Sources ofSources external of competitive external competitive internal andinternal external and funding external sources funding sources 33.7% 33.7% funding forfunding 1 , forbased 1 , on based actual on actual (total 1 ,1(total MNOK 1 ,1 MNOKapprox. 1, approx. M ) 1, M ) expenditureexpenditure (total 1 , (total MNOK 1 , MNOK approx. 1, approx. M ) 1, M ) Internal fundingInternal funding 24.9% 24.9% External fundingExternal funding South EasternSouth Eastern Norway Regional Norway RegionalHealth Authority Health Authority 68.6% 68.6% The ResearchThe Research Council of Council Norway of Norway 21.2% 21.2% The NorwegianThe Norwegian Cancer Society Cancer Society UniversityUniversity of Oslo of Oslo InternationalInternational sources sources Other privateOther sources private sources EmployeesEmployees Other publicOther sources public sources 73 73 68 68
49 49
37 37 32 32 34 3432 32 (FTEs) (FTEs) Female Female CompletedCompleted PhDs PhDs ArticlesArticles published published 18 18 Male Male andand M.Sc.-degrees M.Sc.-degrees First or lastFirst authorship or last authorshipCo authorCo author 4 34 3 Impact factorImpact median factor median
ManagementManagementTechnical TechnicalPersonell PersonellPhD studentsPhD studentsPost doctorsPost doctorsResearchersResearchers 244 244 108 108 220 220 15 15 108 108 186 186 13 13 EmployeesEmployees by Gender by GenderFTEs byFTEs Employer by Employer EmployedEmployed by by 9 9 79 579 5 (total 384) (total 384) (total 350) (total 350) (total 384) (total 384) 8 8 10 10 19 19 18 18 3.5 3.5 16 16 136 136 112 112 107 107 15 4615 46 23 4923 49 140 140
244 244 281 302 281 302 1 1 1 1 1 1 1 1 1 1 1 1
M.Sc. degreesM.Sc. degreesPhDs PhDs IMPACT FACTORIMPACT FACTOR Mean . . . Female FemaleMale Male ICR OUSICR OUSUiO OtherUiO Other ICR OUSICR OUSUiO OtherUiO Other Mean . . . Median Median . . .1 .1
10 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 11 Oslo University Hospital Comprehensive Cancer Centre
The Institute for Cancer Research (ICR) has through school and the Cancer Registry of Norway, giving its 65 years of history built research activity at a high unique infrastructure for innovation, education international level within basic and translational and population-based research. Several Centers cancer research. Furthermore, the collaborations of Excellence, up to date- core facilities, strong between ICR and clinicians within the next door international and national collaboration, and not at Radium Hospital (now part of Oslo University least the highly qualified, enthusiastic and dedicated Hospital) has led to a large number of clinical trials staff are all essential elements. Most are full time and multiple innovations for the benefit of patients. scientists and technicians, in addition to clinicians This interaction has since been extended to the entire in combined research positions, and researchers in Comprehensive Cancer Centre within Oslo University combined positions as university professors. In order Hospital (OUH CCC, accredited by OECI in 2017). ICR to fully exploit its potential, the Institute is strongly is closely associated with The University of Oslo, but dependent on even further interaction with the is organized within the Division of Cancer Medicine clinical environment and the Cancer Registry. in OUH, which is internationally quite unique for a Being the core engine within research in OUH research institute, further securing close interaction CCC, the Institute will benefit from the integrated between basic/translational and clinical research. For organization of all cancer related activities, and will the last ten years ICR has been located in a modern play a key role in further promoting OUH CCC as a research building and today next door to the Oslo leading cancer centre in Europe. Cancer Cluster Innovation Park with Ullern high
Sigbjørn Smeland Gunnar Sæter Head of Division of Cancer Medicine, Research Director, Division of Cancer Medicine Chair, OUH CCC Board Head, OUH CCC Research Committee
12 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 13 16 Department of Cancer Genetics 22 Department of Cancer Immunology 30 Department of Molecular Cell Biology 36 Department of Molecular Oncology 42 Department of Radiation Biology 48 Department of Tumor Biology 54 Department of Core Facilities Departments
14 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 15 Department of Department of Cancer Genetics
Headed by Therese Sørlie
Our aim is to improve risk estimation, achieve earlier ual treatment decisions in early breast cancer diagnosis and improve prediction of treatment response • OPTIMA-Optimal personalized treatment of early and outcomes for patients with early and advanced breast cancer using multi-parameter analysis stages of breast, lung, pancreatic and ovarian cancer. • ComIT - Evaluation of the benefit of radiation in combi- Our research is translational in nature and through nation with immune therapy for lung cancer molecular classification, data integration, pan-cancer • TREM – Lung cancer patients with EGFR mutations and analyses and functional studies; we work towards primary TKI-resistance facilitating the implementation of discoveries to clinical • ThoRaT - Lung cancer patients receiving radiotherapy use. A common theme across groups is to achieve deeper • NorPACT-1 and 2 - Neo-adjuvant chemotherapy for “Our mission is to molecular understanding of inter- and intra-tumor pancreatic cancer heterogeneity and tumor evolution using human tumor • ICON - Randomized phase IIb study evaluating immu- improve the lives cohorts and mouse models. We are an interdisciplinary nogenic chemotherapy combined with ipilimumab and of cancer patients team of 50 members with medical doctors, molecular nivolumab in patients with luminal B breast cancer biologists, bioinformaticians and highly specialized • ALICE – Atezolizumab combined with immunogenic with solid tumors engineers organized in 4 research groups and one lab- chemotherapy in patients with metastatic triple-nega- by performing technology unit. Two of the group leaders hold part-time tive breast cancer clinical positions. The lab technology unit reinforces the • Oslo2 - Observation trial including comprehensive translational department’s skills of “state of the art” technology and biobanking research” improves exchange of knowledge across research groups and cancer types. We have extensive institutional, national and international collaborations and are partners in several We have a pipeline for high-quality biobanking (>200 networks and consortia; the National Breast Cancer 000 vials, > 3000 patients) and data handling of patient Research Network, the Regional Research Network on cohorts with long-term follow-up and perform multilevel Extracellular Vesicles, Personalized Cancer Treatment molecular characterization of tumors down to single cell and Metaflammation, International Cancer Genome levels. We are involved in the following clinical studies: Consortium, EuroPDX, the Breast Cancer Association • NeoAva - Neoadjuvant chemotherapy in breast cancer Consortium; and EU funded projects (EpiMark, Cancer- with/without bevacizumab. ID, Gender-Net Plus). We host The National Competence • IBCT - Improved breast cancer therapy in the neoadju- Center for Lung Cancer. The total number of peer vant and metastatic setting reviewed publications in 2018 was 76. • EMIT -Establishment of molecular profiling for individ-
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 17 Department of Cancer Genetics Breast Tumor Translational Initiation Studies in Solid Tumours
”With starting point in clinical studies and clinical “Understanding cell fate decisions in tumor questions, we do molecular analyses aiming at progression” improving outcome for cancer patients”
Group leader: Therese Sørlie Group leader: Åslaug Helland
ABOUT PROJECTS The group counts 11 members, including one professor • Characterize the functional effect of breast cancer risk ABOUT PROJECTS (TS), one senior researcher and project leader (SN until variants Our group focuses on translational studies on solid • Molecular characterization (-omics) of pancreatic- and March 2018), one scientist, three postdocs, three PhD • Characterize subtype-specific progression pathways of tumours, with a special interest in pancreatic, lung, lung cancers students, one master student and two engineers. We pre-invasive lesions in the breast ovary and colorectal cancers. We do whole genome • Proteogenomic analysis of pancreatic tumors and hosted en ERASMUS student for 2 months. Two members • Investigate the role of Hedgehog/GLI1 signaling in analyses on patient material, aiming at identifying characterization of circulating biomarkers in free plas- are MD and one is DVM. Our group studies molecular breast cancer progression predictive and prognostic biomarkers. We are analysing ma and exosomes aspects of breast tumor initiation and progression • Explore the role of LGR5-expressing cells in mammary mRNA, miRNA, DNA, methylation, glycosylation, • Identification of circulating plasma biomarkers in col- including functional effects of known risk variants, tumorigenesis mutations and proteins. By increasing the understanding orectal cancers (the Nordic VII clinical trial) identifying cell(s) of origin of molecular subtypes and • Investigate the role of FOXA1 in endocrine resistant of the underlying biology of tumour development, we • Protein (TMA) analyses in lung cancers the transition from in situ to invasive breast cancer. We breast cancer aim at improving cancer patient care. We also study • Serum predictive markers for therapy response have a broad expertise in laboratory technologies which therapy resistance. Several of our projects include • Elucidate mechanisms for therapy resistance includes high-throughput genomic technologies, in vivo RECENT ACHIEVEMENTS material from patients included in clinical studies, and • Expand biomarker identification material to stool (mi- lineage-tracing, 2D and 3D in vitro culture techniques, 6 publications by group members in 2018. One student we have clinical and follow-up data from all patients. crobiome) and urine in situ hybridization, confocal microscopy, and FACS completed the Medical Student Research Programme and We are organized into three project groups, headed • Investigate combination of radiotherapy and immuno- analysis. We use patient cohorts and mouse models one master thesis completed. by Elin H. Kure (Professor USN), Odd Terje Brustugun therapy (transgenic and patient derived xenograft - PDX) in our and Åslaug Helland (Professor UIO) , with a total • Gender differences in side effects on immunotherapy studies. We also have expertise in bioinformatics and of 17 members. Six of these are MDs. We are three statistical modeling. researchers, three postdocs, six PhD-students, one study RECENT ACHIEVEMENTS nurse and four engineers. In 2018, the group published 21 papers in peer-review AIMS journals. We have had several talks at national and Our aim is to identify the cellular origins of breast AIMS international meetings, and are PIs on >20 translational tumors and the mechanisms underlying tumor initiation The ultimate goal is to personalise cancer treatment, and and clinical studies. An ERA-network we are part of and further development into the heterogeneous improve prognosis. We aim for: received funding (Gender-net). We are partners in molecular subtypes. Through an increased • Identification of biomarkers in blood samples, for diag- several HSØ networks (NORSMAN, ReMics, NIRO), and understanding of how early lesions progress to more nostics, follow-up and prognostication received approximately 13 mill NOK in research funding advances stages, we aim to contribute to improved • Identification of tumour biomarkers for prediction of (Elin Kure 1.2 mill, Odd Terje Brustugun 2 mill, Åslaug strategies for early intervention and more precise therapy response and for prognostication Helland 10 mill). treatment.
18 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 19 Department of Cancer Genetics Cancer Genomic Genome Alterations in Variation Breast Cancer
“Germ-line and somatic genetic and epigenetic “Exploring inter- and intra-tumor heterogeneity to variants in cancer and pharmacogenomics” improve molecular classification of breast cancer”
Group leader: Vessela Kristensen Group leader: Hege G. Russnes
ABOUT of ER-negative breast cancer (Nature Genetics) as high- ABOUT AIMS The group at ICR hosts two project groups, lead by lighted in CNN and other media world-wide. The group was founded January 2018 and have a total of Our group aims at defining, refining and implementing two senior scientists, and consists of 4 postdocs, 2 PhD • Genomic instability. We observed a systemic shift in 2 scientists, 1 postdoc, 3 research engineers, one MD-PhD molecular classification and biomarker analyses to students, 2 MSc students, 2 research technologists genomic aberrations in a time series analysis of neoad- student and one MSc student. In addition, 1 prof. emerita improve stratification of breast cancer patients into and 1 ERASMUS student in 2018. Two other postdocs juvant chemotherapy and bevacizumab-treated breast (A-L Børresen-Dale, UiO), 1 researcher (group leader treatment relevant groups. We are addressing the impact are shared with other groups at the Department and carcinomas (published in Genome Medicine) A. Matheliér, NCMM), 1 oncologist (L. Ottestad) and 1 of inter- and intra-tumor heterogeneity as well as host Institute. Vessela Kristensen is a professor I at the • DNA methylation at enhancers was identified in professor in bioinformatics (O. C. Lingjærde, UiO) are response on disease progression, response to therapy Faculty of Medicine, UiO, and works towards intensive distinct breast cancer lineages (Published in Nature associated with the group (part-time). and patient outcome. and fruitful collaboration between ICR and University communications) Focus of the group is to reach a more fundamental of Oslo, where she also leads a group of 3 postdocs, 2 • Data integration: Integrative Genome-wide character- understanding of the biological dynamics of breast PROJECTS PhD students, 1 MSc and 1 research technologist. Group ization of the human disease landscape (published in cancer through high-throughput molecular analyses of • Somatic Genetics of Breast Cancer, from single genes members work closely together and in collaboration with Cell Systems) DNA, mRNA, miRNA and protein, both at diagnosis and to whole genome sequencing breast clinicians, pathologists and oncologists. • Non-canonical transcriptomes: Wide-spread alterna- during disease progression. • Single-level and multi-level data analyses of DNA/ tive exon usage was identified in clinically distinct As partners in several clinic trials we perform “state RNA/protein/metabolic alterations of primary tumors AIMS subtypes of BC (published in Scientific Reports) of the art” analyses of patient material, both on bulk and metastases at various stages of the disease to The Cancer Genome Variation group is working to • Immune signaling: Bioinformatic approaches to profile tumors, single cells and liquid biopsies, at various stages improve classification of breast cancer understand how genetic variation affects occurrence the tumor microenvironment in association with dis- of the disease. The group is active in the IMI/EU funded • Intra tumor heterogeneity of somatic alterations, gene expression patterns and ease progression, ER activity, genomic complexity and project CancerID aiming at standardizing liquid biopsies • Liquid biopsies; cell-free tumor DNA in blood, genome wide copy number alterations in human age (Publications in OncoImmunology, highlight in New for cancer diagnostics. Hege G. Russnes is also senior circulating tumor cells (CTCs) and disseminated tumor tumours http://ous-research.no/kristensen/ England J Medicine and others). consultant at Dept. of Pathology, OUS where she is cells (DTCs) scientific head of “Unit for translational Oncopathology”, • Prediction of early vs. late relapse of breast cancer PROJECTS RECENT ACHIEVEMENTS a lab performing molecular diagnostics for clinical trials. Together with our collaborative network we are part of Publication activity. 20 publications in 2018, 1 book She is also appointed “Young Associated Investigator” at RECENT ACHIEVEMENTS Convergence grant from UiO-Life Science (Personalised chapter. NCMM (Centre for Molecular Medicine Norway). • 5 original publications in 2018 (affiliated members had Patient Care, PerCaThe) and we are member of the 24 publications in addition) TRANSCAN EpiMark EU network. Projects: • One master thesis completed and defended • Genome variation: In the breast cancer association consortium we identified 65 new breast cancer risk loci (published in Nature) and ten variants - with risk
20 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 21 Department of
Cancer Immunology
“Our goal is to Headed by Johanna Olweus improve cancer diagnostics and ABOUT • Therapeutics, by therapy through The Department of Cancer Immunology (DCI) consists of – genetically engineered T and NK cells cutting edge re- five research groups (Olweus, Taskén, Sioud, Myklebust, – immune priming with siRNA and antigen-targeting Malmberg) and one project group (Kyte). Four DCI to DC search on tumor members are full professors at the University of Oslo. – genetically engineered human antibodies and lytic immunology and Groups at the DCI are partners of two K.G. Jebsen Centers peptides (Cancer Immunotherapy and B-cell malignancies) – cell therapy across HLA barriers to overcome lymphocyte biology” and several EU-funded research programs in cancer immune tolerance immunotherapy. The groups provide complementary – clinical trials using experimental immunotherapy expertise in molecular and cellular immunology, – small molecules including a broad experimental tool-box for antigen discovery and studies of immune cells at the single cell RECENT ACHIEVEMENTS (2018) level. The aim is to decipher the molecular regulation • 20 publications; 11 with first/last authors from DCI of key cellular components of the innate and adaptive (mean IF 7,8) immune system, including dendritic cells (DC), B cells, • 5 filed DOFIs and one granted patent on technology to T cells, regulatory T cells (Treg) and NK cells. The identify T cell receptors key driving force is to develop better tools for cancer • 5 PhD degrees diagnostics and new therapeutic strategies. The latter • Renewed 2-year collaborative agreement with Fate include investigator-initiated clinical trials to alleviate Therapeutics to develop off-the-shelf NK cell thera- immune suppression and improve the use of checkpoint py. Licensed pending patent concerning a method for inhibition, and the design of gene-edited T- and NK cells selective expansion of educated NK cells. for adoptive cell therapy. Clinical trials: PROJECTS: • Reported the first Phase I/II clinical trial based on • Lymphocyte biology, by deciphering transfer of allogeneic NK cells to patients with high- – ontogeny and function of B, T and NK cells risk AML and MDS (Björklund et al., Clinical Cancer – tumor heterogeneity (signaling and mutanome) Research 2018) – immune cell recognition elements (antigen • Recruited first 100 patients to the ASAC trial that exam- discovery) ines the effect of reversing prostaglandin E2-mediated • Biomarkers, by profiling of inhibition of tumor immunity in patients with metastat- – lymphocyte repertoires ic colorectal cancer by the end of 2018 (www.asac.no) – the tumor and its microenvironment – T-cell receptors and humoral immunity
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 23 Department of Cancer Immunology Experimental NK Cell Immunotherapy Biology and Cell Therapy
“Our focus is to develop new strategies for T-cell based immunotherapy” “Towards the next generation NK cell therapy”
Group leader: Johanna Olweus Group leader: Karl-Johan Malmberg
ABOUT Strategy 2 ABOUT RECENT ACHIEVEMENTS The group counts 16 members (F/M 60/40); 1 full • A novel TCR reactive to a recurrent mutation occur- The Malmberg Lab in Oslo counts 12 members (F/M: • Reported the first Phase I/II clinical trial based on professor (JO), 6 postdocs, 6 PhD students and 2.5 ring in 7% of patients with Acute Myeloid Leukemia 7/5); 1 full professor (KJM), 1 scientist, 1 project manager, transfer of allogeneic NK cells to patients with high- engineers, and two associated clinicians. Three members was discovered and characterized 2 postdocs, 6 PhD students, 2 engineers. Malmberg risk AML and MDS. (Björklund et al., Clinical Cancer have MD background. Twelve members are recruited • Tumor-reactive T cells in biobanked material from is a visiting Professor at the Karolinska Institute (KI) Research 2018). from abroad. The group is partner of a K.G. Jebsen patients responding to immunotherapy were sorted and a partner in the K.G. Jebsen Center for Cancer • Defined a method for selective expansion of adaptive Centers (2013-); “Cancer Immunotherapy (JCIT)”. for single cell T-cell receptor sequencing using our Immunotherapy. Affiliated to the group is a Project NK cells and showed their efficacy against acute leu- Olweus is Director of JCIT, which was awarded maximal recently established platform (Lymvac II trial) group in Translational Cancer Immunotherapy led by kemia and as a platform for CAR engineering. (Cancer prolongation in 2016 (two years), till 2020. • A patient-derived xenograft model for Acute Myeloid Jon-Amund Kyte. Immunology Research 2018). Leukemia was established in collaboration with Karo- • Identified Bim splicing as an important regulator or Aims: To find new immunotherapeutic T-cell based linska Institute AIMS IL-15 addiction in NK cells, with implications for cell strategies that overcome the major challenge of self- The group seeks to develop new strategies for cell- therapy (Journal of Immunology 2019). tolerance in cancer, and couple clinical trials with Recent achievements (2018-): Described a technology based immunotherapy based on insights into the • Described a role for lysosomal remodeling in tuning penetrating mechanistic analyses. Two principally for identification of neoantigen specific T cells from functional regulation of natural killer (NK) cells. We use NK cell function (Nature Communications, 2019). distinct approaches are pursued in an interdisciplinary healthy donors (Ali/Foldvari/Giannakopoulou et a combination of single-cell assays, including live cell • Innovation: Main inventor of a pending patent con- and translational program: al, Nature Protocols in press, 2019). Patent granted on imaging, high-dimensional immune profiling by mass cerning a method for selective expansion of educated Strategy 1: Use of T cell-based alloreactivity to target self- technology for identification of specific T-cell receptors cytometry, flow cytometry and RNA-seq to decipher NK cells. Licensed to Fate Therapeutics Inc. January antigens. (WO 2015/071763A2). The research group continued the cellular and molecular mechanisms involved in 2018. A clinical trial exploring this concept will be Strategy 2: Identification and targeting of cancer-specific their research collaboration with biotech company calibration of effector function in human NK cells. The launched during 2019. “Modulation of function of neo-antigens. Kite Pharma (acquired by Gilead) on development of Kyte group aims to develop new combinations of check immune effector cells”. A PCT application describing T-cell receptors to target cancer. One PhD student point inhibition and CAR-engineering. the use of agents to altered signalling from secretory PROJECTS graduated and two DOFIs were accepted by Inven2. granules was filed 25 September 2017. Strategy 1 Olweus was invited speaker at a large number of PROJECTS • Renewed a 2-year collaborative agreement with Fate • Several novel TCRs targeting self-antigens were international conferences in 2018, including the Nobel 1) Diversification of human NK cell repertoires in health Therapeutics to develop off-the-shelf NK cell therapy. discovered and characterized, and two DOFIs were Forum, European Congress in Immunology, Keystone and disease accepted by Inven2 Symposium (Colorado) and 2nd International NTNU 2) Cell therapy with iPSC-derived NK cells Symposium on biomarkers in cancer.
24 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 25 Department of Cancer Immunology Lymphoma Immunomodulation Biology and Targeted Therapies
“Understanding B-cell lymphoma biology to identify “Our goal is to develop novel biological therapies new therapeutic targets and treatment strategies” and biomarkers to improve cancer treatment”
Group leader: June Helen Myklebust Group leader: Mouldy Sioud
ABOUT • Clonal evolution and recurrent mutations associated ABOUT AIMS The group counts 13 members with research background with therapy relapse The group consists of 6.5 members, including 1.5 Our aim is to develop antibodies and peptides for use in in medicine, biology and biotechnology, and includes one • Functional characterization of recurrent driver muta- postdocs, 1 research assistant, 1 PhD student, 2 master cancer therapy, and to fingerprint immune responses professor/assistant group leader (Erlend B. Smeland), tions students and the group leader (DEA Pharm, PhD) with in patients with the aim to uncover new serological 1 associate professor (JHM), 1 scientist (Kanutte Huse, • Novel targets for immune checkpoint blockade formal research experience in immunology, molecular/ markers associated with disease activity. 50% research and 50% at Flow Cytometry core facility), • Cancer sensitivity drug screen and preclinical testing cell biology, microbiology, and medicine. Sioud is a 5.5 postdocs, 1 postdoc located at MGH/Broad Institute, • Clinical register studies visiting professor at University of Tunis. The group is a PROJECTS Boston (Jillian Wise), 2 PhD students and 1 technician. part of the OUS-focus area cancer immunotherapy and • Analysis of cancer cell surface proteome changes Five members have MD background and four members RECENT ACHIEVEMENTS H2020 NANO-D-SIRE consortium. Research in the group using high-throughput display technologies are recruited from abroad (USA, China, Macedonia, We identified the co-inhibitory receptor TIGIT as a is focused on (i) fingerprinting the changes in cancer • Development of antibodies and peptides for cancer Sweden). The group is part of KG Jebsen Centre for B-cell potential new target for immune checkpoint blockade in cell surface and patient sera using high-throughput immunotherapy malignancies (JHM is co-director). B-cell lymphoma (Josefsson, Clin Cancer Res 2018 and display technologies, and (ii) the development of targeted • Fingerprinting immune responses Cancer Immunol Res 2019), and that the malaria drug immunotherapies. • RNAi and CRISPR as immune modulators AIMS Artesunate had potent anti-lymphoma activity (Våtsveen, The group performs translational studies in B-cell J Hematol Oncol 2018). The group collaborated with OUS In addition to several breakthrough findings (e.g., Sioud RECENT ACHIEVEMENTS lymphoma to define clonal evolution patterns, cancer clinicians to validate a prognostic assay for identification & Sørensen 1998, Nature Biotech), our previous studies • 5 publications, including a 15 pages long paper pub- driver genes, actionable targets and new targets for of high risk mantle cell lymphoma patients (Holte, Br J uncovered the mechanisms responsible of RNA sensing lished in the well-known FASEB J. It describes the immunotherapy. Haematol 2018), and demonstrated that chemotherapy- by immune cells and gene regulation by endogenous development of a new human monoclonal antibody for free initial treatment of advanced indolent lymphoma antisense transcripts (Røsok & Sioud 2004, Nature Biotech; universal use in cancer immunotherapy. PROJECTS had durable effect with low toxicity (Lockmer, J Clin Sioud 2006, Nature Biotech; Sioud 2006, Trends Mol Med). • New targeted lytic peptides against macrophages and We apply whole exome and RNA sequencing, high- Oncol 2018). Three PhD students graduated in 2018: With respect to clinical translation, we engineered malignant cells (manuscript submitted). dimensional flow cytometry/mass cytometry and mass Chloé B. Steen, Lise K. Bollum and Sarah E. Josefsson. the first siRNA-modified dendritic cell cancer vaccine • A book on RNAi and CRISPR technologies to be pub- cytometry imaging to characterize tumor cells and that is available to patients under compassionate use. lished by Springer Nature. intratumor immune cells from patient biopsies. We also This immunogenic vaccine demonstrated promising use CRISPR/Cas9 genomic editing and have established responses in cancer patients (Sioud 2019, Cancers). To date, the group has published 188 peer-reviewed patient-derived xenograft (PDX) mouse models for pre- original articles (mean IF = 5.865) and reviews, with 1st clinical drug testing. Ongoing projects are: and/or last authorship on 85% of the papers.
26 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 27 Department of Cancer Immunology Cell Signalling and Immune Regulation
“We want to perturb tumor immune evasion mechanisms to boost anti-tumor immunity”
Group leader: Kjetil Taskén
ABOUT • Cancer drug sensitivity screening in Chronic Lympho- The group relocated from NCMM and joined the cytic Leukemia and Multiple Myeloma Department of Cancer Immunology in 2018. In 2018 • Acetyl Salicylic Acid Intervention study in metastatic the group counted 17 members (F/M: 9/8), 1 senior colorectal cancer (ASAC) consultant, 2 researchers, 9 postdocs, 1 PhD student, 2 technicians and 1 M.Sc. student in addition to the RECENT ACHIEVEMENTS PI. The group is part of K.G. Jebsen Center for Cancer Highlights include winning a major grant from the RCN Immunotherapy and K.G. Jebsen Centre for B Cell Biotek2021 Digital Life Norway programme for a new Malignancies. systems pharmacology project to model on our data from CDSS to see if we can predict drug combinations AIMS that will synergize in a precision medicine approach (PIs The Taskén group aims to understand intracellular Taskén, Enserink, Frigessi, OUH/UiO). This is a pending signalling networks, their anchoring and localization research question and important to make the best use of through scaffold proteins, how these signalling the patient sample for patient benefit as we cannot test networks mediate physiological and pathophysiological all combinations. processes and can be perturbed using drug-like small Another highlight and milestone included molecules. We aim to understand tumor immune evasion the establishment of a new company SERCA strategies, and how we can perturb such strategies to Pharmaceuticals by Inven2 based on an innovation boost anti-tumor immunity. We proceed with cancer project in my lab that has been running for 10 years drug sensitivity screening (CDSS) to explore individual where we have developed small molecule PPI disruptors drug responsiveness and resistance patterns in patient with application in ischemia reperfusion injury. cancer cells and aiming to develop models to assist Publication highlights include papers in Oncotarget and individualised clinical decisions in precision medicine in Sci. Rep. on CLL patients from our precision medicine oncology and haematology. programme, in J. Immunol. (Jan. 2019) on regulatory T cells and tumor immune suppression in CLL by PROJECTS idelalisib and on signalling complexes in Mol. Biol. Cell. • T cell function in cancer and immune-related diseases Furthermore, in co-authored papers we have contributed • Identification of regulatory T cell targets that can be to understanding the autoimmune phenotype of patients perturbed to reverse tumor immune suppression with CTLA4 deficiency (JACI 2018) and metabolic • Role of Prostaglandin E2, cAMP and AKAPs in signal- regulatory programmes for aerobic glycolysis (Nature, ing and regulation of T cell function Jan 2019). • Targeting the cAMP signalling pathway for cancer immunotherapy
28 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 29 Department of Molecular Cell Biology
Headed by Harald Stenmark
“Uncovering The department has a staff of 78 and hosts 4 research exosome secretion and biomarkers for prostate cancer. In the cellular groups (Enserink, Rusten, Sandvig and Stenmark), 10 general, the department’s groups have been successful in basis of cancer project groups, and a departmental service unit. Research obtaining national and international external funding. in the department comprises various aspects of cancer development” relevant cell biology, including membrane traffic, cell Three of the groups of the department (Stenmark, Rusten signaling, cell metabolism and cell division. In addition, and Enserink) are members of a Norwegian Centre the department carries out biotechnological research on of Excellence, Centre for Cancer Cell Reprogramming nanoparticles and translational research on leukemia (CanCell), which is led by Harald Stenmark. Kirsten drug sensitivity and cancer derived exosome biomarkers. Sandvig has been heading a national project on Biodegradable Nanoparticles in Cancer Diagnosis and A common goal for researchers in the department is Therapy, which ends in April 2019. Harald Stenmark to uncover novel molecular mechanisms that control heads the Norwegian Advanced Light Microscopy cellular functions related to cancer. The department’s Infrastructure Network, NALMIN. Stenmark is also research strategy is to combine molecular cell member of a Convergence Environment under UiO Life biology with biochemistry, genetics, drug screening Science, called “Programmable cell-like compartments”. and advanced imaging in order to address relevant Jorrit Enserink participates in a new project under the scientific questions. Recent key achievements from the Norwegian Centre for Digital Life, called “Pipeline for department’s scientists include studies on autophagy and individually tailoring new treatmets in hematological tumor growth, growth factor signaling and intracellular cancers”. transport, molecular mechanisms of cell division,
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 31 Department of Molecular Cell Biology Cellular Cancer Membrane Molecular Dynamics Medicine
“Understanding how remodelling of cellular “Identifying weak points in the molecular networks membranes contributes to cancer” that drive cancer”
Group leader: Harald Stenmark Group leader: Jorrit Enserink
ABOUT ABOUT PROJECTS The group studies the dynamics of cellular membranes RECENT ACHIEVEMENTS The group, which started recently at the Institute for • High-throughput drug combination screens to identi- with the aim of understanding their relevance to cancer. • Establishment of protein dynamics during endosomal Cancer Research (November 2016), currently consists fy drug synergies and to reveal correlations between Cellular membrane dynamics processes studied by the downregulation of growth factor receptors (Wenzel et of one group leader (with 20% professorship at driver mutations and drug sensitivity profiles group include endocytosis, autophagy, and cell division. al., Nature Communications 2018). Department of Molecular Biosciences), two externally • Development of novel immune therapy for AML The group employs advanced molecular biology methods • Identification of a novel molecular mechanism for funded senior scientists, seven post-docs, one clinician • Modeling of leukemia in fruit flies to better understand in combination with biochemistry and advanced light controlling positioning of the mitotic spindle (Malerød in a 20% post-doc position, two PhD students, five MSc the genetic networks that drive AML and electron microscopy technologies. As model systems et al., EMBO Journal 2018) students and one Erasmus student. A large fraction of • Genome-wide CRISPR-Cas9 screens in leukemic cells the group uses cell cultures, cell invasion models, • Identification of a novel molecular mechanism for the group consists of scientists from abroad , including to identify novel mechanisms of resistance to tyrosine organoid models, and fruit flies. repair of damaged lysosomes (Radulovic et al., EMBO the Netherlands, Austria, Spain, Colombia and the UK. kinase inhibitors The group has 34 members from 12 nations and is Journal 2018) The group is mainly focused on basic cancer biology • Cellular responses to nutrient stress; particularly the headed by Harald Stenmark (group leader) and Camilla • An Advanced Grant from the European Research and personalized medicine, using a wide range of identification of the upstream pathways that control Raiborg (assistant group leader). Its 6 project groups are Council (2.5 MEUR) was awarded on the project “Co- models such as budding yeast, fruit flies and zebrafish, the dynamics of autophagy led by Andreas Brech, Kaisa Haglund, Camilla Raiborg, incidence detection of proteins and lipids in regula- human and mouse cell lines, and primary human cancer Kay O. Schink, Eva Wenzel, and Antoni Wiedlocha. tion of cellular membrane dynamics”, led by Harald samples. RECENT ACHIEVEMENTS Stenmark. • Dr. Helene Knævelsrud, a senior researcher in the AIMS • Project leader Kaisa Haglund obtained research grants AIMS group, was elected to the Young Academy of Sciences. The principal aim of the group is to understand how from both the Norwegian Cancer Society and the Research is aimed at understanding cancer cell biology, • The group is a founding member of the Norwegian membrane dynamics contribute to tumour suppression and Research Council of Norway in 2018. She was also with the ultimate goal of developing precise cancer Center of Excellence “CanCell”, which was awarded in how their dysfunction may promote cancer development. awarded Ragnar Mørk’s Prize 2018 for excellent cancer treatments. A major focus is on hematopoietic cancers, 2017. research. including –but not limited to– Acute Myeloid Leukemia • Funding obtained: Two research grants (one of which PROJECTS • Assistant group leader Camilla Raiborg obtained a re- (AML). A second research theme is to better understand awarded to Ignacio Garcia, a senior researcher in the • Phosphoinositides in regulation of membrane dynamics search grant from the Norwegian Cancer Society in 2018. cellular responses to sudden environmental changes. group) and one innovation grant from The South-East- • Mechanisms of autophagy and lipid droplet biogene- • PhD student Anette Lie Jensen was awarded the “best ern Health Authorities, as well as funding within the sis, and their role in cell metabolism short talk” award at the Biochemical Society confer- Center for Digital Life funded by the Norwegian Re- • Membrane dynamics in cell invasion and metastasis ence “New horizons in ESCRT biology” in London search Council (together with Prof K. Tasken and Prof • Centrosome dynamics in cancer 17-20 April 2018. A Frigessi). • Cytokinesis in development and carcinogenesis • Members of the group published 12 original papers • The group published three articles, including one in • The b-catenin destruction complex in physiology and and 2 reviews in 2018. the journal Cell. Two MSc degrees were completed. cancer • Membrane dynamics in promotion of genome integrity
32 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 33 Department of Molecular Cell Biology Tumor-host Intracellular Biology Transport
“Tumor-host interactions during cancer progression” “All the way from basic research to translation”
Group leader: Tor Erik Rusten Group leader: Kirsten Sandvig
ABOUT AIMS ABOUT AIMS The research group counts 12 members representing The principal aim is to understand tumor-host Sandvig’s group, counting 16 members, is interested in The projects aim at increasing our knowledge about 8 nationalities in 2019 (Finland, India, Ireland, Iran, interactions that facilitate carcinogenesis in order to the mechanisms of endocytosis, intracellular transport intracellular transport, nanoparticles, and biomarkers in Germany, Hungary, France, and Norway): 1 group leader, uncover novel ways to intercept cancer. and secretion. Uptake of receptors and ligands and order to provide a rational basis for diagnosis, treatment 2 scientists, 4 postdocs and 1 PhD student, 1 technician correct intracellular sorting of endocytosed molecules and prevention of cancer. and 3 master students. PROJECTS are crucial for maintenance of a normal differentiated Cancer can be viewed as animal development • Oncogene-induced epithelial disintegration and invasion. phenotype. In some studies we are using protein PROJECTS derailed. Our overarching interest is to understand the • Tumor-microenvironment interactions and growth toxins such as ricin and Shiga toxin, which are well • Characterization of intracellular transport mechanisms by which tumor and host cells mutually support. established as markers for studies of membrane traffic, • Biodegradable nanoparticles in cancer diagnosis and engage each other in reciprocal interactions to facilitate • Mechanisms of cancer cachexia. and which can be used as agents in cancer diagnosis therapy carcinogenesis. These interactions occur locally in the • Roles of autophagy in metabolic reprogramming, and therapy. Our expertise is also applied to investigate • Exosomes and prostate cancer tumor microenvironment, but also systemically causing nutrient mobilization and breakdown of muscle and uptake of nanoparticles, and in 2013 we obtained a organ dysfunction such as in cancer cachexia - the adipose tissue during Cancer Cachexia. grant from the Norwegian Research Council to build RECENT ACHIEVEMENTS: catastrophic wasting of muscle and adipose tissue. We national competence in nanomedicine. This project, • Mechanistic studies of different types of endocytosis believe that studying these processes can uncover new RECENT ACHIEVEMENTS “Biodegradable nanoparticles in cancer diagnosis and and intracellular transport. ways to intercept carcinogenesis. • Discovery that malignant tumors induce a stress re- therapy”, headed by Sandvig, involves collaboration • Further studies of exosome biogenesis and release, as To mechanistically probe how tumor cells and non- sponse in the tumor microenvironment that supports with ten other Norwegian groups working in academia, well as biomarkers for prostate cancer. tumor cells and organs communicate to foster tumor tumor growth through nutrient-generating autophagy research institutes, hospitals and industry, and runs • Investigations of cytotoxic effects of different types of growth and cause cancer cachexia we develop novel (Katheder, N.S., et al, Nature 2017). until March 2019. The Sandvig group is also involved in nanoparticles with and without drugs in vitro and in vivo. genetic tools in Drosophila. These tools will allow us to • The tumor suppressor LKB1,responsible for the Peu- an INNO INDIGO granted project, which started April • In 2018 the group published on all these topics; 6 arti- selectively and independently manipulate tumor and tz-Jegher cancer syndrome, is controlled by endocytic 2016. INNO INDIGO is an innovation-driven initiative for cles in different journals and 2 articles in the biology either tumor microenvironment or somatic organs in vivo. vesicle trafficking and its derailment contributes to the development and integration of Indian and European preprint server bioRxiv. Concerning innovations, see We investigate the molecular genetic mechanisms and tumor growth (O´Farrell, F. et al, Nature Cell Biology, 2017). research. We also characterize exosomes from prostate separate paragraph. cell biology of genetically defined experimental tumor- • Former PhD student Nadja Katheder was awarded cancer cells and patients with the goal of detecting lipid, host interactions using a mix of human cell culture H.M. the King’s gold medal for best PhD thesis in 2018. RNA and protein biomarkers. Our research spans all and the fruit fly Drosophila melanogaster, as an animal • Tor Erik Rusten obtained a “Toppforsk” grant from the the way from basic to translational medicine, including model system. In this work we employ a wide array of Research Council in 2018. innovation. The work published by the Sandvig group techniques and collaborate with experts in cell biology, is well cited, and Sandvig’s H-index is now 72 (~330 genetics, imaging, electron microscopy, tumor biology, publications). The group has extensive national and metabolism, bioinformatics and clinical cancer cachexia international collaboration. in order to survey, measure and mechanistically understand these complex aspects of cancer biology.
34 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 35 Department of Molecular Oncology
Headed by Ragnhild A. Lothe ”Biological discoveries for precision cancer medicine” As a research department within the Oslo University on MPNST, the European network for study on Hospital (OUH) Comprehensive Cancer Centre, it is our Cholangiocarcinoma, the Global Testicular Cancer responsibility and goal to accomplish high quality and Consortium, and Cooperation Studies on Colorectal interdisciplinary biomedical research for improved Cancer (COST action). precision medicine and management of cancer patients. Our main research programs are devoted to colorectal In 2018, we published 19 papers including the following cancer and prostate cancer, and we have a longstanding prime journals: Ann Intern Med, Ann Oncol (2), Cell, Clin project portfolio also on other solid tumor types. Our Cancer Res, Eur Urol (2), Sem Cancer Biol. expertise in biomedical research spans several disciplines During the past 3-years, scientists affiliated with our from cell biology to translational research, including department have published 69 scientific papers, with st1 also active partnerships in clinical studies, and we have and/or last authorships on 54% and with a mean IF of a broad range of advanced technologies and analytical 7.1. Five PhD and 9 MSc students with main supervisors tools established in-lab. The department scientists from the department received their academic degrees are inventors of several biomedical patents and active during 2016-2018. The innovation projects have been innovation projects. granted funding from U of Oslo, the Health Region and Research Council, and we were granted 4 patents, 2 PCT The department host three research groups (38 applications and 2 priority applications in the period. employees in total) and the group leaders are adjunct professors at the University of Oslo. The scientists in the Our main research goals for the next three to five years department are devoted to teaching and supervision, are three-fold, (i) to decipher spatio-temporal tumor and 58 MSc/PhD degrees with supervisors from our heterogeneity in colorectal cancer and prostate cancer, department have successfully been completed since the (ii) to monitor minimal residual disease, early recurrence inauguration of the department in 2006. and clonal evolution by analyses of repeated liquid biopsies and tumor samples, and (iii) to predict treatment Members in the research groups are partners of the response in translational studies and within clinical trials K. G. Jebsen Colorectal Cancer Research Centre, the by a combination of genomics and ex vivo drug screening OUH priority area for colorectal cancer, the Norwegian of tumor cell-derived organoid cultures. Cancer Genomics Consortium, and several international networks including a European multicenter study
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 37 Department of Molecular Oncology Genetics Epigenetics
“Genomics – irreversible mistakes in cancer and a “Epigenomics – reversible changes in cancer and source for clinical biomarkers” a source for clinical biomarkers”
Group leader: Ragnhild A. Lothe Group leader: Guro E. Lind
ABOUT splicing expands the prognostic value of KRAS beyond ABOUT RECENT ACHIEVEMENTS Our main research program involves translational mutation status in early stage CRC, highlighting In the group of Epigenetics we are studying DNA Using methylome sequencing in combination with studies of primary and metastatic colorectal cancers molecular heterogeneity in the clinically relevant KRAS methylation alterations by integrating genome- standardized digital PCR technology, we have identified (CRC), using genomics, drug screening, digital pathology wild-type subgroup (Eilertsen et al., Int J Ca 2019). wide methylome data with detailed candidate gene novel DNA methylation biomarkers for non-invasive and functional analyses. The group has 22 employees From analyses of ~2000 CRC samples and preclinical characterization. The research is performed across monitoring of bladder cancer. The biomarker panel (group leader, 7 scientists/ postdocs, 9 PhD students, models we identified the long non-coding RNA MIR31HG cancer types, with a main focus on colorectal and achieves an outstanding accuracy in urine from bladder 5 research assistants/engineers) and 2 current MSc as a bona fide prognostic marker in CRC, providing urological cancer. In 2018 the group counted ten cancer patients and healthy controls. Blinded validation students, and includes two project groups in Cell clinical stratification beyond the major gene expression members, including three postdocs, two PhD student, has been initiated in an international prospective urine- signaling and Computational oncology. phenotypes, and with prognostic value independent of two engineers, two MSc students and the group leader. series. The pilot reveals a perfect classification of cancers tumor immune and stromal cell infiltration (Eide et al., and controls. Both the biomarkers and the optimized AIM Int J Ca 2018). CDX2 is an emerging prognostic biomarker AIMS technology have been protected by patent applications. Our overarching goal is to translate novel biomedical with implications also for the decision to treat early- 1) To identify epigenetic biomarkers with clinical impact, The PhD of Pharo, covering parts of this work, is knowledge into improved patient stratification and stage CRCs with adjuvant chemotherapy. Our analyses including markers for early detection and monitoring awaiting defense. treatment of CRC. indicate that its prognostic impact is greatest in late stage of cancer. disease, and drug screen data of 69 chemotherapeutics in 2) To analyze and understand the underlying biology To evaluate the biomarker accuracy for detecting PROJECTS preclinical models support also a predictive potential for of these aberrations and how they affect the cancer recurrence of bladder cancer, we are, in collaboration • Prognostic and predictive biomarkers (CRC and response to such standard therapies (Bruun et al., Mol development. with the Wahlqvist team at Aker, following 50 post- malignant peripheral nerve sheet tumors, MPNST) Oncol 2018). Finally, pharmacogenomic analyses of cell surgery individuals for two years. Recruitment has been • Modeling tumor heterogeneity and clonal evolution in lines and patient-derived xenografts identified HSP90 PROJECTS completed and >half the patients have been followed >1 CRC inhibitors as potent drugs to overcome chemoresistance • Epigenetic subclassification and prognostic markers year. Preliminary data indicate that the urine test is more • Pharmacogenomics of metastatic CRCs using in patients with an aggressive subtype of CRC (Sveen et for colorectal cancer accurate than the routinely used cystoscopy. Presenting patient-derived organoid models al., Clin Cancer Res 2018). We have also written a review • Mechanisms of the DNA methylation machinery the project at the clinical autumn meeting, Lind received • E3 ubiquitin ligases in intercellular communication of the clinical potential of various combination therapies • Methylome-based early detection and monitoring of the NUF* price. The preliminary results have released and CRC pathogenesis with HSP90i against CRC (Kryeziu et al., BBA-Reviews on urological cancers “Klinbeforsk” funding to initiate a prospective national Cancer, 2019). multi-center study evaluating the clinical utility of the RECENT ACHIEVEMENTS In a European multicentre study of MPNST, we test. The group also received funding from the Cancer We have identified new biomarkers and new clinical identified a subgroup of patients with poor prognosis Society and HSØ including a career grant to Jeanmougin. associations of well-known biomarkers in CRC. defined by an aberrant TP53 network (Høland M et al., Addressing the gene expression-based consensus Modern Pathol, 2018). molecular subtypes (CMSs) as a framework, we Peter Andreas Wold Eide defended his PhD “Colorectal *Norsk Urologisk Forening demonstrated that the poor prognostic value of KRAS cancer subtypes and pharmacological sensitivities”, and BRAF mutations is specific to individual subtypes Faculty of Medicine, and May-Britt Five and Sebastian (Smeby et al., Ann Oncol 2018). Furthermore, aberrant Basing completed their MSc degrees, U of Oslo, in 2018.
38 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 39 Department of Molecular Oncology Genome Biology
“Transcriptomics –the expressed genome mistakes and a source for clinical biomarkers”
Group leader: Rolf I. Skotheim
ABOUT RECENT ACHIEVEMENTS The Genome Biology group studies how genomes and During 2018, the group continued the development of transcriptomes are altered in cancer cells by using both a large prostate cancer research program, primarily computational biology and wet-lab based approaches. utilising a biobank resource with multiple frozen Mutation analyses in cancer clearly benefit from tissue cores from multifocal primary prostate cancer. knowing which genes and variants that are actually The first major research paper from this effort was expressed. In this line, the group has particularly published in the prestigious journal European Urology specialized in RNA-level analyses, and the projects with Marthe Løvf as a first author. Here, we performed focus on prostate cancer, although we are also involved the first large in-depth genomic heterogeneity study with projects on testicular and colorectal cancers. An of primary prostate cancer. High-coverage exome interdisciplinary set of competences is required to sequencing of 89 tumor foci from 41 patients and perform meaningful genome-scale cancer research. As demonstrated convincingly that different tumour foci such, personnel in the group have their basic education within the same patient only exceptionally have any across the disciplines of biology, informatics, and somatic gene mutations in common. These results have medicine. Through 2018, the group consisted of eleven major implications for any implementation of gene- members, including one researcher, two postdocs, one based testing in future treatment of prostate cancer engineer, two PhD students, three MSc students, a study patients as information from all tumor foci is necessary nurse and the group leader. to draw valid conclusions about the cancer. The group was also involved in one other important study on AIMS prostate cancer, where Andreas M. Hoff published as The research group aims to improve the diagnosis and shared first author on a study of metastatic castration- management of cancer by utilizing genome technologies. resistant prostate cancer in the journal Cell. This This includes identification and characterization of genes study, originating from the Meyerson lab at the Broad that are critical for development of cancer. Institute, where Hoff recently spent 12 months as a postdoc, investigated the genomic aberrations of the PROJECTS androgen receptor locus and identified a novel tandem • Interfocal heterogeneity of prostate cancer duplication phenotype. The group continued to develop • RNA variation caused by aberrant splicing and as a bioinformatics pipelines for high-throughput sequencing source of cancer biomarkers of DNA and RNA and utilized these in analyses of • Fusion gene identification and characterisation data from several cancer cohorts. In 2018, Eirik Berg Nordheim completed his MSc degree.
40 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 41 Department of Radiation Biology
Headed by Kristian Berg
“Our goal is to develop new The Department has more than 60 employees organized radiation-based treatment regimens with improved predictive methods in 4 research groups and 6 project groups. The research specificity and efficacy towards cancer cells at the department is focused on the biological responses • to develop treatment strategies utilizing non-ionizing and treatment to ionizing and non-ionizing radiation, including radiation combined with photosensitizing agents, strategies for γ-radiation, radiation from radionuclides, ultraviolet either to induce tumour cell kill directly or via radiation, visible light as well as proton therapy. internalization of therapeutic or sensitizing agents improved Our department is actively engaged in revealing the mechanisms involved in DNA repair, cell-cycle KEY ACHIEVEMENTS THE LAST 3-4 YEARS INCLUDE radiation therapy” regulation, genomic instability and immune responses • Pancreatic carcinoma xenografts treated with sunitinib after radiation, the impact of hypoxia on the radiation show less abnormal microvessels but larger hypoxic response and predictive markers for the outcome of regions after treatment than before treatment. radiotherapy of cancer patients. The department is • Cervical cancer patients with tumors showing high also involved in delivering radionuclides to cancer hypoxic fraction in combination with high interstitial tissue. Another research area is the use of visible fluid pressure have particularly poor prognosis with a light to activate photosensitive compounds that are 5-year survival rate of only 13 %. used for cancer detection and therapy. In that respect • A novel mechanism of activation of the DNA damage a technology has been developed, photochemical kinase ATR (Ataxia Telangiectasia and Rad3-related) internalization (PCI), which enables site-directed was identified intracellular delivery of anticancer therapeutics. Both • PCI has been found efficient as a methodology to PCI and ionizing radiation induce reactive oxygen enhance antigen presentation during anti-cancer species as a part of their mechanism of action. Our vaccination. Several new recombinant targeted protein vision is to develop a radiobiological understanding toxins have been developed and are under preclinical of response to ionizing and non-ionizing radiation on evaluation. A phase I clinical trial documenting the the molecular, cellular and physiological level, and to safety and efficacy of PCI has been published in Lancer utilize this knowledge to design new strategies for the Oncology treatment of cancer. Our research strategy involves • A production unit for biomolecular therapeutics has basic radiobiological research, translational and clinical been established studies. • A new method to image hypoxia in prostate cancer based on integration of images reflecting oxygen con- OUR GOALS ARE sumption and supply has been developed • to understand the molecular and physiological • We gained important new knowledge about the regula- mechanisms behind tumour response to radiation, tion of translation in response to cellular stress as well and to develop predictive methods and treatment as about the function of the stress-response kinase strategies GCN2 in human cells • to utilize acquired knowledge to establish new
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 43 Department of Radiation biology Photochemical Clinical Internalization Radiation Biology
“Our goal is to develop and optimize the PCI “Our goal is to discover biomarkers and molecular technology for treatment of solid cancers” targets for combination therapies with radiation”
Group leader: Kristian Berg Group leader: Heidi Lyng
ABOUT PROJECTS ABOUT PROJECTS Group members: 22, including 5 researchers, 3 postdocs, • Design and development of recombinant immunotox- Group members: 10, including one researcher, four • Genetic alterations and chemo-radioresistance in 4 PhD students, 7 technical positions and 3 MSc students, ins for activation by PCI postdocs, three PhD students, and two technicians. cervical cancer including the project groups of Asta Juzeniene, Pål • Light-controlled delivery of cancer immunotherapeu- • Molecular hypoxia biomarkers in cervical and prostate Kristian Selbo, Anette Weyergang and Theodossis tics including PCI of 1) immunotoxins targeting cancer The focus is to develop molecular biomarkers that can cancer Theodossiou. stem cells (CSCs) and 2) CSC-derived vaccines. identify patients at risk of radiotherapy failure and to • Combined molecular and imaging biomarkers in • Utilize new vehicles for targeted delivery of small mo- find targets for therapeutic intervention in a combined cervical and prostate cancer Project Photochemical Internalization (group leader lecular drugs to endocytic vesicles for activation by PCI radiotherapy regimen. The research projects are run in Berg, project leaders Selbo, Weyergang and Theodossiou): • Evaluation of the vasculature as a target for PCI and close collaboration with medical doctors and physicists RECENT ACHIEVEMENTS Endocytic entrapment is a hurdle for therapeutic further utilize these effects to reach a curative end- at the hospital. The work is based on tumor biopsies In 2018, the group published 3 articles and contributed utilization of macromolecular therapeutics with point and blood samples collected at diagnosis or during to a review article with collaborators in Germany. intracellular targets. Photochemical internalisation • Using mitochondria-powered chemiluminescence to therapy. Whole genome methodology is used, including For the paper Hompland T et al Combined MR imaging (PCI) is a technology for cytosolic release of therapeutic non-invasively treat inaccessible tumours microarray and sequencing techniques, which provides of oxygen consumption and supply reveals tumor hypoxia macromolecules subjected to endocytosis. PCI is invented • Utilizing other radiation sources to induce PCI effects new insight into the disease and enables identification and aggressiveness in prostate cancer patients, which was and developed in our research group and is currently • Targeted alpha radionuclide therapy for bone and vis- of novel biomarkers and drug targets. We also explore published in Cancer Research, we received the OUS evaluated in clinical trials. ceral metastases of osteosarcoma, prostate and breast whether functional tumor images (MRI/PET) can aid the article prize for first half year of 2018. In this paper, cancer translation of the molecular findings into radiotherapy we report a novel method to visualize hypoxia based Project Targeted alpha therapy (project leader Juzeniene): practice. on diagnostic, multiparametric diffusion weighted MR Metastases are the primary cause of death in cancer RECENT ACHIEVEMENTS images that potentially can be translated into clinical patients. Targeted alpha-particle therapy is a promising • Documented the potential of PCI of bleomycin to in- AIMS practice using the hospital’s current state-of-the-art treatment for eradicating micrometastases. duce anti-tumor immunity. • Understand molecular mechanisms behind infrastructure and diagnostic procedures without • Established a biomolecule production unit based on radioresistance of cervical and prostate cancer additional increase in treatment cost. AIMS recombinant technology. • Develop biomarkers and find drug targets for Project Photochemical internalization: • New grants in 2018: FET-OPEN project (Theodossiou), personalized radiotherapy of patients with these The main aim of our group is to develop and optimize the 2nd FET-OPEN of the group; PhD stipend from HSE diseases the PCI technology for treatment of solid cancers with a (Selbo); Project support from Radforsk (Weyergang) curative endpoint. • The following project groups were established in 2018: - Anette Weyergang (project leader): Recombinant Project Radionuclide therapy: Light Activated Therapeutics The main goal is to develop a novel technology with - Pål Kristian Selbo (project leader): Light-controlled potentially broad therapeutic applications for cancer delivery of cancer immunotherapeutics; micrometastases by means of dual targeted alpha - Theodossis Theodossiou (project leader): Protonics particle radiation. • No. of papers in 2018: 11 (1 non peer reviewed) • PhD thesis: 1 • MSc thesis: 1
44 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 45 Department of Radiation biology Radiation Biology Radiation and Tumor Biology and Physiology DNA Damage Signaling
“Our goal is to obtain new knowledge about cellular “Our goal is to identify strategies for personalized responses to radiation and utilize it to improve radiation therapy of cancer” cancer therapy”
Group leader: Einar K. Rofstad Group leader: Randi Syljuåsen
ABOUT PROJECTS ABOUT PROJECTS Group members: 9, including 2 researchers, 4 postdocs, 2 • Clinical MRI of locally-advanced cervical carcinoma Group members: • Pre-clinical exploration of the effects of checkpoint PhD students, and 1 technician. • Preclinical MRI of cervical carcinoma, pancreatic carci- 13.4 including 4.1 researchers, 2 postdocs ,4 PhD students kinase (CHK1, WEE1, ATR) and PARP inhibitors noma, and malignant melanoma and 3.3 technicians. • Functional roles of Protein phosphatase 1 (PP1) The focus of the group is to improve the outcome • Antiangiogenic and antifibrotic treatment of tumors targeting subunits in DNA damage signaling of radiation therapy of cancer. Poor outcome is a • Mechanisms governing the physicochemical microen- In radiotherapy ionizing radiation is used to cause DNA • Identification of drugs that inhibit DNA repair after consequence of radiation resistance and elevated vironment of tumors damage in cancer cells. The DNA damage is rapidly radiation, through flow cytometry-based compound metastatic propensity of the primary tumor, and our sensed and a network of intracellular DNA damage screens research is based on the hypothesis that poor outcome RECENT ACHIEVEMENTS signaling cascades is activated. These signaling cascades • Centrosomal and ciliary proteins in cell cycle is caused primarily by an abnormal physicochemical The group published 5 papers in 2018. Important findings influence whether the cells die or survive, through regulation and genome integrity- roles and targets in tumor microenvironment. Xenografts of human cervical include: regulation of DNA repair, cell cycle checkpoint and cancer etiology, diagnostics and treatment carcinoma, pancreatic carcinoma, and malignant • Pancreatic ductal adenocarcinoma xenografts treat- cell death pathways. Our group works on the border • The role of GCN2 and translational regulation in the melanoma are used as preclinical tumor models. In ed with sunitinib (antiangiogenic agent) show less between basic and translational radiation research. We cell cycle and cellular stress addition to standard molecular biology methods, abnormal microvessels after treatment than before conduct basic projects to identify novel mechanisms important methods include intravital microscopy, treatment, but due to treatment-induced vessel prun- of DNA damage signaling, in addition to more applied RECENT ACHIEVEMENTS: MRI, and probe measurements of physicochemical ing, the overall function of the microvasculature is projects to understand how inhibitors of DNA repair In 2018 totally 8 articles were published (including parameters. impaired after treatment, resulting in increased tumor and checkpoints can be used in an optimized manner articles in press). Members of the group were senior/ hypoxia. for cancer treatment. Three project groups, headed by first authors on 3 of these, published in Nucleic Acids AIMS • Patients with locally advanced cervical cancer with tum- Beata Grallert, Trond Stokke and Sebastian Patzke, are Research, Journal of Cell Science and Scientific Reports. To reach the primary goal, our research is divided into ors showing low hypoxic fraction in combination with members of our group. 4 M.Sc degrees were completed. One new grant was two arms with the following aims: low interstitial fluid pressure have particularly good obtained from the Norwegian Cancer Society. • To develop MRI-based methods that can provide in- prognosis (5-year survival rate of 100 %) whereas those AIMS formation on the physicochemical microenvironment, with tumors showing high hypoxic fraction in combina- • Obtain new knowledge about cellular responses to metastatic propensity, and radiocurability of tumors tion with high interstitial fluid pressure have particular- radiation, with focus on cell cycle checkpoints, DNA • To develop treatment strategies for normalizing the ly poor prognosis (5-year survival rate of 13 %). damage signaling and repair, and explore how such physicochemical microenvironment, decreasing the knowledge can be used to improve radiotherapy. metastatic propensity, and enhancing the radiocura- bility of tumors
46 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 47 Department of Tumor Biology “Preclinical and clinical efforts towards precision oncology”
Headed by Gunhild M. Mælandsmo
The department has four research groups and 56 national project aiming to sequence tumors across nine employees with a common vision to better understand tumor types. All exomes have been sequenced and are the biological mechanisms involved in cancer currently being analyzed. Several papers are now under progression and metastasis. Our strategy is, through publication. basic and translational research in the areas of cancer biology and computational science, to enhance systems NoSarC - Norwegian Sarcoma Consortium, a national understanding and thereby identify novel intervention project aiming to collect a prospective biobank and strategies. We emphasize multidisciplinary competence study disease development and treatment of sarcoma. and collaboration between researchers, clinicians and Exome sequencing is ongoing and preclinical models are patients to stimulate the necessary synergy for improved generated for studies of candidate drugs. Collection of cancer care. samples was successfully completed in 2018. MetAction - Actionable targets in cancer metastasis. A We are performing basic, translational and clinical diagnostic pipeline was established which allowed the research, and our scientific goal is to provide knowledge first clinical trial in Norway where treatment decision is for clinical translation of precision cancer medicine. We based on targeted NGS data. 50 patients were enrolled, will do so by contributing with expertise in genomics and actionable targets detected in 13 and long-term clinical bioinformatics and by utilizing patient samples as model effects where observed in two patients. systems for investigation of therapeutic efficacy. We have MOVEMBER - Identifying biomarkers distinguishing a large collection of patient-derived xenograft models indolent and aggressive prostate cancer. Candidate from different types of human cancer. The models are biomarkers have been identified using Norwegian utilized for biological studies of disease progression, cohorts of serum, urine and tissue, and are currently and for preclinical evaluation of novel drugs and drug undergoing validation in independent national and combinations. international cohorts. The EuroPMP Cost Action – European research network To foster a strong link between translational and clinical in rare cancer pseudomyxoma peritonei was initiated in research we have several researchers holding part-time September 2018. clinical positions. An ambition for the department is to participate in design and conduct of clinical trials, and Other clinical studies with substantial collaborative to provide molecular and bioinformatics competences in research; multidisciplinary tumor boards in the area of precision NeoAva: Bevacizumab in combination with neoadjuvant cancer medicine. chemotherapy in breast cancer (patient inclusion ended) I-BCT: DNA targeted chemotherapy to breast cancer Key achievements over the last 3-4 years include project patients with an aggressive phenotype leader responsibilities in large collaborative projects in ImmunoPeCa: Immunotoxin in Peritoneal Carcinomatosis the area of precision cancer medicine: Biobank Norway - a national initiative to coordinate NCGC - The Norwegian Cancer Genomics Consortium, a biobank activities for research purposes)
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 49 Department of Tumor biology Metastasis Translational Biology and Cancer Therapy Experimental Therapeutics
“Context-induced cellular plasticity - the route to resistance and metastasis” “New treatment for metastatic colorectal cancer”
Group leader: Gunhild M. Mælandsmo Group leader: leader Kjersti Flatmark
ABOUT 2. Preclinical research investigating novel drugs and ABOUT genomics, microRNA, mRNA, and immune cell Employees: The group has 20 members with drug combinations In 2018, the Translational Cancer Therapy group analysis, participation in the BigMed project) multidisciplinary background and expertise (cell- and • Mechanistic studies and assessment of treatment comprised 16 members (including part-time employees - Novel drugs and therapeutic concepts in models of molecular biologists, medical doctors, physicists, efficacy in patient-derived models in vivo and ex vivo and students) with a broad variety of expertise, peritoneal and liver metastases laboratory- and animal technicians), including two MDs • Biomarker detection by molecular and functional including basic biologists, translational scientists, • Translational studies within the METIMMOX in shared clinical positions. Several of the technicians techniques and clinician-scientists. Our approach to research is multicentre trial (Colorectal Cancer Metastasis – are trained in specialized technologies and compose • Response evaluation of experimental drugs (often translational, encompassing methods from biochemistry Shaping Anti-Tumor Immunity by Oxaliplatin), which resources for all groups in the department. in collaboration with commercial partners, eg.: and cell biology, preclinical drug testing in animal will investigate the combination of oxaliplatin and Research focus: Investigations on mechanisms of Lytix Biopharma) models, biomarker studies in clinical cohorts and checkpoint inhibition (nivolumab) in microsatellite resistance and metastasis for improved treatment of 3. Clinical trials in precision medicine – clinical and interventional clinical trials. Extensive collaboration stable CRC cancer. translational efforts has been established within the Institute, with clinical • Commercial development of MOC31PE and BM7PE Methodology: Molecular and functional analyses • NeoAva: bevacizumab in combination with departments, nationally and internationally. immunotoxins for cancer therapy utilizing clinical samples, human cell cultures and neoadjuvant chemotherapy for patients with locally patient-derived models (ex vivo, in vitro and in vivo). advanced breast cancer (patient inclusion closed) AIMS RECENT ACHIEVEMENTS • I-BCT: extended DNA-targeted chemotherapy Our long-term aim is to make new, efficacious • Group members were credited with 14 publications in AIMS to breast cancer patients with an aggressive treatment(s) available to patients with colorectal 2018 Metastatic progression is the major clinical challenge phenotype cancer (CRC). This will be accomplished by bringing • The multicenter METIMMOX trial started accrual in and the principal cause of death in cancer patients. To • MetAction: Actionable target identification in the clinic and lab together in translational research March 2018, and all study centers have now opened combat metastatic cancer our goal is to understand metastatic cancer for palliative targeted treatment projects utilizing 1) preclinical models for efficacy for accrual. the underlying biological mechanisms causing therapy (patient inclusion closed) and mechanistic studies 2) clinical cohort studies to • Grant support was obtained from the Norwegian Can- resistance, invasion and re-growth. Knowledge on these understand CRC biology and identify biomarkers and cer Society (project support) and from the South-East processes is vital for identification of molecules that can RECENT ACHIEVEMENTS therapeutic targets 3) clinical intervention trials to test Norway Regional Health Authority (PhD project). be utilized as prognostic and predictive biomarkers or • The group was credited with 8 publications in 2018, new drugs and therapeutic concepts in patients • Our COST Action, EuroPMP, European Research Net- as targets for therapy. We are working with malignant of which two with group members as first and/or last work on rare cancer pseudomyxoma peritonei, was melanoma, breast cancer and prostate cancer. author; two Master degrees completed PROJECTS initiated with official kick-off in September. EuroPMP • One clinical intervention trial in breast cancer open for • Peritoneal metastasis – molecular targets and new currently comprises >50 members from 16 European PROJECTS inclusion (I-BCT) therapies countries. 1. Basic research revealing mechanisms causing • Successful establishment of a user board for breast - Personalizing CRC therapy – identification of • Two DOFIs filed treatment resistance and metastasis cancer research biomarkers and therapeutic targets in locally • Molecular and cellular determinants regulating • One major grant approved for further studies on strat- advanced and metastatic CRC, involving generation cancer cells plasticity, with special emphasis on the ification biomarkers in breast cancer and use of our extensive biobanks, molecular role of tumor-stroma interactions • Two DOFIs filed and bioinformatics analyses (subprojects include:
50 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 51 Department of Tumor biology Computational Molecular Cancer Biology of Genomics Sarcoma
“Towards precision medicine to improve treatment “Enabling the transition to clinical utility” of sarcomas”
Group leader: Eivind Hovig Group leader: Jørgen Wesche
ABOUT PROJECTS ABOUT material of 3-4 national cohorts of sarcomas (~500 The 10-member group has strong interest in the • Development of solutions for integrative cancer The 15-member group has a long-standing interest in the samples). The project will provide unique, population development of computational approaches in cancer sequencing towards diagnostics, and participation in biology of mesenchymal tumors (sarcomas). The current based datasets including the many rare subtypes of genomics in general, and in melanoma systems international efforts for development of best practice focus is on precision medicine for sarcomas. To achieve sarcomas. biology, with an emphasis on the MITF master switch methods, including being computational leaders of the this, the group has broad expertise in basic cell biology, • Establishment of ex vivo drug sensitivity/resistance of melanocytes. Currently, activity is centered on Norwegian Cancer Genomics Consortium, partner of genomics and translational research and, in addition, screen for sarcoma primary tumors, and search for computational aspects of deep sequencing for cancer, the BIGMED ICT lighthouse and of Elixir Norway, and one MD in a shared clinical position. The group is part of novel anti-sarcoma drugs using drug screens on with downstream analysis. The group facilitates participates in the Center of Innovation Excellence Big a Centre of Excellence (CanCell). panels of liposarcoma and osteosarcoma cell lines. precision cancer medicine towards the clinic, leveraging Insight for the knowledge economy. • Exploration of “liquid biopsies”, as a non-invasive the participation in the BIGMED RCN-financed ICT • Further development of statistical genomics based on AIMS methods for detection of tumor-derived DNA in blood, lighthouse project. our software, the Genomic HyperBrowser. This is an The group aims to improve the treatment of to monitor disease progression, treatment response The group collaborates with deCODE, Iceland, on the internationally used tool for multipurpose integrated sarcoma patients by combining extensive genomic and tumour evolution. characterization of a familial cancer biobank, with 16000 statistical analysis of genomic data. characterization of clinical cohorts with preclinical genotyped samples, and where 2000 Norwegians have • Melanoma signaling perturbations for systems investigation in cell lines and xenografts to better RECENT ACHIEVEMENTS been whole genome sequenced. We pursue both the understanding, including MITF, BRAF and CDKN2A understand the biology of sarcomas. The generation and • 15 publications in 2018 heritable cancer information from this effort, as well as aberrations characterization of in vitro and in vivo sarcoma models • 1 PhD degree was completed. a characterization of the ethnic Norwegian population • Understanding the consequences for modulation of make the framework for pre-clinical studies. • The group obtained 4 major grants. genetics as a communal resource for Norway. immune responses in melanoma Sarcomas are rare cancers with poor treatment options, • 1 DOFI was filed. • Familial cancer project, including a close collaboration and we aim to use our biological knowledge to identify • A sarcoma user board was successfully established. AIMS with deCODE, Iceland new treatments opportunities by repurposing approved We aim to drugs for other cancers types. • apply and develop novel methodology for computa- RECENT ACHIEVEMENTS tional studies of cancer-related processes, including • Group members were credited with 14 publications in PROJECTS statistical genomics, 3-dimensional DNA conformation, 2018, of which 7 with group members as first and/or • Sarcoma cell biology – Gaining understanding of the drug prediction algorithms and mutational processes last author. development and progression of rhabdomyosarcoma, • contribute insight on heritable cancer-predisposing • 1 Master degree was completed liposarcoma and osteosarcoma, and potentially DNA-variation in the Norwegian population identify biomarkers and novel drug targets. A main • characterize the geographical stratification aspects of focus is the study of the role of fibroblast growth the Norwegian population factor receptors (FGFRs). • develop solutions for precision cancer medicine to- • Norwegian Sarcoma Consortium (NoSarC) – wards the clinic Biobanking and genomic characterization of patient • understand signaling processes in melanoma
52 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 53 Department of Core Facilities
“Providing cutting-edge Headed by Leonardo A. Meza-Zepeda technology and competence to The Department of Core Facilities runs seven regional campuses of OUH, as well as the light microscopy core and national technology platforms financed by the South- facility at the Institute for Biosciences, University of excel research” Eastern Regional Health Authorities and the Research Oslo. The core facility for ALM is a Eurobioimaging Council of Norway, providing advanced competence, node, providing state-of-the-art technologies in the infrastructure and services to regional, national and fields of biological and medical imaging. Services include international users. The Department aims to deliver training, courses, access to microscopes and microscopy easy access to cutting-edge advanced technologies and performed by competent core facility personnel. competence, and to improve research quality through optimal choice of technology, ultimately increasing ADVANCED ELECTRON MICROSCOPY the scientific competitiveness of our users. The Unit Leader: Ellen Skarpen Department of Core Facilities is organized in three units; Scientifically responsible: Andreas Brech Flow Cytometry and Pre-Clinical Imaging, Advanced Facility staff: 1 Microscopy and Genomics and Bioinformatics, with a total of 19 employees. More information at: www.ous- The Core Facility for Advanced Electron Microscopy research.no/corefacilities. (AEM) includes nodes at the Radium Hospital and Rikshospitalet, and provides service, training and access ADVANCED LIGHT MICROSCOPY to microscopes for ultrastructural studies. Available Unit Leader: Ellen Skarpen techniques at the facility include conventional plastic Scientifically responsible: Harald Stenmark embedding, immune EM, correlative light/electron Facility staff: 2 microscopy (CLEM), high pressure freezing, electron tomography, cryo-EM and STEM. The facility staff The Core Facility for Advanced Light Microscopy (ALM) is actively developing new methods in order to offer offers services in various types of ALM, including state-of-the-art microscopy solutions for researchers. confocal microscopy, live-cell microscopy and super- We cooperate with the imaging platform at the Institute resolution microscopy. Current instruments include a for Biosciences, University of Oslo and are part of the Zeiss LSM 880 FAST airyscan microscope, a Zeiss LSM Norwegian Advanced Light Microscopy node within 710 confocal microscope, and an OMX Blaze microscope EuroBioImaging. for structured illumination and STORM super-resolution imaging, as well as live-cell microscopy. The core facility cooperates with nodes at the Rikshospitalet and Ullevål
INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 55 Department of Core Facilities
Bioinformatics High-throughput Sequencing and Unit Leader: Susanne Lorenz Microarrays (Genomics) Scientifically responsible: Eivind Hovig Unit Leader: Susanne Lorenz Facility staff: 6 Scientifically responsible: Leonardo A. Meza-Zepeda Facility staff: 5 The Bioinformatics Core Facility (BCF) provides service, support and advice in the field of bioinformatics. By The Genomics Core Facility (GCF) provides state-of-the- combining biology with computer science, statistics art high-throughput genomic services to the Norwegian and mathematical modelling we offer support for scientific community. The GCF offers an extensive analysis and interpretation of biological data including portfolio of complex technologies and competence genomics, transcriptomics and proteomics for basic and to study genome structure, dynamics and function translational research. using high-throughput sequencing, NanoString and The BCF has a specific focus on developing and providing microarray technologies. Our highly experienced solutions for precision medicine and cancer-related service personnel provide advanced support to clinical, projects. Our service also includes support with data translational and basic research projects. Our services handling and storage by providing approved solutions for include standard and custom solutions to study the sensitive data. The operation of the BCF is aligned with transcriptome, genome and epigenome from multi- the national and local Elixir bioinformatics infrastructure genes analysis to genome-wide level. The core facility project, and also interacts with USIT, University of Oslo, collaborates with similar nodes at the Ullevål campus to facilitate the use of high-performance computing for sequencing and microarray services. The GCF is a resources. founding member of the Norwegian Consortium for Sequencing and Personalised Medicine (NorSeq) running Flow Cytometry the National platform for sequencing technology, and Unit Leader: Trond Stokke provides the sequencing infrastructure and competence Scientifically responsible: Trond Stokke for the National Personalised Medicine initiative Facility staff: 3 (NCGC). In 2018 we have established the first single- cell sequencing service in Norway, providing expertise The Flow Cytometry Core Facility (FCCF) provides and instrumentation for single cell analysis using 10x analysis and sorting services for users within the Genomics and BD Rhapsody platforms. In addition, we South-Eastern Health Region of Norway. We have have implemented the NanoString nCounter technology received grants for a new state-of-the-art analyzer (BD to provide targeted genomic, transcriptomic and Symphony) with 5 lasers that may measure up to 28 proteomic services. fluorescence parameters simultaneously. In total, the core facility provides services using 3 analyzers and Preclinical Imaging Facility two sorting instruments. Flow cytometry analysis is Unit Leader: Trond Stokke performed by the users themselves. Sorting experiments Scientifically responsible: Tord Hompland are either performed by experienced core facility Facility staff: 2 personnel (in the BD Aria), or by the users in the Sony SH100 sorter. The FCCF has possibilities for high- The Preclinical Imaging Facility provides access to a throughput screening, processing and staining of cells in state-of-the-art non-invasive imaging equipment for mice 96- or 384-well plates, followed by automated analysis. and rats. The equipment is situated within the animal We also have a “mass-spec flow cytometer” (CyTOF 2, facility and consist of a 7T Bruker MRI, IVIS spectrum which will be upgraded to Helios). This instrument can and Zeiss Stereo Macroscope for optical imaging, and a measure up to 60 parameters simultaneously at single Multirad 225 small animal irradiator capable of doing cell resolution. We have recently obtained grants for an x-ray imaging. The facility also provides all the necessary add-on to the Helios, Hyperion, which allows for imaging equipment for in vivo research on small animals or of sections labeled with up to 60 heavy metal-tagged tissue/organ samples from larger animals or humans. antibodies. The FCCF collaborates with facility nodes at A comprehensive library of standard off-the-shelf the Rikshospitalet and Ullevål campuses of OUH. imaging protocols are available, and custom-protocols can be developed upon user request. We are at present developing a protocol for synchronization of images obtained by MRI, IVIS and X-ray imaging. The service offered by the core facility includes design, development and running of the imaging experiment, as well as post processing of the data in addition to instrument specific training. The core facility collaborates with the Preclinical MRI node at the Ullevål campus.
56 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 57 60 62 68 Centre of Excellence K. G. Jebsen Norwegian The Centres of Excellence Centres Cancer Genomics (CoE) scheme is a national The K.G.Jebsen Foundation programme under the auspices Consortium supports Centres for Medical The establishment of of the Research Council of Research of high international Norwegian Cancer Genomics Norway. The granted CoE quality as part of its program Consortium (NCGC) was (CanCell) is funded for 5 + for translational medicine. recommended by the Regional 5 years (if recommended for The centres are selected Health Authorities and the extension following a mid-term in collaboration with the Universities. The consortium Research evaluation). The total basic Norwegian Medical Faculties includes research groups and funding is ~167 million NOK. and University Hospitals clinicians from the Norwegian for a period of 4 years with University Hospitals, and its centres the possibility of a 2-year total basic funding was 75 extension. The selected million NOK received from the Centres receive 16-18 million Norwegian Research Council. NOK in basic funding over The final report from NCGC the first four years from the was delivered to the Minister Foundation and support from for Health in March 2019. the host institutions, University of Oslo (KG Jebsen Centre for Cancer Immunotherapy, KG Jebsen Centre for B Cell Malignancies) or Oslo University Hospital (KG Jebsen Colorectal Cancer Research Centre).
58 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 59 ABOUT Centre for Cancer Cell Reprogramming (CanCell) is a • Demonstration that control of tRNA synthesis occurs Norwegian Centre of Excellence (CoE) which opened via regulation of RNA polymerase III activity (Herrera 01.01.2018 and has a planned CoE funding period of 10 et al., Nucleic Acids Research 2018). years. CanCell is led by Harald Stenmark at Institute for Cancer Research, whereas Anne Simonsen at Institute of • Identification of a mechanism which mediates lyso- Basic Medical Sciences is co-director. The centre consists some repair, and demonstration that this mechanism of 6 research groups and has 7 associate members promotes cell viability (Radulovic et al., EMBO Journal (Eivind Hovig, Åslaug Helland, Yngvar Fløisand, Philippe 2018). Collas, Arnoldo Frigessi, Emmet McCormack, and Terje Johansen) and 4 international visiting professors • Demonstration that SNX18 regulates ATG9A traffick- (Kristian Helin, Ivan Dikic, Eileen White, and Eyal ing from recycling endosomes during autophagy by Gottlieb). By the end of 2018, CanCell had 98 members. recruiting the GTPase Dynamin-2 (Søreng et al., EMBO Reports 2018). AIMS CanCell’s vision is to identify novel vulnerabilities • CanCell published 20 papers in 2018 in journals of of cancer cells that can be targeted for cancer cell good international reputation. CanCell scientists were reprogramming. The centre’s founding hypothesis is that first or corresponding authors of 11 of these papers. pathway intersections between chromatin regulation, One PhD student was graduated in 2018. membrane dynamics, cell signaling and metabolism during cancer progression represent potential “Achilles’ • CanCell members have been successful in obtaining heels” of cancer cells. These will be identified through major external grants in 2018, including grants from close cooperations between specialists within these four the European Research Council, the Norwegian Cancer cellular processes, and will be targeted by genetic and Society, the Research Council of Norway, and the pharmacological regimens to achieve reprogramming of South-Eastern Norway Regional Health Authority. cancer cells into harmless (or dying) cells. GROUP LEADERS/STEERING COMMITTEE PROJECTS CanCell was established by the following 6 group leaders, • Membrane dynamics in cancer who also serve as CanCell´s steering committee: • Autophagy in immunity and cancer • Molecular medicine of leukemia Harald Stenmark, Institute for Cancer Research, OUS, • Tumour-host interactions and Institute of Clinical Medicine, UiO • Molecular biology of sarcomas Centre for Cancer • Mechanisms of epigenetic regulation in cancer Anne Simonsen, Institute of Basic Medical Sciences, UiO, and Institute for Cancer Research, OUS RECENT ACHIEVEMENTS Cell Reprogramming • Demonstration that the centromere directs mitotic Jorrit Enserink, Institute for Cancer Research, OUS, and chromosome condensation, a collaboration between Department of Biosciences, UiO Enserink’s group and Yves Barral’s group at ETH (CanCell) Zürich (Kruitwagen et al., Cell 2018). Ragnhild Eskeland, Institute of Basic Medical Sciences, UiO Headed by Harald Stenmark • Identification of a novel mechanism for controlling positioning of the mitotic spindle (Malerød et al., EMBO Tor Erik Rusten, Institute of Clinical Medicine, UiO, and Journal 2018). Institute for Cancer Research, OUS
“Reprogramming • Establishment of timing and mechanisms of protein Jørgen Wesche, Institute for Cancer Research, OUS, and recruitment during receptor sorting into multivesicular Institute of Clinical Medicine, UiO of cancer” endosomes (Wenzel et al., Nature Communications 2018).
• Identification of a protein tyrosine phosphatase that controls fibroblast growth factor receptor activity and drug sensitivity (Kostas et al., Molecular & Cellular Proteomics 2018).
60 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 61 ABOUT • Renewed a 2-year collaborative agreement with Fate In the K.G. Jebsen Center for Cancer Immunotherapy Therapeutics to develop off-the-shelf NK cell therapy. (JCIT) hosted by the University of Oslo, five Norwegian • Licensed pending patent concerning a method for and one Dutch research group have come together to selective expansion of educated NK cells to Fate Thera- find new immunotherapeutic strategies that overcome peutics Inc. January 2018. A clinical trial exploring this the major challenge of self-tolerance in cancer. JCIT was concept will be launched during 2019. “Modulation of granted maximal prolongation following the first 4-year function of immune effector cells”. period, throughout 2019. The partnering groups of JCIT • Included 9 patients in Lymvac-2, an experimental span complementary competencies ranging from basic immunotherapy trial combining intratumoral immu- proteomics, cell signaling and T-cell receptor engineering notherapy with anti-PD1 for treatment of patients with to expertise in experimental clinical immunotherapy follicular lymphoma, in collaboration with Merck. trials. This places the center in a unique position • Recruited first 100 patients to the ASAC trial that to pursue novel therapeutic opportunities, and the examines the effect of reversing prostaglandin E2-me- strong focus on translating therapeutic opportunities diated inhibition of tumor immunity in patients with is a fundamental characteristic of JCIT. Results from metastatic colorectal cancer by the end of 2018 (www. basic research are pursued through the necessary asac.no). translational steps to testing in patients, and in-depth • Demonstrated that idelalisib preferentially inhibits mechanistic studies of patient material obtained in human regulatory T cells, which enhances anti-tumor experimental clinical trials are performed with the aim immunity but also contributes to adverse effects in of improved designs of immunotherapeutic strategies. patients with chronic lymphocytic leukemia (Chellappa et al, J Immunol., in press des 2018). AIMS Three principally distinct approaches are pursued in an interdisciplinary and translational program: 1. Use Home page of T-cell and NK-cell based alloreactivity to overcome http://www.med.uio.no/klinmed/english/research/ self-tolerance. 2. Identification and targeting of cancer- centres/kgj-cancer-immunotherapy/ specific neo-antigens. 3. Enhancement of effector T-cell function by counteracting inhibitory mechanisms. Group leaders/ Steering committee Johanna Olweus (MD, PhD, Director), Dept of Cancer PROJECTS Immunology, Institute for Cancer Research, Oslo • Epitope discovery to identify targets for immunotherapy University Hospital (OUH)-Radiumhospitalet and • Identify immune cells expressing immune receptors University of Oslo (UiO) that recognize and kill cells that express the identified targets Karl-Johan Malmberg (MD, PhD, deputy Director), Dept • Molecular cloning, genetic transfer and profiling of of Cancer Immunology, Institute for Cancer Research, K.g. Jebsen immune receptors OUH-Radiumhospitalet and UiO • Enhance cytotoxic lymphocyte function by overcom- K.G. Jebsen Center for ing inhibitory mechanisms Arne Kolstad (MD, PhD), Dept of Oncology, OUH- colorectal • In vivo evaluation of immune modulating therapies Radiumhospitalet Cancer Immunotherapycancer research RECENT ACHIEVEMENTS Kjetil Taskén (MD, PhD), Dept of Cancer Immunology, • Reported a new method to validate thousands of Institute for Cancer Research, OUH-Radiumhospitalet Headed by Johanna Olweus antibodies in parallel using mass spectrometry data as and Inst. of Clinical Medicine, UiO centre reference. (Sikorski et al, Nat Methods 2018) • Reported the first Phase I/II clinical trial based on Fridtjof Lund-Johansen (MD, PhD), Dept of Immunology, transfer of allogeneic NK cells to patients with high- OUH-Rikshospitalet risk AML and MDS (Björklund et al., Clinical Cancer “Our goal is to Research 2018). Ton Schumacher (PhD), The Netherlands Cancer • Reported low and variable tumor reactivity of the in- Institute, Amsterdam develop new tratumoral TCR repertoire in human cancers (Scheper et al, Nat. Med. 2018) therapeutic • Described a role for lysosomal remodeling in tuning strategies that NK cell function (Goodridge et al, Nature Communications, 2019). overcome immune • Patent granted on technology for identification of spe- tolerance to target cific T-cell receptors (WO 2015/071763A2) • Described a technology for identification of neoantigen cancer” specific T cells from healthy donors (Ali et al, Nature Protocols in press, 2019)
62 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 63 ABOUT • Demonstrated that the PI3Kδ inhibitor idelalisib en- The K.G. Jebsen Centre for B-cell malignancies was hances anti-tumor immunity preferentially through established in June 2018 and is hosted by the University inhibition of human regulatory T cells in patients with of Oslo. B-cell malignancies include lymphomas (Non- CLL (Chellappa et al, J Immunol. in press 2018). Hodgkin and Hodgkin lymphomas), B-cell leukemias • Identified the co-inhibitory receptor TIGIT as a poten- (ALL, CLL) and multiple myeloma. The centre bridges tial new target for immune checkpoint blockade in 4 basic/translational research groups with 3 clinical B-cell lymphoma (Josefsson et al, Cancer Immunol. Res. in groups; placing us in a unique position to translate press 2018) pre-clinical results into clinical trials. The centre utilizes • Identified that bone marrow T helper cells with a Th1 “cutting edge” technologies for deep profiling of tumor phenotype can induce activation and proliferation of biopsies, including whole exome DNA sequencing, bulk leukemic cells in precursor B-ALL patients (Traxel et al, and single cell RNA sequencing, single cell proteomics Oncogene 2018) by mass cytometry and mass cytometry imaging, cancer • Identified and characterized a novel mechanism sensitivity drug screens, and development of integrative of action of CD4+ T cell-mediated immunotherapy bioinformatics’ pipelines for precision medicine. (Fauskanger et al, Front Immunol. 2018; Haabeth et al. Can- Patient-derived xenograft (PDX) models and syngeneic cer Res. 2018) tumor mouse models are used for pre-clinical testing of new treatments. Collectively, the Centre represents a multidisciplinary integration of life science research with Home page preclinical development of personalized medicine, drug https://www.med.uio.no/klinmed/english/research/ discovery and cell-based immunotherapy, as well as centres/kgj-b-cell-malignancies/ clinical trials and establishment of best practice on how to treat B-cell malignancies. GROUP LEADERS/STEERING COMMITTEE AIMS The centre aims to identify, develop and test new Ludvig A. Munthe (MD, PhD, Centre Director), Div. therapeutic options for patients with B-cell malignancies for Laboratory Medicine, Dept. of Immunology, OUH- and to initiate new therapeutic trials in both industry- Rikshospitalet and Institute for Clinical Medicine, K.G. Jebsen Centre for and investigator driven initiatives. University of Oslo (UiO) PROJECTS June H. Myklebust (PhD, Assistant Director), Institute for • Identify molecular biomarkers to guide precision med- Cancer Research, Dept of Cancer Immunology, OUH- B-cell malignancies icine and to identify high risk patients Radiumhospitalet and UiO • Deciphering signal integration and interactions with Headed by Ludvig A. Munthe and June H. Myklebust the tumor microenvironment to reveal actionable tar- Geir E. Tjønnfjord (MD, PhD), Div. for Cancer Medicine, K.g. Jebsen gets and targets for immunotherapy Dept. of Haematology, OUH-Rikshospitalet and UiO • Develop novel therapeutics: identify antigens for vaccination, T cell epitope discovery, and CAR T cell Hilde Schjerven (PhD), Dept. of Immunology, OUH- colorectal design Rikshospitalet and Dept. of Laboratory Medicine, “From basic • Preclinical testing: immunotherapy and personalized University of California, San Francisco. cancer research medicine research and • Translating results into clinical initiatives – from Harald Holte (MD, PhD), Div. for Cancer Medicine, Dept. centre preclinical studies bench to bedside and back of Oncology, OUH-Radiumhospitalet to precision RECENT ACHIEVEMENTS/CLINICAL TRANSLATION Erlend B. Smeland (MD, PhD), Institute for Cancer • The centre currently encompasses 67 clinical trials of Research, Dept. of Cancer Immunology, OUH- medicine for B-cell which 13 are in startup, 28 are actively recruiting and Radiumhospitalet and UiO malignancies” 24 are in follow up; 21 of these are phase II studies and 28 are phase III studies Kjetil Taskén (MD, PhD), Institute for Cancer Research, • Participated in the multicenter double-blind, rand- Dept. of Cancer Immunology, OUH-Radiumhospitalet omized, placebo-controlled phase 3 trial for testing the and UiO efficacy of the proteasome inhibitor ixazomib given orally as maintenance therapy following autologous stem cell transplantation (TOURMALINE-MM3) in mul- tiple myeloma (Dimopoulos et al, Lancet in press 2018) • Participated in the international clinical phase II trial for testing of CD19 CAR T cell therapy in adult relapsed or refractory Diffuse Large B-Cell Lymphoma, and reported a 52% overall response rate (Schuster SJ et al, N Engl J Med. in press 2018).
64 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 65 ABOUT talk at the AACR-meeting “Intestinal Stem Cells and Colon Colorectal cancer (CRC) is a major health burden, and Cancer: Biology to Therapy” in Washington D.C. in Sept 2018. the focus of our Centre is to meet the challenges in the The annual meeting of the Centre was held in November at management of the disease, by improved patient monitoring the Norwegian Academy for Science and Letters, Oslo. Key and stratified treatment. The Centre is hosted by the Clinic invited speakers were international and national oncologists for Cancer Medicine, Oslo University Hospital (OUH). The Rodrigo Dienstmann – VHIO-Barcelona, David Church- Centre PIs are also partners in the OUH SMART-CRC priority University of Oxford, Anne Hansen Ree - Ahus, Bjørn area (2014-18). Home page: www.colorectalcancer.no Erikstein – OUS (Director).
GROUP LEADERS/STEERING COMMITTEE Clinical research • Professor Ragnhild A. Lothe (MSc, PhD, Centre leader), Centre surgeons participated in an international multicentre Dept. of Molecular Oncology, Institute for Cancer Re- study showing that differences among European countries search, OUH and Institute for Clinical Medicine, University in survival from CRC was best explained by patient selection of Oslo (UiO) for surgery (Benitez et al., Lancet Oncol 2019). For elderly • Professor Arild Nesbakken (MD, PhD, deputy Centre lead- rectal cancer patients specifically (>80 years), variation in er), Dept. of Gastrointestinal Surgery, OUH and Institute 5-year relative survival depended on variation in the use for Clinical Medicine, UiO of preopereative radiotherapy, and on the resection rate • Until 2018/06: Associate Professor Mette Kalager (MD, in stage IV (Claassen et al., Brit J Ca 2018). Furthermore, PhD), Institute of Health and Society, UiO, and Dept. Epi- complications following CRC surgery have been evaluated in demiology, Harvard T.H.Chan School of Public Health, USA frail older Norwegian patients (Ommundsen et al., Eur J Surg • Professor Rolf I. Skotheim (MSc, PhD), Dept. of Molecular Oncol 2018), and by the European Society of Coloproctology Oncology, Institute for Cancer Research, OUH, and Dept. collaborating group, in which professor Nesbakken has of Informatics, UiO. participated with data from patients enrolled in our Centre • Senior Consultant Marianne G. Guren (MD, PhD), Dept. of project (Colorectal Dis. 2018 20: 1028-1040; plus 5 additional Oncology, OUH publications in Suppl 6: 15-32, 33-46, 47-57, 58-68, 69-89). • From 2018/06: Professor Guro E. Lind (MSc, PhD), Dept. Molecular Oncology, Institute for Cancer Research, OUH Translational research and Dept. of BioSciences, UiO Benefiting from the national public health system and our collaboration with the Cancer Registry of Norway, we are Our Centre has an active Patient advisory board established assembling a national population-representative patient in 2016. series. Diagnostic tumor material from 5,000 patients from all health regions will be collected and used for development AIM of prediction models for patient outcome based on clinical Translate biomedical knowledge of CRC in the context of and molecular biomarkers. tumor heterogeneity into improved stratified medicine. We completed several biomarker studies in 2018. KRAS K.G. Jebsen mutation is a clinically relevant biomarker and a negative PROJECTS predictive factor for anti-EGFR treatment in metastatic • Clinical and molecular biomarkers for improved risk strat- CRC. We found that its prognostic value is dependent on Colorectal Cancer ification of patients the tumor’s gene expression subtype (Smeby et al., Ann • Model tumor heterogeneity and clonal evolution to moni- Oncol 2018). Furthermore, among KRAS wild-type cancers, tor early relapse and treatment failure aberrant splicing by low relative expression of KRAS-4A vs Research Centre • Pharmacogenomic profiling of organoid models derived KRAS-4B transcript variants identify patients with inferior from the patients’ own tumor cells for therapy guidance, survival (Eilertsen et al., Int J Ca 2018). From analyses of Headed by Ragnhild A. Lothe identification of biomarkers for response prediction, and more than 2000 tumor samples and pre-clinical models, development of synergistic drug combinations we identified a microRNA as a novel bona fide prognostic marker in CRC, independent of cytotoxic lymphocyte and RECENT ACHIEVEMENTS fibroblast infiltration (Eide et al., Int J Ca 2018). We also In 2018, we were granted a 2-year prolongation period of the refined the prognostic and predictive value of CDX2 in CRC Centre, to continue the translational and clinical research (Bruun et al., Mol Oncol 2018). Non-invasive analyses of “High quality program on primary and metastatic CRC. the clinical biomarkers CEA and CA19-9 in liquid biopsies The PI groups published 33 peer-reviewed papers related (serum) was found to provide independent poor prognostic translational to CRC in 2018 (incl ahead of print), including Ann Oncol information in metastatic CRC, and elevated CA19-9 was research to the (2), BBA Reviews on Cancer, Clin Cancer Res, Lancet Oncol associated with BRAF mutations (Thomsen et al., Brit J Ca (2), Sem Cancer Biol. Peter Andreas W. Eide defended 2018). benefit of his PhD at the Institute for Clinical Medicine, UiO. Anita In a recent study of pre-clinical models, we demonstrated colorectal cancer Sveen was appointed assoc. professor at the Institute for that HSP90 inhibitors have the potential to overcome Clinical Medicine, UiO, and received a young researcher chemoresistance in an agressive subtype of CRC (Sveen*, patients” talent grant from the Research Council of Norway. The Bruun* et al. Clin Cancer Res 2018), and we have written first 15 patients were successfully included in our newly a review on the clinical and preclinical evidence for established ex vivo pharmacogenomics pipeline, involving combination treatments with HSP90i in CRC (Kryeziu et al, drug screening and molecular profiling of patient-derived BBA-Reviews on Cancer, 2019). organoids from multiple CRC liver metastases of each patient. The initial results were presented in an invited
66 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 67 ABOUT to extension to phase II studies. Several trials are in The Norwegian Cancer Genomics Consortium (NCGC) is progress by the partners. a group of oncologists and researchers from all health The main hub of NCGC is at the ICR and its core facility regions of Norway who are collaborating to determine for genomics, and five of the co-principal investigators the potential of cancer genome analysis for prediction are from the ICR. The other main nodes are at the of therapeutic outcomes or selection of novel targeted University of Oslo, Haukeland University Hospital therapies. (Bergen), St Olav University Hospital (Trondheim), University Hospital of Northern Norway (Tromsø), and AIMS the University of Tromsø. The NCGC also has an ELSA Precision oncology, or personalized cancer medicine, work package, which addresses important societal issues is expected to provide huge benefits to the patients by including innovation, health economy, law and ethics, as better adapting the treatment, especially by targeted well as professional and societal dialogue. drugs, to the specific properties of the disease of the individual. The hope is that this will at least give RECENT ACHIEVEMENTS prolonged survival and better quality of life, and at the The data from the sequenced samples are currently same time reduce the morbidity, expense and wasted being deeply investigated, and a number of preclinical resources on unsuccessful treatments. A main obstacle is studies in cell lines are under way. A database has the difficulty to prove the efficacy in ever smaller patient been generated at 1000genomes.no with all the genetic groups, and thus the reluctance of the public health variants (SNPs) detected in the germ lines (blood services to introduce the new treatments. samples), and the frequencies in the cohort. Other environments are preparing to add Norwegian SNP data, PROJECTS which will be a valuable resource for many types of • Exome sequencing and mutation profiling of nine genetic research and diagnosis. selected cancer types Upon completion of the two first large projects funded • Establishment and characterisation of relevant by the Norwegian Research Council, a printed report preclinical models has been made which provides an introduction to the • Validation of novel targets in preclinical models field, recommendations to the Health Service, evaluation • Investigation of predisposing gene variants by the institutional board members, and overview of “The use of tumor • Establishing of national infrastructure for the storage the projects and results so far. A pdf version can be genome analysis and analysis of large-scale sensitive patient data downloaded from rapport.kreftgenomikk.no (Norwegian • Design of small-scale trials to identify potential of only). The report was presented to the Minister of to better tailor candidate drugs Health, Bent Høie, in a meeting in March 2019. cancer treatment” • Develop decision support tools for pathologists and oncologists to better interpret genome diagnostic data CLINICAL TRANSLATION for therapeutic interventions The project is investigating patient samples either K.g. Jebsen prospectively collected, or being part of clinical trials, The projects include the determination of the DNA with the aim to gain biologically based clinical insight. sequence, the detailed structure, of all genes in the Oncologists are strong partners. The detection of novel colorectal patient and the tumour, identification of mutations therapeutic targets and their evaluation in pre-clinical that reveal mechanistic insights or can suggest specific studies may have immediate clinical value. The team cancer research treatments. Trial-derived biobanks from melanomas, maintains a systematic professional outreach and leukemias, sarcomas, and breast cancers are being dialogue, with continuous discussions on the strategies Norwegian investigated for predictive biomarkers, as are biobanks and how they may be implemented in the clinics at centre containing sarcomas, colon, prostate, myeloma, and institutional meetings, external conferences and public .No lymphoma samples from standard-of-care treated meetings. Cancer Genomics patients. The leukemia trial investigated is from the first-in-man trial of an Axl inhibitor from BerGenBio. A GROUP LEADERS/STEERING COMMITTEE enomic s prospective, population-based cohort of all Norwegian The project has a leader group consisting of Ola Consortium er G sarcoma patients for 3 years is being accrued (see Myklebost (ICR, head), Ragnhild A Lothe (ICR), Harald an c NoSarC.no), and in addition to the 200 sample pairs Holte (KRE), Leonardo A Meza-Zepeda (ICR), Eivind Headed by Ola Myklebost C exome sequenced by NCGC, about 150 additional pairs Hovig (ICR), Per Eystein Lønning (HUS), Bjørn Tore are being sequenced with additional funding from the Gjertsen (HUS), Anders Waage (St Olav US), Ole Morten Radium Hospital Legacy. Up to now approximately Seternes (UiT), Tom Dønnem (UNN). Our Board consists 1800 samples from 630 patients have been sequenced. of Erlend Smeland (OUH, Head), Jónas Einarsson (RF/ Promising targets for which drugs are available, but OCC), Hilde I. Nebb (UiO), Knut Martin Torgersen (Pfizer), without documentation of clinical effect in the cancers Bjørn Gustafsson (StOlav/NTNU), Tove Flem Jacobsen investigated, are tested pre-clinically in relevant cell (Link Medical), Olav Mella (HUS/UiB), Anne Sameline culture and xenograft models. The intention is to propose Grimsgaard (UNN/UiT). small, exploratory clinical trials to indicate activity in see CancerGenomics.No selected patients, and that promising results could lead
68 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 69 SPAIN IRELAND
FRANCE THE NETHERLANDS SPAIN IRELAND UNITED KINGDOM BELGIUM FRANCE THE NETHERLANDS GERMANY SWITZERLAND UNITED KINGDOM BELGIUM ITALY CZECH REPUBLIC InternationalGERMANY SWITZERLAND DENMARK HUNGARY ITALY CZECH REPUBLIC NORWAY CROATIA DENMARK HUNGARY SWEDEN INDIA NORWAY CROATIA CollaborationFINLAND SINGAPORE SWEDEN INDIA POLAND ISRAEL FINLAND SINGAPORE S AUSTRIA RUSSIA POLAND ISRAEL ST S TUNISIA AUSTRIA RUSSIA T ST T UNI SIA S T TH TH S S T TH TH S S T T T H S T H T H T H S T S S S S ST SS S T S ST SS
T S AUSTRALIA FINLAND HUNGARY • Garvan Institute, Sydney • Biomedicum Helsinki, University of • University of Szeged, • Kinghorn Cancer Centre, Sydney Helsinki, Helsinki Szeged • Monash University, Melbourne • Finnish Institute of Molecular Medi- cine, Nordic EMBL partner, Helsinki ICELAND AUSTRIA • Tampere University of Technology, • University of Iceland, • Medical University of Vienna, Vienna Tampere Biomedical Center, Reykjavik • Zora Oy, Espoo BELGIUM INDIA • Catholic university of Brussels, FRANCE • Indian institute of Technology, Brussels • Centre National de Génotypage, Hyderabad • Ghent University, Ghent Paris • Savitribai Phule Pune University, • Katholieke University Leuven, • EurOPDX - European Consortium Pune Leuven on Patient-derived Xenografts, Paris • Universiteit Hasselt, Genk • Institut Gustave Roussy, Paris IRELAND • Institut National de la Sante et de la • National Institute for Bioprocessing CANADA Recherche Medicale, Paris Research and Training (NIBRT), • McGill University, Montreal • Institute Cürie, Paris Dublin • Princess Margaret Hospital, Toronto • Institute of Systems and Synthetic SPAIN THE NETHERLANDS • University of Oxford, Oxford • University of Ottawa, Ottawa Biology Genopole, UEVE, CNRS, ISRAEL • CABIMER, University of Sevilla, Sevilla • Leiden University, Leiden • Wellcome Sanger Institute, Hinxton Évry • Technion - Israel Institute • Centre for Biological Studies, • Netherlands Cancer Institute (NKI), CROATIA • International Agency for Research of Technology, Haifa Madrid Amsterdam USA on Cancer (IARC), Lyon • Radboud University Nijmegen, • Buck Institute for Research on • University of Zagreb, Zagreb • Weizmann Institute, Rehovot • Fundacion Instituto Valenciano de • Oregon State University, • Université Lyon, Villeurbanne Nijmegen Aging, Novato, California Oncologica (FIVO), Valencia Corvallis, Oregon • Université Paris-Sud, Orsay • The Netherlands Proteomics Centre, • Dana Farber Cancer Institute, CZECH REPUBLIC ITALY • ICGC, Technical validation group • Princeton University, New Jersey Utrecht Boston, Massachusetts • Charles University, Prague • IFOM, Milan and Ivo Gut, Barcelona • Rutgers Cancer Institute of New • University Medical Center, • Dartmouth College, Hanover, • Institute of Experimental Biology, GERMANY • International School for Advanced • University of Lleida, Lleida Jersey Groningen New Hampshire Masaryk University, Brno • EMBL, Heidelberg Studies, Trieste • University of Valencia, Valencia • Stanford University, California • VU Medical Center, Amsterdam • Duke University Medical Center, • Institute of Molecular Genetics, • Institut für Biochemie, University of • Istituto Nationale di Tumori, Milano • Universitat Politècnica de València, • The Mount Sinai Hospital, New York Durham, North Carolina Academy of Sciences of the Czech Stuttgart, Stuttgart • The Rizzoli Institute, Bologna POLAND Valencia • The University of Kansas Hospital, • Fred Hutchinson Cancer Research Republic, Prague • Jacobs University, Bremen • University of Bologna, Bologna • Faculty of Biotechnology, University • Vall d’Hebron Institute of Oncology, TUNISIA Kansas Center, Seattle, Washington • National Institute of Public Health, • University of Bayreuth, Bayreuth • University of Padova, Padova of Wroclaw, Wroclaw Barcelona • University of Tunis, Tunis • Tisch Cancer Institute, New York • Georgetown University, Washington DC Prague • University of Bochum, Bochum • University of Salento, Lecce • Jagiellonian University, Kraków • UCSF, Helen Diller Family Cancer • Harvard University, • University of Cologne, Cologne • University of Gdansk, Gdansk SWEDEN UNITED KINGDOM Centre, San Francisco, California Boston, Massachusetts DENMARK • University of Freiburg, Freiburg NORWAY • Karolinska Institutet and University • Cambridge Cancer Institute, Cambridge • University of Albany, New York • University of Heidelberg, Heidelberg • Johns Hopkins Medicine, • Aalborg University Hospital, Aalborg • Cancer Registry of Norway, Oslo PORTUGAL of Stockholm, Stockholm • Hampshire Hospitals/Southampton • University of California, • University of Mainz, Mainz Baltimore, Maryland • Aarhus University Hospital, Aarhus • Haukeland University Hospital, • Institute of Molecular Pathology and • Lund University, Lund University, Southampton Berkeley, California • University of Marburg, Marburg • Lawrence Berkeley National • Copenhagen University Hospital, Bergen • The Sahlgrenska Academy at • London Research Institute,The • University of Chicago, Illinois Immunology, University of Porto Laboratory, Berkeley, California Copenhagen • Norwegian University of Life the University of Gothenburg, Francis Crick Institute, London • University of Colorado, • Portuguese Oncology Institute, • Lineberger Comprehensive Cancer • University of Copenhagen, GREECE Sciences, Ås. Gothenburg • Royal National Orthopaedic Denver, Colorado Porto Center, Chapel Hill, North Carolina Copenhagen • National and Kapodistrian University • Norwegian University of Science • Uppsala University Hospital, Hospital, Stanmore, Middlesex • University of Illinois, • Masonic Cancer Center and Univer- • University of Southern Denmark, of Athens, Athens and Technology, Trondheim Uppsala • The Beatson Institute for Cancer Champaign, Illinois RUSSIA sity of Minnesota, Minneapolis Odense • National Centre for Scientific • Stavanger University Hospital, Research, Glasgow • University of Washington, • Institute of Cytology and Genetics, • Massachusetts General Hospital, Research “Demokritos”, Athens Stavanger SWITZERLAND • The European Bioinformatics Seattle, Washington Novosibirsk Boston, Massachusetts • University of Ioannina, Ioannina • Trondheim University Hospital- • University Hospital Zurich, Zurich Institute (EMBL-EBI), Hinxton • Washington University, • MD Anderson Comprehensive St. Olavs Hospital, Trondheim • University College London Medical St Louis, Missouri SINGAPORE Cancer Center, Houston, Texas • University hospital of North Norway, School, UCL, London • Weill Medical College of Cornell • Cancer Science Institute of • National Institutes of Health (NIH), Tromsø • University of Cambridge, Cambridge University, New York Singapore, Singapore Bethesda, Maryland • University of Bergen, Bergen • University of Liverpool, Liverpool • University of Oslo, Oslo
70 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 71 Recent Innovations
Registered Declaration of Inventions (DOFIs) and Patent Applications
Research group Department DOFI # Bioinformatics Core Facility Core Facilities 18155 J. Wesche group Tumour Biology 18154 K. Flatmark group Tumour Biology 18153 G. Lind group Molecular Oncology 18146 J. Olweus group Cancer Immunology 18140 K. Tasken group Cancer Immunology 18130 J. Myklebust group Cancer Immunology 18118 J. Enserink group Molecular Cell Biology 18104 J. Enserink group Molecular Cell Biology 18098 G. Mælandsmo group Tumour Biology 18053 K. Sandvig group/G. Mælandsmo Molecular Cell Biology/Tumour Biology 18030 group/K. Flatmark group J. Olweus group Cancer Immunology 18003 J. A. Kyte group Cancer Immunology 18126
Application type Research group Department DOFI # Priority Application J. Enserink group Molecular Cell Biology 16126 Priority Application J. Myklebust group Cancer Immunology 16123 Priority Application G. Lind group Molecular Oncology 18146 Priority Application G. Lind group Molecular Oncology 17135 PCT Application G. Lind group Molecular Oncology 17135 PCT Application K. Flatmark group Tumour Biology 15189 PCT Application A. Weyergang group Radiation Biology 16153 PCT Application T. Theodossiou group Radiation Biology 17061 PCT Application R. Lothe group Molecular Oncology 16092
72 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 INSTITUTE FOR CANCER RESEARCH | ANNUAL REPORT 2018 73 B, Eloy C, Bjøro T, Sobrinho-Simões M, haug C, Geier O, Reitan E, Sætre DO, bolic tumor burden in patients with Skotheim RI, Soares P (2018) Breivik B, Reese T, Jacobsen KD, Hel- non-small cell lung cancer under- CRABP1, C1QL1 and LCN2 are land Å, Emblem KE (2018) going palliative thoracic radiation Publications biomarkers of differentiated thyroid Brain metastases with poor vascular therapy carcinoma, and predict extrathyroi- function are susceptible to pseudo- Adv Radiat Oncol, 3 (2), 130-138 dal extension progression after stereotactic radia- PUBLICATIONS 2018 Large scale changes in the transcrip- and is a repressor of peroxidasin BMC Cancer, 18 (1), 68 tion surgery Eide PW, Eilertsen IA, Sveen A, Lothe tome of Eisenia fetida during regen- Mech Dev, 155, 34-47 Adv Radiat Oncol, 3 (4), 559-567 RA (2018) Abravan A, Eide HA, Løndalen AM, eration Chèneby J, Gheorghe M, Artufel M, Long noncoding RNA MIR31HG is Helland Å, Malinen E (2018) PLoS One, 13 (9), e0204234 Brustugun OT, Grønberg BH, Fjell- Mathelier A, Ballester B (2018) Dominguez-Valentin M, Evans DGR, a bona fide prognostic marker with Mapping Bone Marrow Response birkeland L, Helbekkmo N, Aanerud M, ReMap 2018: an updated atlas of Nakken S, Tubeuf H, Vodak D, Ek- colorectal cancer cell-intrinsic prop- in the Vertebral Column by Positron Birkeland E, Zhang S, Poduval D, Grimsrud TK, Helland Å, Møller B, Nils- regulatory regions from an integra- strøm PO, Nissen AM, Morak M, erties Emission Tomography Following Geisler J, Nakken S, Vodak D, Me- sen Y, Strand TE, Solberg SK (2018) tive analysis of DNA-binding ChIP- Holinski-Feder E, Martins A, Møller P, Int J Cancer (in press) Radiotherapy and Erlotinib Therapy za-Zepeda LA, Hovig E, Myklebost O, Substantial nation-wide improvement seq experiments Hovig E (2018) of Lung Cancer Knappskog S, Lønning PE (2018) in lung cancer relative survival in Nucleic Acids Res, 46 (D1), D267-D275 Genetic variants of prospective- Eilertsen IA, Sveen A, Strømme JM, Mol Imaging Biol (Epub ahead of print) Patterns of genomic evolution in Norway from 2000 to 2016 ly demonstrated phenocopies in Skotheim RI, Nesbakken A, Lothe RA advanced melanoma Lung Cancer, 122, 138-145 Christensen T, de Gruijl F, Hamblin M, BRCA1/2 kindreds (2018) Andersen E, Chollet ME, Myklebust CF, Nat Commun, 9 (1), 2665 Ishibashi Y, Kamada K, Sage E, Saltiel Hered Cancer Clin Pract, 16, 4 Alternative splicing expands the Pinotti M, Bernardi F, Chuansumrit A, Bruun J, Sveen A, Barros R, Eide J, Sliwa M, Theodossiou T, Wu SP, prognostic impact of KRAS in mi- Skarpen E, Sandset PM, Skretting G Björklund AT, Carlsten M, Sohlberg E, PW, Eilertsen I, Kolberg M, Pellinen Bassani D, Nonell S, Shore A (2018) Dominguez-Valentin M, Nakken S, crosatellite stable primary colorectal (2018) Liu LL, Clancy T, Karimi M, Cooley S, T, David L, Svindland A, Kallioniemi O, Outstanding Reviewers for Tubeuf H, Vodak D, Ekstrøm PO, Nis- cancer Activation of Endoplasmic Reticu- Miller JS, Klimkowska M, Schaffer M, Guren MG, Nesbakken A, Almeida R, Photochemical and Photobiological sen AM, Morak M, Holinski-Feder E, Int J Cancer, 144 (4), 841-847 lum Stress and Unfolded Protein Watz E, Wikström K, Blomberg P, Wah- Lothe RA (2018) Sciences in 2017 Martins A, Møller P, Hovig E (2018) Response in Congenital Factor VII lin BE, Palma M, Hansson L, Ljungman Prognostic, predictive, and pharma- Photochem. Photobiol. 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(2018) 224Ra-Labeled Calcium Carbonate PUBLICATIONS 2019 Chellappa S, Kushekhar K, Munthe Structural Alterations Driving Cas- Microparticles in Mice with Intraperi- LA, Tjønnfjord GE, Aandahl EM, Ok- Taylor-King JP, Baratchart E, Dhawan A, Tunsjø HS, Kalyanasundaram S, tration-Resistant Prostate Cancer toneal Ovarian Cancer Berge LAM, Andreassen BK, Steneh- kenhaug K, Taskén K (2019) Coker EA, Rye IH, Russnes H, Chap- Charnock C, Leegaard TM, Moen AEF Revealed by Linked-Read Genome Transl Oncol, 11 (2), 259-267 jem JS, Larsen IK, Furu K, Juzeniene The PI3K p110δ Isoform Inhibitor Ide- man SJ, Basanta D, Marusyk A (2018) (2018) Sequencing A, Roscher I, Heir T, Green A, Veierød lalisib Preferentially Inhibits Human Simulated ablation for detection of Challenges in the identification of Cell, 174 (2), 433-447.e19 Westrøm S, Malenge M, Jorstad IS, MB, Robsahm TE (2019) Regulatory T Cell Function cells impacting paracrine signalling methicillin-resistant Staphylococcus Napoli E, Bruland ØS, Bønsdorff TB, Cardiovascular, antidepressant and J Immunol, 202 (5), 1397-1405 in histology analysis argenteus by routine diagnostics Vodák D, Lorenz S, Nakken S, Larsen RH (2018) immunosuppressive drug use in Math Med Biol (in press) APMIS, 126 (6), 533-537 Aasheim LB, Holte H, Bai B, Mykle- Ra-224 labeling of calcium carbonate relation to risk of cutaneous mela- Cheng J, Demeulemeester J, Wedge bost O, Meza-Zepeda LA, Hovig E microparticles for internal α-therapy: noma: a protocol for a prospective DC, Vollan HKM, Pitt JJ, Russnes HG, Terkelsen T, Haakensen VD, Saldova Tutturen AEV, Dørum S, Clancy T, (2018) Preparation, stability, and biodistri- case-control study Pandey BP, Nilsen G, Nord S, Bignell R, Gromov P, Hansen MK, Stöckmann Reims HM, Christophersen A, Lundin Sample-Index Misassignment Im- bution in mice BMJ Open, 9 (2), e025246 GR, White KP, Børresen-Dale AL, H, Lingjaerde OC, Børresen-Dale AL, KEA, Sollid LM, de Souza GA, Stamn- pacts Tumour Exome Sequencing J Labelled Comp Radiopharm, 61 (6), Campbell PJ, Kristensen VN, Stratton Papaleo E, Helland Å, Rudd PM, Gro- aes J (2018) Sci Rep, 8 (1), 5307 472-486 Blin M, Le Tallec B, Nähse V, Schmidt MR, Lingjærde OC, Moreau Y, Van Loo mova I (2018) Characterization of the Small Intes- M, Brossas C, Millot GA, Prioleau MN P (2019) N-glycan signatures identified in tinal Lesion in Celiac Disease by Våtsveen TK, Myhre MR, Steen CB, Weyergang A, Fremstedal AS, Skarp- and Debatisse M (2019). Author Correction: Pan-cancer analy- tumor interstitial fluid and serum of Label-Free Quantitative Mass Spec- Wälchli S, Lingjærde OC, Bai B, Dil- en E, Peng Q, Mohamedali KA, Eng Transcription-dependent regulation sis of homozygous deletions in pri- breast cancer patients: association trometry lard P, Theodossiou TA, Holien T, Sun- MS, Cheung LH, Rosenblum MG, Wal- of replication dynamics modulates mary tumours uncovers rare tumour with tumor biology and clinical out- Am J Pathol, 188 (7), 1563-1579 dan A, Inderberg EM, Smeland EB, tenberger J, Berg K (2018) genome stability. suppressors come Nat. Struct. Mol. 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Mensali N, Dillard P, Hebeisen M, Lo- Biochim Biophys Acta Rev Cancer etrance in Fertile Ages, Recurrent kevold ES, Woldbæk PR, Helland Å, EMT and Cancer Progression in 3D Neoplasia,( in press) renz S, Theodossiou T, Myhre MR, 1871: 240-247 De-Novo Mutations and Genetic Drift Brustugun OT, Øynebråten I, Corthay Culture Fåne A, Gaudernack G, Kvalheim G, Cancers (Basel), 11 (2) A.(2019) J Mammary Gland Biol Neoplasia (in Josefsson SE, Beiske K, Blaker YN, Myklebust JH, Inderberg EM, Wälchli Landsverk HB, Sandquist LE, Sridha- Immune Cell Composition in Human press) Førsund MS, Holte H, Østenstad B, S (2019) ra SC, Rødland GE, Sabino JC, de Nilsen A, Jonsson M, Aarnes EK, Non-small Cell Lung Cancer. Kimby E, Köksal H, Wälchli S, Bai B, NK cells specifically TCR-dressed to Almeida SF, Grallert B, Trinkle-Mulcahy Kristensen GB, Lyng H (2019) Front Immunol.9:3101 Brynildsen J, Petäjä L, Myhre PL, Smeland EB, Levy R, Kolstad A, Huse kill cancer cells L, Syljuåsen RG (2019) Reference MicroRNAs for RT-qPCR Lyngbakken MN, Nygård S, Stridsberg K, Myklebust JH (2019) EBioMedicine (in press)
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Nilsen A, Jonsson M, Aarnes EK, Lockmer S, Wise JF, Wahlin BE, Methods Mol Biol (in press) Kristensen GB, Lyng H (2019) Østenstad B, Liestøl K, Kimby E, Ros- Reference MicroRNAs for RT-qPCR enwald A, Smeland EB, Holte H, Ling- Thimiri Govinda Raj DB, Khan NA, Assays in Cervical Cancer Patients jærde OC, Brodtkorb M (2019) Venkatachalam S, Chu DT, Arumugam and Their Application to Studies of A clinico-molecular predictor iden- S (2019) HPV16 and Hypoxia Biomarkers tifies follicular lymphoma patients Step-by-Step Protocol for Superpara- Transl Oncol, 12 (3), 576-584 (in press) at risk of early transformation after magnetic Nanoparticle-Based Endo- first-line immunotherapy some and Lysosome Isolation from Nyakas M, Aamdal E, Jacobsen KD, Haematologica (in press) Eukaryotic Cell Guren TK, Aamdal S, Hagene KT, Methods Mol Biol (in press) Brunsvig P, Yndestad A, Halvorsen B, Sukonina V, Ma H, Zhang W, Barte- Tasken KA, Aukrust P, Maelandsmo saghi S, Subhash S, Heglind M, Foyn Zhang R, Lai L, He J, Chen C, You D, GM, Ueland T (2019) H, Betz MJ, Nilsson D, Lidell ME, Nau- Duan W, Dong X, Zhu Y, Lin L, Shen Prognostic biomarkers for immuno- mann J, Haufs-Brusberg S, Palmgren S, Guo Y, Su L, Shafer A, Moran S, therapy with ipilimumab in metastatic H, Mondal T, Beg M, Jedrychowski MP, Fleischer T, Bjaanæs MM, Karlsson A, melanoma Taskén K, Pfeifer A, Peng XR, Kanduri Planck M, Staaf J, Helland Å, Esteller Clin Exp Immunol (in press) C, Enerbäck S (2019) M, Wei Y, Chen F, Christiani DC (2019) FOXK1 and FOXK2 regulate aerobic EGLN2 DNA methylation and expres- Olsvik HL, Svenning S, Abudu YP, glycolysis sion interact with HIF1A to affect Brech A, Stenmark H, Johansen T, Nature (in press) survival of early-stage NSCLC Mejlvang J. (2019) Epigenetics, 1-12 (in press) Endosomal microautophagy is an Switlyk MD, Salberg UB, Geier OM, integrated part of the autophagic Vlatkovic L, Lilleby W, Lyng H, Seiers- Aasen T, Leithe E, Graham SV, Kamer- response to amino acid starvation. tad T. (2019) itsch P, Mayán MD, Mesnil M, Pogoda Autophagy. 2019 182-183. (In press) PTEN Expression in prostate cancer: K, Tabernero A (2019) relationship with clinicopathologic Connexins in cancer: bridging the Røsok BI, Høst-Brunsell T, Brudvik features and multiparametric MRI gap to the clinic K, Carling U, Dorenberg E, Lothe RA, findings Oncogene (in press Bjørnsson B, Bjørnbeth BA, Sandstrøm American Journal of Roentgenology, P. (2019) (in press). Characterization of Early Recur- rences Following Liver Resection by Szwed M, Sønstevold T, Øverbye ALPPS and Two Stage Hepatectomy A, Engedal N, Grallert B, Mørch Ý, (TSH) in Patients with Colorectal Sulheim E, Iversen TG, Skotland T, Liver-metastases and Small Future Sandvig K, Torgersen ML (2019) Liver Remnants Small variations in nanoparticle (FLR). HPB (Elsevier), In press structure dictate differential cellular stress responses and mode of cell Schuldiner M, Scorrano L, De Matteis death MA, Emr SD, Giordano F, Hajnoczky Nanotoxicology, 1-22 (in press) G, Kornmann B, Lackner L, Levine T, Pellegrini L, Reinisch K, Rizzuto R, Sim- Ten Broeke SW, Rodríguez-Girondo men T, Stenmark H and Ungermann C M, Suerink M, Aretz S, Bernstein I, (2019). Capella G, Engel C, Gomez-Garcia Coming together to define mem- EB, van Hest LP, von Knebel Doeberitz brane contact-sites. M, Lagerstedt-Robinson K, Letteboer Nature Comm. 10, (In press) TGW, Møller P, van Os TAM, Pineda M, Rahner N, Olderode-Berends MJW, Shao B, Bjaanæs MM, Helland Å, von Salomé J, Schackert HK, Spruijt L, Schütte C, Conrad T (2019) Steinke-Lange V, Wagner A, Tops CMJ, EMT network-based feature selection Nielsen M (2019) improves prognosis prediction in The apparent genetic anticipation in lung adenocarcinoma PMS2-associated Lynch syndrome PLoS One, 14 (1), e0204186 families is explained by birth cohort effect Silva A, Bassim S, Sarkozy C, Mottok Cancer Epidemiol Biomarkers Prev (in A, Lackraj T, Jurinovic V, Brodtkorb M, press) Lingjaerde OC, Sehn LH, Gascoyne RD, Weigert O, Steidl C, Kridel R (2019) Thimiri Govinda Raj DB, Khan NA, Convergence of risk prediction mod- Venkatachalam S, Chu DT (2019) els in follicular lymphoma Step-by-Step Protocol for Super- Haematologica (in press) paramagnetic Nanoparticle-Based Plasma Membrane Isolation from Steen CB, Leich E, Myklebust JH, Eukaryotic Cell
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