UCL CANCER INSTITUTE

UCL Workshop on Nervous System Tumour Research

Monday 8 September 2014 9am-5.30pm

Royal College of General Practitioners 30 Euston Square London

Contact [email protected] [email protected] Introduction

Tumours of the nervous system London Cancer, an integrated cancer have a high cost and unmet need system working with UCL Partners, has with over 10,000 new cases and one of the largest paediatric (GOSH), almost 5,000 deaths each year in adolescent (UCLH, NHNN) and adult the UK, many survivors are left (NHNN, BH & BHRUT) neuro-oncology with significant disability. services in the UK. There are strong clinical research interests in imaging, Brain tumours are the leading cause neurosurgery, oncology (radiotherapy of childhood cancer deaths and one and medical oncology) and neuro- of the first causes of cancer death in rehabilitation with multiple principal economically active adults. Critically, investigators of local, national and there has been little improvement in international clinical studies. survival rates for high-risk brain tumours These are exciting times for neuro- in both adults and children. Cancer oncology research given the fundamental Research UK, the main sponsor of this discoveries in the area of (epi)genomics event, has identified brain cancer as of nervous system tumours. It is now one of its four cancers with substantial crucial to translate these breakthroughs unmet need and has stated that they will into novel therapies and improve the often increase focus on these tumours and dismal prognosis of these neoplasms. prioritise them within funding streams. We are convinced that this can be achieved only by fostering interactions Nervous system tumour research is and collaborative efforts across different a major theme across many research research groups and disciplines. institutions in the London area. In particular, neurological disease and As part of this effort, we have organized neurosciences research represent a great the Nervous System Tumour Workshop, proportion of UCL’s biomedical science which will provide an overview of neuro- activity. Notably, there are two Brain oncology research in the London area Tumour Charity-funded programmes and at other leading European research at UCL Cancer Institute/IoN and ICH institutions, and, critically, it will represent covering adult and paediatric neuro- a forum to discuss future research oncology translational research, with the directions in this area. latter involving researchers at the Institute of Cancer Research and Newcastle University.

2 Welcome

On behalf of UCL and the UCL Cancer Institute Director Tariq Enver, it is our pleasure to welcome you to this one-day CRUK and BRC sponsored workshop.

We have an exciting programme with a focus on Nervous System Tumour Research, which we hope will provide a stimulating forum for discussion on how Professor Paolo Dr Darren to facilitate future collaborative neuro- Salomoni Hargrave oncology research in the London area Brian Cross Consultant and beyond. Professorial Paediatric Research Associate Oncologist Samantha Dickson Great Ormond Some of the major themes under Brain Cancer Unit, Street Hospital discussion will include: UCL Cancer Institute London • Clinical Neuro-oncology • Target Identification and Validation • Imaging • Basic Mechanisms and Organising Committee Experimental Models Professor Paolo Salomoni - UCL Cancer Institute We have three outstanding plenary speakers who will provide an insight into Dr Darren Hargrave - their own research programmes and Great Ormond Street Hospital, London more broadly neuro-oncology research at their respective institutions. Professor Tariq Enver - Director, UCL Cancer Institute We extend a special thanks to all of our speakers and chairs and to our sponsors. Dr Matt Wakelin - We hope that you enjoy hearing about the Office of Vice Provost (Health) outstanding work taking place and that Ms Rachel Heatley - you will take the opportunity to interact Office of Vice Provost (Health) with other attendees throughout the day.

3 Programme

Registration Theme: Target identification/ 8.45–9.20am Validation

9.20–9.30am 10.45–11.00am Dr Darren Hargrave and Dr Robin Ketteler Professor Paolo Salomoni – High-throughput screening in – Introduction primary cells and 3D model systems

Session 1 – Plenary Talk 11.00–11.15am 9.30–10.00am Dr Chris Jones Chair: Professor Paolo Salomoni – Unique genetic and epigenetic drivers of paediatric high grade Professor Ruggero De Maria glioma – Strategies for glioblastoma stem cell targeting 11.15–11.30am Dr Tim Forshew Session 2 – Molecular stratification, tumour 10.00am–12.30pm heterogeneity and minimally Chairs: Professor John Anderson invasive genetics and Dr Naomi Fersht Theme: Neuro-oncology Break: 11.30–11.45am 10.00–10.15am Dr Darren Hargrave – Targeted therapies in paediatric Theme: Imaging neuro-oncology; opportunities and challenges 11.45am–12.00pm Professor Xavier Golay 10.15–10.30am – The role of Exchange-mediated MRI contrast in animal models of Dr Jeremy Rees brain cancer – Imaging of Low-Grade Gliomas: anticipating malignant transformation 12.00–12.15pm Dr Adam Badar 10.30–10.45am – Multimodal in vivo imaging of cell therapies targeted at brain tumours Professor Anthony Chalmers – Improving outcomes for glioblastoma patients by targeting 12.15–12.30pm intrinsic and microenvironment Discussion related radiation resistance

4 Session 3 – Plenary Talk 3.00–3.15pm 12.30–1.15pm Dr Juan Pedro Martinez-Barbera Chair: Dr Darren Hargrave – Adult pituitary stem cells induce tumours in a non-cell autonomous Professor Stefan Pfister manner – Clinical neuro-oncology in the omics era Break: 3.15–3.30pm

1.00-1.15pm 3.30–3.45pm Discussion Professor Silvia Marino – Chromatin modifiers in brain Lunch: 1.15–2.15pm tumourigenesis

3.45–4.00pm Session 4 – Professor Sebastian Brandner 2.15–4.15pm – Neural stem cells in the Chairs: Professor Bill Richardson and pathogenesis of brain tumours Professor Nick Wood Theme: Basic Mechanisms and 4.00–4.15pm experimental models Dr Tom Jacques – The neuropathology perspective: 2.15–2.30pm Tissue research at Great Ormond Professor Alison Lloyd Street – Links between nerve injury and NF1 tumourigenesis Session 5 – Plenary Talk

4.15–4.45pm 2.30–2.45pm Chair: Professor Jonathan Ledermann Professor Paolo Salomoni – Nuclear subdomains and Professor Phillipe Lambin chromatin function in nervous – Research in Neuro-oncology: system tumourigenesis What should we do? The Maastricht point of view 2.45–3.00pm Professor Denise Sheer 4.45–5.30pm – Defining the genetic and - Discussion and Closing epigenetic landscape in paediatric Remarks low-grade gliomas Drinks Reception

5 Chairs

Professor John Anderson Dr Naomi Fersht Dr Darren Hargrave Professor of Experimental Consultant Clinical Oncologist Consultant Paediatric Paediatric Oncology University College Hospital Oncologist UCL Institute of Child Health and National Hospital for Great Ormond Street Neurology and Neurosurgery Hospital London

Professor Jonathan Ledermann Professor Bill Richardson Professor of Experimental Professor of Biology Paediatric Oncology Wolfson Institute for Biomedical Research UCL Institute of Child Health UCL Division of Medicine

Professor Paolo Salomoni Professor Nick Wood Brian Cross Professorial Professor of Clinical Research Associate Neurogenetics Samantha Dickson Brain Cancer Unit UCL Institute of Neurology UCL Cancer Institute

6 Plenary Speakers

Professor Ruggero De Maria, MD Professor Stefan M. Pfister Scientific Director, Regina Elena Head, Division of Pediatric National Cancer Institute, Rome, Italy Neurooncology (German Cancer Research Center (DKFZ) Heidelberg Professor Ruggero De Maria graduated in Medicine and specialized in Stefan Pfister was appointed acting head Endocrinology. He is Scientific Director of the Division Pediatric Neurooncology of the Regina Elena National Cancer at the German Cancer Research Center Institute (Rome, Italy) and is internationally (DKFZ) in 2012. Since 2014 he is renowned for his research on cancer professor for pediatric neurooncology at stem cells. the DKFZ and heading the department permanently. Being a pediatrician by His research aims to discover innovative training, Pfister received his MD from biomarkers and develop novel cancer Tübingen University, and his clinical therapies. Other research comprises education at Mannheim and Heidelberg studying microRNA and microenvironment University Hospitals. in solid tumours. As a physician-scientist, he completed He is President of the Italian Alliance postdoctoral fellowships with Christopher Against Cancer, the association of all Rudd at the Dana-Faber Cancer Institute/ comprehensive cancer institutes in Harvard Medical School, and with Peter Italy, and holds several Editorial Board Lichter at the German Cancer Research positions on internationally renowned Center, Division of Molecular Genetics. scientific journals. Pfister´s research focuses on the He has over 140 publications and sits on genetic and epigenetic characterization various prestigious Advisory Boards. of childhood brain tumours by applying next-generation profiling methods and subsequently translating novel findings into a clinical context. For his translational neurooncology projects, Pfister received amongst others the German Cancer Award in 2012.

7 Plenary Speaker Speakers

Professor Philippe Lambin Dr Adam Badar Doctor of Medicine (MD, Université Research Associate, UCL Centre for Catholique de Louvain, Belgium), Advanced Biomedical Imaging Doctor of Sciences (PhD), Specialist in Radiation-Oncology, Professor of Adam Badar obtained his PhD in the field Radiation Oncology of Imaging Sciences at Kings College London specializing in the development Professor Philippe Lambin is a Clinician, of protein-based radiopharmaceuticals for Radiation Oncologist and pioneer in PET and SPECT imaging. translational research with a focus on tumour hypoxia, imaging and Decision Adam now leads the preclinical nuclear Support Systems. imaging unit within the Centre for Biomedical Imaging (CABI) at University He has a PhD in Radiation Biology College London. and is Professor at the University of Maastricht (Radiation Oncology) and at Adam is involved in multiple multimodality the University of Eindhoven (Functional (PET/SPECT/CT/MRI/Optical) imaging Imaging). He is co-author of more than projects and closely supports the 315 peer reviewed scientific papers evaluation of novel and established (Hirsch Index: 59), co-inventor of more radiotracers in various animal models of than 13 patents (filed or submitted) and human disease. (co) promoter of more than 30 completed PhD’s. His own research focuses on supporting the advance of cellular therapies by Moreover, Professor Lambin has extensive developing non-invasive strategies to experience with clinical trials. He was track T and stem cells in animal and man. one of the international experts in the Flims workshop Methods in Clinical Cancer Research, organised jointly by the FECS, AACR and ASCO and he is leading several clinical trials (see www. clinicaltrials.gov: his name is mentioned as Principal Investigator in 18 clinical trials).

8 Speakers

Professor Sebastian Brandner Professor Anthony Chalmers Professor of Neuropathology, UCL Chair of Clinical Oncology, University Institute of Neurology of Glasgow

Professor Brandner’s group studies the role Professor Chalmers’ main research of CNS stem cells in the pathogenesis of interest is in improving outcomes for primary brain tumours. Their study led to patients with glioblastoma by combining the discovery that adult brain stem cells can radiotherapy with targeted drug therapy, give rise to brain tumours. The translational but his research interest in radiotherapy- aspect of this study demonstrated that the drug combinations extend across tumour brain tumour microenvironment strongly sites. His clinical practice at the Beatson modifies tumour genetics, directing West of Scotland Cancer Centre is the pathway for growth dynamics, and devoted to the treatment of patients ultimately therapeutic responsiveness with brain tumours, and he runs the of brain tumours, with implications for Translational Radiation Biology laboratory understanding how to properly model and in the Institute for Cancer Sciences. treat disease more effectively. He is Deputy Chair of the NCRI Clinical They also have long-standing experience and Translational Radiotherapy Research in the generation and analysis of mouse Working Group (CTRad) and leads the models of developmental and neoplastic CTRad Radiotherapy-Drug Combinations phenotypes and have strong links with UCL Consortium. Cancer Centre, the Blizard Institute and the Brain Tumour Unit at the National Hospital. Prior to taking up his post in Glasgow in September 2010 he studied at Oxford Recently, they have established xenograft University Medical School and UCLA and model systems to study human brain has worked in a number of cancer centres tumours in vivo, which have strengthened in the UK including the Royal Marsden their network on brain tumour research. Hospital, Mount Vernon Hospital, the Middlesex Hospital and the Sussex He also leads the Division of Neuropathology Cancer Centre in Brighton. His scientific to deliver the diagnostic and research training has taken place at the Gray infrastructure of the UCLH Brain cancer Cancer Institute, where he undertook a centre, one of very few departments in the PhD in Radiation Biology, and the MRC UK that provides molecular pathology Genome Damage and Stability Centre at analysis for all patients operated on a the University of Sussex. glioma.

9 Speakers

Dr Tim Forshew Professor Xavier Golay Senior Research Associate, Research Professor of MR Neurophysics and Department of Pathology, UCL Cancer Translational Neuroscience, UCL Institute Institute of Neurology

Dr Forshew is a new group leader Professor Golay received a Master of at UCL. His team focuses on the Science Degree in Physics from the Swiss development of novel techniques for the Federal Institute of Technology of Lausanne analysis of cancer mutations. in 1994. He then moved to the Swiss Federal Institute of Technology of Zurich, His current research is based on where he worked as a research assistant detecting cancer DNA released by solid in the group of Professor Peter Boesiger tumours into bodily fluids such as blood towards his PhD on Functional MRI. and urine. Major clinical focuses of the group are sarcoma and childhood brain In 1999, he moved to Johns Hopkins tumours. University, Baltimore, as a post-doctoral fellow. In 2002 Dr Golay took up the During his time at Cambridge University position of Head of the Laboratory of he was part of the team that first Molecular Imaging at the Singapore demonstrated detecting solid tumour Bioimaging Consortium. mutations through next generation sequencing of blood plasma. In October 2008, he was appointed Chair of MR Neurophysics and Translational As a postdoctoral Researcher at QMUL Neuroscience at the UCL Institute of he won the 2009 Jeremy Jass Prize for a Neurology in London. In May 2012, study identifying fusion genes in Pilocytic Professor Golay was promoted to the Astrocytoma. position of Head of the Department of Brain Repair and Rehabilitation at the UCL Institute of Neurology.

His research interests include the development of MRI as a translational tool for neurological diseases, measuring identical image-based biomarkers from mouse to human, and from the laboratory to the clinical settings.

10 Speakers

Dr Darren Hargrave Dr Thomas Jacques MA PhD MRCP Consultant Paediatric Oncologist, FRCPath Great Ormond Street Hospital, London HEFCE Clinical Senior Lecturer & Honorary Consultant Paediatric Dr Darren Hargrave is a Consultant Neuropathologist paediatric oncologist at Great Ormond Street Hospital, London having previously Dr Jacques is a neuropathologist who worked at the Royal Marsden, London. runs a research group at the UCL Institute of Child Health focusing on brain tumours He specialises in paediatric neuro- and epilepsy. He provides the diagnostic oncology and the development of new neuropathology service for Great Ormond anti-cancer drugs for children and Street Hospital. adolescents. He trained in the UK and Canada and is a member of both national He holds a national HEFCE Clinical and international groups in the fields Senior Lectureship and has published of paediatric neuro-oncology and drug over 75 papers and a textbook of surgical development. pathology.

He was the Chair of the SIOPE High Dr Jacques received the Cavanagh prize Grade Glioma working group. He is a of the British Neuropathological Society. Chief/ Principal Investigator of several He is the chair of the scientific committee completed, on-going and planned clinical and chief investigator of the CCLG trials in paediatric cancer. tumour bank.

His research interests include: the biology He is also the secretary of the of childhood malignant glioma and DIPG, clinical practices group of the British the use of innovative imaging techniques Neuropathological Society and executive in childhood cancer, neurofibromatosis editor at Neuropathology and Applied related tumours and drug development Neurobiology. of targeted therapies in childhood and adolescent oncology.

11 Speakers

Dr Chris Jones Dr Robin Ketteler Research team leader, Divisions of TRCC Leader, MRC Laboratory for Molecular Pathology and Cancer Molecular Cell Biology, UCL Therapeutic, The Institute of Cancer Research Robin Ketteler studied biochemistry at the Free University Berlin and Dr Jones’ lab is focused on translating graduated at the Max-Planck-Institute for genomics findings to new treatments Immunobiology in Freiburg, Germany. in paediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG), and is After post-doctoral work at the active in international paediatric brain Massachusetts General Hospital, Boston, tumour collaborative groups and clinical Robin established the Translational trials. Research Resource Centre at MRC LMCB, University College London in Dr Jones achieved his PhD in 1998 2009. from the University of London, after first attaining a Bachelor of Science with This academic high-throughput screening First Class Honours in Toxicology and centre facilitates siRNA, cDNA and Pharmacology. He was elected Fellow chemical screening in primary cells and of the Royal College of Pathologists in cell lines. 2008 for his significant contribution to molecular pathology research. He was Main research interests focus on awarded a Readership in 2013. autophagy, protein trafficking, mitogenic signaling and virus infection. Dr Jones is the Translational Science Lead for international clinical trials in paediatric high grade glioma for the International Society for Paediatric Oncology (SIOP) European Brain Tumour Group.

He is a Fellow of the Royal College of Pathologists and is Biology Lead for the International Society for Paediatric Oncology European High Grade Glioma Working Group.

12 Speakers

Professor Alison Lloyd Professor Silvia Marino Professor of Cell Biology, MRC Professor of Neuropathology, Barts Laboratory for Molecular Cell Biology, and The London School of Medicine UCL and Dentistry, QMUL

Professor Lloyd is studying schwannoma Silvia Marino is Professor of Neuropathology - a cancer affecting Schwann cells, which at Barts and The London School of Medicine surround and protect our nerve cells. and Dentistry, Queen Mary University of Professor Lloyd and her team are finding London and also Honorary Consultant out more about how Schwann cells grow Neuropathologist at Barts and The London out of control, leading to cancer. NHS Trust and at the National Hospital for Neurology and Neurosurgery, Queen Square. In particular she studies the signals that determine how Schwann cells switch After studying Medicine at the University their characteristics, and how this of Turin in Italy, Professor Marino trained process goes out of control in cancer. in Neuropathology and Histopathology Her research will shed light on how at the University of Zurich in Switzerland. schwannomas and other types of tumour She trained in molecular genetics with develop, and will give clues for new ways Professor Anton Berns at The Netherlands to prevent and treat these diseases in the Cancer Institute in Amsterdam as a Marie future. Curie Postdoctoral Fellow of the European Community studying the role of the tumour The tumours that her work is most suppressor Rb and p53 in the pathogenesis relevant to are the tumours that develop of medulloblastoma in genetically in the peripheral nervous system in engineered mouse models. She established patients with NF1. her own laboratory research group in 2002 firstly at the Institute of Pathology, University of Zurich and then since 2006 at the Blizard Institute in London, studying basic cellular and molecular mechanisms controlling the development of the central nervous system and how these mechanisms can contribute to brain tumourigenesis when deregulated. She is particularly interested in Polycomb- mediated regulation of gene expression in normal and neoplastic neural stem cells.

13 Speakers

Dr JP Martinez-Barbera Dr Jeremy Rees Wellcome Trust Research Fellow, UCL Consultant Neurologist, National Institute of Child Health Hospital for Neurology and Neurosurgery and UCLH Dr Martinez obtained his PhD at the University of Cadiz (Spain). He then moved to the Dr Jeremy Rees is an Honorary Senior University of Lund as a postdoctoral Lecturer in UCL’s Institute of Neurology scientist in the laboratory of Dr. Stefan with a specialty interest in Neuro-oncology. Krauss, where he changed field to work in He qualified in 1988 with distinctions in developmental biology. In 1997, he joined Medicine, Surgery and Therapeutics. the laboratory of Dr. Rosa Beddington to pursue the analysis of the Hesx1 null mutant After general professional training in mouse he had engineered. In February 2003 various postgraduate London teaching he started his laboratory at the UCL-Institute hospitals and following a period of research of Child Health funded by a Research Career culminating in the award of a PhD, he Development Fellowship from the Wellcome completed his specialist neurology training Trust and sponsored by Dr. Andrew Copp. In in London and Memorial Sloan Kettering 2008, he was awarded a University Award Cancer Center, New York. He has been a from the Wellcome Trust to characterize the consultant since 1999 and also consults molecular mechanism underlying the forebrain at the Royal Marsden Hospital, Royal defects observed in Hesx1-deficient mice. His National Orthopaedic Hospital and Mount research program aims to understand normal Vernon Cancer Center. He was the Clinical development and pathology of the brain Lead for the neuro-oncology service at and associated structures. Developmental UCLH at NHNN until 2013. disorders of the brain have an overall significant prevalence in humans and include He is the Brain Tumour Pathway Director, congenital defects as well as childhood taking responsibility for the strategic brain tumours. For the last several years development and integration of care for his group has provided important insights patients with brain tumours in London into normal brain and pituitary development. Cancer. He has published extensively on They have also contributed significantly brain tumours and has recently co-edited a to the understanding of the aetiology textbook on Neuro-oncology. and pathogenesis of human congenital hypopituitarism and pituitary tumours (eg His research interests including advanced craniopharyngioma). Their aim is to reveal the imaging techniques in Low-Grade Gliomas aetiology and pathogenesis of these human and paraneoplastic neurological syndromes. disorders using a multidisciplinary approach..

14 Speakers

Professor Paolo Salomoni Professor Denise Sheer Brian Cross Professorial Associate Professor of Human Genetics Samantha Dickson Brain Cancer Unit, Blizard Institute, Barts and The UCL Cancer Institute London School of Medicine & Dentistry, QMUL Paolo Salomoni was appointed Brian Cross Professorial Research Associate A major focus of Denise’s research is to at the UCL-Cancer Institute, Department understand how paediatric brain tumours of Cancer Biology in 2009. He leads the arise and grow. Samantha Dickson Brain Cancer Unit, funded by The Brain Tumour Charity. He Her team have conducted genetic is also part of the UCL Centre for Stem profiling of a large set of paediatric Cells and Regenerative Medicine and of low-grade gliomas from St Jude UCL Neuroscience. Paolo started his PhD Children’s Research Hospital, and training at the Kimmel Cancer Center, are complementing these studies Philadelphia, under the supervision of with epigenetic analysis on the same Bruno Calabretta. tumour set.

He then moved to the Memorial Sloan- They are also collaborating with Dr Kettering Cancer Center, New York, in Thomas Jacques at ICH/UCL, to identify the laboratory led by Pier Paolo Pandolfi. significant microRNA profiles, and to After finishing his postdoctoral training develop minimally invasive diagnostic at MSKCC, he moved to the Medical tests for paediatric brain tumours. Research Council Unit in Leicester, where he was programme leader track and then programme leader. The main focus of his group is on molecular mechanisms underlying cell fate control in normal and neoplastic stem cells, and how alterations of these mechanisms contribute to cancer in the brain and other tissues. In particular, his research team investigates two main processes involved in tumourigenesis alteration of chromatin function and the interchromatin space and metabolic deregulation.

15 UCL CANCER INSTITUTE

With grateful thanks to our sponsors: Cancer Research UK and UCL Hospitals Biomedical Research Centre

www.cancerresearchuk.org/ www.uclhospitals.brc.nihr.ac.uk/ www.ucl.ac.uk/cancer