PIONEERING RESEARCH 2016/17

Transcription

1 PIONEERING RESEARCH 2016/17 OUR ANNUAL RESEARCH PUBLICATION

2 CONTENTS HIGHLIGHTS 2 50 Welcome from Investing in the future: Iain Foulkes How our fellowships make a difference 4 16 Tackling hard-to-treat cancers We focus on pancreatic cancer and brain tumours and share some of the exciting research going on and investments we're making. 36 A recipe for successful drug development We take a look at the unique role CRUK plays in supporting early studies of anti-cancer therapeutics. Our facts & figures 2016/17 8 Our funding decisions 10 Progress against our Research Strategy 12 Our UK-wide network 21 Hacking into normality: 54 Our prizewinners 56 Honouring a giant of translational research: Stan Kaye 58 Behind closed doors: An insight into our funding committees 60 Gerard Evan Measuring the impact of research 22 Catching cancer earlier: 62 A new frontier for early The last word OUR FRONT COVER: THE SPHERE OF INFLUENCE The striking visualisation used on the cover of our 2016/17 publication is based on data relating to CRUK-funded research. Using Researchfish submissions, the graphic visualises a selection of over 1000 research papers resulting from CRUK funded research and published in the last five years. Each paper is visualised through a dot surrounded by a collection of rings. These rings represent the citation links between papers either where the paper has been cited by others or where it has cited other papers. The larger and denser the rings, the more citations. The visualisation demonstrates the influence CRUK-funded research has on the wider scientific community and the ongoing exchange of knowledge. Note: Colours do not represent anything specific and are purely aesthetic. 26 Grand Challenge Meet the first multidisciplinary, international teams funded through our Grand Challenge. 46 Microbiome and cancer The microbiome has been a buzz word for years, but what s all the fuss about with regards to the possible link with cancer? Patient perspective detection research 32 Catalysing a step change in population research 42 Open for business: Inside the Francis Crick Institute Public engagement 64 Acknowledgements 1

3 WELCOME FROM IAIN FOULKES WE WILL LOOK TO PLAY OUR ROLE IN STRENGTHENING THE UK AS A WORLD-LEADING DESTINATION FOR CANCER RESEARCH This year has been another busy year for CRUK as we continue in implementing the ambitions in our Research Strategy. Our ambitions are big, and this year we made progress towards these through strengthening our infrastructure across the UK, announcing our first Grand Challenge teams, and continuing to support novel, exciting work across our portfolio. One of our biggest infrastructure success stories has been our Centres programme. This year we announced funding for the next five years for our CRUK Centres across the UK and, jointly with the Departments of Health for the devolved nations, for the Experimental Cancer Medicine Centres (ECMC) network. These demonstrate our commitment to the long-term support for these locations, each a hub of excellence, linking up expertise at the local level and connecting across the national network. Through our Accelerator Awards we are making it easier for researchers to collaborate between Centres, and through the expansion of these awards to include European partners, we aim to drive progress in translational research by building outstanding global networks. Our network of ECMCs is coming into its own. Some of our biggest studies such as TRACERx, the National Lung Matrix trial, and the newly funded PRECISION-Panc initiative would not be happening without the ECMCs. Excitingly, TRACERx has taken only three years to produce some really important insights the recent Nature and New England Journal of Medicine papers resulting from the study may be transformative for lung cancer patients by predicting the likelihood of relapse and detecting it earlier. It s been great to see the breadth of the portfolio building on these new platforms. By giving investigators better access to clinical samples and other reagents, we re enabling more high-quality discovery science, and whilst this is contributing greatly to our efforts across the board, it s particularly important for our priority area of cancers of unmet need. Strong communities studying lung and oesophageal cancers are now emerging, and this year we ll be focussing on strengthening our efforts in brain cancer, where our funded researchers are excellent, but not nearly numerous enough. This year we have taken the next steps on our journey towards international funding, to support the best people wherever they are, with the announcement of our first Grand Challenge and Catalyst Award teams. Through Grand Challenge, the panel was overwhelmed by the high calibre of the applications, so we found a way to fund four exceptional teams, with funding awarded through the first round totalling 71 million. We should definitely view Grand Challenge and our other international schemes as fantastic vehicles for UK scientists to forge links with their international counterparts something which can only be of benefit to everyone concerned. It s right to celebrate our successes in large scale infrastructure projects and international expansion, but we should never forget that home-grown discovery science comprises almost half our portfolio. There s been a big growth in programmatic funding, and we re currently supporting 95 clinical and non-clinical fellows, and around 140 programme awards. Our commitment to this core science is fundamental to our strategy and aims. We are continually striving to do more to accelerate the translation of research, and have always encouraged our researchers to think hard about the potential of their work to benefit patients and the population at large. We ve had some amazing successes: supporting the development of eight cancer drugs now in widespread use globally, testing over 100 new drugs in cancer patients, and taking many more anti-cancer therapies into clinical trials. In a step change in ambition, we ve recently created a new division, Research and Innovation, with the vision of making CRUK the world-leading global cancer research and innovation organisation. This single operation will enhance our scope and capability to go from the first funding of a research idea all the way through to a fully developed or commercialised innovation. We are now in a strong position to partner with organisations that can help at the earliest stages and ensure those ideas progress as rapidly as possible. We ve also had some set backs this year too. We were all saddened by the news of the recent fire at the CRUK Manchester Institute. However, with no one hurt, the team in Manchester is exploring options for getting back up and running in the short-term and how to re-build for the long-term. We ll continue to work with them and do everything we can to support our colleagues at the Manchester Institute recover from this devastating event. I d like to close by saying a little about the political upheavals of the past year. We live in uncertain times, and CRUK s role as an influential scientific organisation has never been so important. Our activities will continue to support collaboration both nationally and abroad and we will always look to play our role in strengthening the UK as a world-leading destination for cancer research. This publication celebrates some of your incredible work over the past year and outlines a few areas of current interest to the wider community and us. Thank you to everyone who contributed to this publication we could not have done it without you. We hope you enjoy reading it. Iain Foulkes Executive Director, Research and Innovation, CRUK 2 3

4 FACTS & FIGURES 2016/17 MILLION Total research activity spend in 2016/17 We are committed to funding high-calibre, innovative research that we believe has the potential to provide the greatest benefit to the public and cancer patients. Our diverse portfolio spans a breadth of research areas, from fundamental discovery research to understand the biology and causes of cancer, through translational research to bring the latest discoveries to the benefit of patients, to drug discovery to identify potential new treatments, clinical research to deliver the best treatments for patients, and population-level research covering epidemiology, prevention and early diagnosis of cancer. OUR PEOPLE We are proud to support 4,000 researchers, doctors and nurses in 90 different institutions across the UK and internationally. Our progress is dependent on these outstanding individuals and teams conducting high-quality research. It is their creativity, passion and expertise that will ultimately lead us to the answers we need to beat this disease. We are dedicated to supporting people from the start of their career through to providing programme awards for world-class group leaders. Currently we support over 550 PhD students, more than 750 post-docs, 95 Fellows, and over 700 Principal Investigators. We have a strong tradition of excellence, having funded seven Nobel Prize winning researchers recognised for their outstanding contribution to cancer research. OUR PATIENTS Our ambitious Research Strategy aims to continue our excellence in discovery research while also accelerating the translation of scientific discoveries into benefits for patients and the public. We support over 250 clinical trials, with more than 22,000 people joining our trials each year. More than 1 in 5 adult cancer patients in the UK take part in a clinical trial a higher proportion than anywhere else in the world. OUR IMPACT CRUK has been at the forefront of advances in cancer research for over 100 years, including helping to fund milestone work that defined the way tamoxifen is used in cancer treatment today. We are also extremely proud to have helped support the development of eight new cancer drugs, including Temodal, Zytiga and Erivedge, that have contributed to this progress. We have a uniquely broad portfolio of cancer-focused projects with more than 30 partnered agents in pre-clinical and clinical development. We are committed to funding curiosity-driven research as well as investing in pioneering new approaches and bringing new disciplines to bear on the cancer problem. FUNDING BY DISEASE TYPE Our funding covers research into a wide range of cancer types. Over 100m Research that underpins all types of cancer 112.0m 10m to 25m Leukaemia 18.1m Brain 13.5m Oesophageal 11.7m Ovarian 13.0m Prostate 22.4m Pancreatic 17.2m Melanoma 12.0m Research underpinning all types of cancer Cancers of unmet need 25m to 100m Colon & rectal 34.7m Under 10m Laryngeal 1.9m Stomach 0.7m Bladder 4.3m Cervical 3.0m Eye 0.5m Sarcoma 5.0m Neuroblastoma 3.6m Hodgkin's lymphoma 2.5m Oral cavity & lip 1.3m Non-Hodgkin lymphoma 8.8m Myeloma 4.3m Pharyngeal 2.8m Endometrial Testicular 0.7m Lung 43.4m 1.5m Cancer types where funding is under 0.5m Other cancer types Breast 32.8m Liver 4.4m Kidney 3.8m Skin (exc. melanoma) 2.6m Small intestine 1.2m Other 2.3m 4 5

5 FUNDING ACROSS LOCATIONS BY DISEASE TYPE We support research in over 90 institutions, with focus in key locations. This chart shows the distribution of 2016/17 funding for the top disease types across locations receiving at least 1 million. The shading represents the percentage of disease type funding at each location, so whilst the shading is comparable between columns, the underlying totals are not. Belfast Birmingham Brighton Bristol Cambridge Underpinning research Lung Colon and rectal Breast Prostate Funding share up to: 10% 20% 30% 40% 50% 60% Research underpinning all types of cancer Cancers of unmet need Other cancer types Leukaemia Pancreatic Brain Ovarian Melanoma Oesophageal Non-Hodgkin lymphoma Sarcoma Liver Myeloma FUNDING ACROSS THE RESEARCH PIPELINE The distribution of our funding across the research pipeline. 6.3 Behaviour related to cancer control 6.1 Patient care & survival issues 5.7 Resources & infrastructure - treatment 5.6 Complementary & alternative approaches - treatment 5.5 Combined localized & systemic therapies 5.4 Systemic therapies - clinical applications 6.5 Education & communication 6.4 Cost analysis & health care delivery Treatment Cancer control, survival & outcomes 6.6 End of life care 6.9 Resources & infrastructure - cancer control, survival & outcomes research Biology 1.1 Normal functioning 1.2 Cancer Initiation: alterations in chromosomes 1.3 Cancer Initiation: oncogenes & TSGs 1.4 Cancer progression & metastasis 1.5 Resources & infrastructure - biology 2.1 Exogenous factors Cardiff Dundee Edinburgh Glasgow Leeds Leicester Liverpool London: Imperial College London London: King s College London London: Queen Mary, University of London 5.2 Localized therapies - clinical applications 4.3 Technology/ marker testing (clinical) 3.5 Complementary & alternative approaches - prevention Early diagnosis, detection & prognosis Prevention Treatment CLINICAL 21% BASIC 48% TRANSLATIONAL 31% Prevention Aetiology/ causes Cancer control, survival & outcomes 2.2 Endogenous factors 2.3 Genes/ polymorphisms existing with exo-/endogenous factors 2.4 Resources & infrastructure - aetiology 6.2 Surveillance London: Francis Crick Institute London: The Institute of Cancer Research London: University College London 5.3 Systemic therapies - discovery and development Early diagnosis, detection & prognosis 3.1 Interventions: personal behaviours affecting risk 3.2 Nutritional science London: Other Manchester Newcastle Upon Tyne Oxford Southampton All other locations 5.1 Localized therapies - discovery & development 4.4 Resources & infrastructure - early detection, diagnosis & prognosis 4.2 Technology/ marker evaluation 4.1 Technology development/ marker discovery 3.6 Resources & infrastructure - prevention 3.3 Chemoprevention 3.4 Vaccines 6 7

6 FUNDING ACROSS OUR COMMITTEES The distribution of 187m funding awarded through our committees in 2016/17, showing amount awarded, number of awards made, and success rate. 2016/17 funding Number of awards Success rate % * Clinical Careers Committee (CCC) supports early-career clinical academic researchers, funding fellowships and bursaries supporting clinicians and health professionals working in areas spanning basic and translational cancer research. Fellowships Bursaries 14.2m 0.2m 61% 33% Clinical Trials 10.6m 38% Clinical Research Committee (CRC) oversees funding and endorsement of late-phase investigator-led clinical trials, and other research supporting or enabling clinical trials. Experimental Medicine Programmes Sample Collections 5.2m 0.8m 33% 10% Biomarker Projects 0.6m 8% Fellowships 0.3m 43% Drug Discovery Committee (DDC) advises on and implements our strategy in the area of drug discovery, funding biotherapeutic and small molecule drug discovery and our drug discovery infrastructure. Programmes Projects 1.6m 2.4m 100% 48% OUR FUNDING DECI IONS Early Diagnosis Advisory Group (EDAG) supports short term project grants for the earlier diagnosis of cancer that have the potential to immediately impact on policy and practice for patient benefit. Grand Challenge (GC) sets the challenges and reviews applications for our Grand Challenge Awards. New Agents Committee (NAC) reviews proposals for the preclinical development and early phase clinical trials of new anti-cancer treatments and diagnostics. Projects Grand Challenge Awards Trial Grants Preclinical Grants Drug Development Projects 0.6m 73.3m 0.5m 0.3m - 45% 44% 67% 46% 57% New Investigator Committee (NIC) supports early-career cancer researchers as they develop their independent research groups. Fellowships 16.1m 29% MILLION Funding allocated through our committees in 2016/17 Every year we invest around 350 million into cancer research, made possible entirely through the generosity of our supporters and the public. They give generously in the expectation that we will deliver benefits to patients and the public, and we take that responsibility seriously. It is incumbent on us to fund research of the highest calibre, and much of this funding is awarded through our committees, each with a specific remit, enabling us to support a breadth of discovery science, translational, clinical, population and behavioural research. We are proud of our funding structures and processes which allow us to evaluate applications across the spectrum of research our researchers want to undertake. Our commitments are split across different funding mechanisms, supporting the best research in the most effective ways, from our core-funded institutes, to funding grants and awards through our committees, and the UK-wide infrastructure network that exists for our whole community to benefit from. Our funding committees are comprised of UK and international experts, ensuring that our decisions are well informed and that we continue to fund pioneering research across a wide range of disciplines. The rigorous process for reviewing funding proposals involves many people across the community, from those who give their time to sit on our funding committees and panels, to peer reviewers who provide expert evaluation of individual applications. It is only through the hard work, enthusiasm and commitment of these many individuals that we can continue to support research that will have the biggest impact and bring significant progress to the field. Pioneer Award Committee (PAC) reviews applications to our Pioneer Award, supporting higher risk, truly novel ideas that have the potential for high reward. Population Research Committee (PRC) supports clinical and public health epidemiology and educational and behavioural research on cancer prevention, screening and early diagnosis. Science Committee (SC) supports our discovery and translational cancer research activity through science programme awards, and builds expertise in cancer immunology and multidisciplinary research. Tobacco Advisory Group (TAG) reviews applications for policy research and policy advocacy activities in tobacco control. Projects Catalyst Awards Programmes Projects Fellowships Programmes Programme Foundation Awards Projects Programmes Projects *Success rate is from full application. Where a scheme has an outline stage, this has not been included in the rate calculations 1.9m 4.4m 6.7m 2.3m 1.3m 27.6m 8.3m 6.8m 0.3m 1.1m 45% 17% 40% 20% 36% 56% 46% 15% 100% 77% 8 9

7 BRINGING IN THE PATIENT PERSPECTIVE Image: CRUK workshop in progress PROGRESS AGAINST OUR RESEARCH STRATEGY Since 2014 we ve launched eight new funding schemes, allocating 140 million to date. These schemes include our Grand Challenge awards bringing international multidisciplinary teams together to tackle the biggest challenges in cancer, our Catalyst Award supporting capacity building and collaboration in population health and our Pioneer Award which backs higher-risk, novel ideas that have the potential to be transformative in tackling cancer. We ve increased our spend in lung, pancreatic and oesophageal cancers and brain tumours, spending a total of 86 million in these four cancer types in 2016/17. These targeted investments are helping to build leadership, train the next generation of researchers and facilitate enhanced collaboration. People affected by cancer drive everything we do. By sharing their experiences, they provide vital insights that help us develop our work. As part of assessing our progress against our Research Strategy, in January 2017 we ran a workshop with 12 patients and people affected by cancer to draw in the perspective of patients to our strategy work. The day was felt to be a positive experience, providing those present with the opportunity to get closer to CRUK s Research Strategy. As one participant, Terry Kavanagh, noted: This was an opportunity to share with the research community my views and opinions as a cancer patient. I felt that my comments were listened to and my input was taken on board. Paul Maclean was new to the scientific side of CRUK s work, but found the workshop hugely worthwhile as he felt patient representatives were being asked to get involved in some fundamental issues within CRUK s core activity. With regards to the progress being made, he reflected: CRUK is clearly making tangible progress in many areas, but could be more focused in specific areas of need. In 2014 we launched our Research Strategy, which set out our research priorities for the next several years. We created an ambitious agenda to develop a research programme that would accelerate progress and see three-quarters of cancer patients surviving cancer within the next 20 years. Three years in, we re taking stock of our progress. Here we showcase some of our highlights. Investing in the right environment for research to flourish remains a priority. We have continued our investment in our institutes, with the Francis Crick Institute opening its doors in 2016, and strengthened our investment in our UK-wide CRUK Centres and Experimental Cancer Medicine Centres (ECMC) network, with 266 million to be invested over the next five years. Our research funding has increased to 386 million in 2016/17, enabling us to fund more research across all areas of our portfolio and supporting high calibre science. Read more about the progress we're making at cruk.org/progress-report Graydon Downs has been living with glioblastoma for almost five years. After the workshop he reflected: Working with CRUK has made me realise that we need to invest in all types of cancer. Finding cures for brain tumours is personally and emotionally important to me. But every type of cancer is painful for somebody. He added: It felt good to be able to give my view on the charity s progress on reaching the goals set out in their strategy

8 UR Institutes (5) Centres (13 including 2 Major Centres) Cancer Imaging Centres (4) Lung Cancer Centre of Excellence (1) Experimental Cancer Medicine Centres (ECMCs) Adult & Paediatric (9) UK-WIDE Experimental Cancer Medicine Centres (ECMCs) Adult only (9) Experimental Cancer Medicine Centres (ECMCs) Paediatric only (2) Clinical Trials Units (8) Drug Discovery Facilities (4) NETW RK GLASGOW EDINBURGH Therapeutic Discovery Labs (2) CRUK-MEDI Alliance Laboratory (1) Manufacturing Facilities (2) Stratified Medicine Programme Technology Hubs (3) Joint Establishments At CRUK we recognise the importance of creating a dynamic and responsive research environment. Our long-term investment has helped to create a thriving network of research at 90 different institutions and in more than 40 towns and cities across the UK and internationally. Our network of researchers and infrastructure includes capabilities ranging from basic biology research all the way through to the delivery of late-phase clinical trials. BELFAST NEWCASTLE LEEDS MANCHESTER LIVERPOOL SHEFFIELD Locations where we support research infrastructure as at 1 April 2017 LONDON Barts Centre ECMC Clinical Trials Unit Clare Hall Laboratories Biotherapeutics Development Unit Imperial Centre ECMC King s Centre Cancer Imaging Centre (joint with UCL) ECMC London Bioscience Innovation Centre Therapeutics Discovery Lab Royal Marsden Hospital Stratified Medicine Programme Technology Hub Francis Crick Institute Institute The Institute of Cancer Research Centre Cancer Imaging Centre Clinical Trials Unit Drug Discovery Facility ECMC UCL Centre Cancer Imaging Centre (joint with King s) Lung Cancer Centre of Excellence (joint with Manchester) Clinical Trials Unit ECMC CARDIFF LEICESTER BIRMINGHAM OXFORD BRISTOL SOUTHAMPTON CAMBRIDGE LONDON 12 13

9 Locations where we fund research A THRIVING RESEARCH NETW RK DISCOVERY SCIENCE Our five core-funded research institutes provide an exceptional environment for discovery science, and have an outstanding track record. We fund around 125 research groups across the CRUK Beatson Institute in Glasgow, the CRUK Cambridge Institute, the CRUK Manchester Institute, the CRUK/MRC Oxford Institute for Radiation Oncology, and the Francis Crick Institute in London Europe s largest singlelocation biomedical research institute under one roof. These institutes provide long-term support and core scientific services. They play a key role in recruiting and retaining world-class researchers and in promoting interdisciplinary collaboration with the wider research community. Alongside our Institutes, we fund over 250 investigator-led programmes of discovery science and population research. THERAPEUTIC DISCOVERY We have an established history of successful drug discovery, having contributed to the discovery or clinical trials of nearly 50 drugs now in clinical development. Our work in therapeutic discovery is supported by four highly equipped small molecule Drug Discovery Units (DDUs) and our Therapeutic Discovery Labs. Our DDUs exploit biological insights derived from CRUK-funded research across the UK, in addition to identifying and validating targets derived from the published literature. These units have a proven track record in small molecule drug discovery, with many clinical candidates now under investigation in patients. Our Therapeutic Discovery Labs focus on biologically-themed multi-project alliances with academia and commercial partners. The team has established successful alliances with AstraZeneca, Teva Pharmaceuticals, Research groups funded across our institutes Forma Therapeutics, MRCT and Merck KGaA. In addition to small molecule development, CRUK has partnered with MedImmune to support facilities focused on accelerating the discovery and development of novel antibodies. The Cancer Research UK-MedImmune Alliance Laboratory brings together CRUK s cancer biology expertise with MedImmune s world class antibody engineering technology, enabling researchers with promising new insights from novel biology to access MedImmune s capabilities and technology in antibody engineering. The research opportunity provided by the laboratory is open to scientists based both in the UK and internationally. THERAPEUTIC DEVELOPMENT Our Centre for Drug Development (CDD) provides a complete pre-clinical and first-inhuman capability in both small-molecule and biological therapeutic development. Its span of expertise includes therapeutic manufacturing and pre-clinical phase to the full clinical trial operations needed to demonstrate the clinical potential of any novel cancer agent. The CDD also operates its own state of the art manufacturing facilities, with the expertise to produce clinical formulations for small-molecule drugs and biologicals including monoclonal antibodies, recombinant proteins and DNA. Ximbio is a platform for researchers to exchange knowledge and trade reagents, enabling the sharing of research tools within the global life science community. It acts as a marketplace for scientists and inventors, allowing them to deposit reagents, thus maximising commercial opportunities for these tools. TRANSLATIONAL AND CLINICAL RESEARCH Our Centres form a unique national network facilitating multidisciplinary translational research of the highest international quality and training the next generation of clinicians and researchers. They drive local partnerships between universities and hospitals, cancer networks and other research charities, to accelerate the translation of research into the clinic. Investigator-led programmes of discovery science and population research Our network of Experimental Cancer Medicine Centres provide a unique service for earlyphase clinical trials, not only for the treatments that we develop and optimise ourselves, but also to industry and other funders whose trials we are able to endorse. We also support Clinical Trials Units (CTUs) which provide the academic cancer research community with expertise to design and run clinical trials at all phases. Our CTUs provide support covering all aspects of clinical trial design, management, database provision and data analysis and publication. They coordinate national and international clinical trials, and other studies which aim to directly influence routine clinical practice. Additionally, our translational research is enhanced by specialist Cancer Imaging Centres, a partnership with the Engineering and Physical Sciences Research Council, which integrate pre-clinical and clinical research to facilitate the improved detection, diagnosis and treatment of cancer. POPULATION RESEARCH In partnership with other agencies, we fund the UK s outstanding infrastructure for population research, including epidemiology and behavioural sciences. We provide the core-funding for the UCL Health Behaviour Research Centre, a pioneering centre for advancing our understanding of behaviours that impact on health and the design and evaluation of behavioural interventions We are a part of the UK Clinical Research Collaboration which funds five Public Health Research Centres of Excellence, including the Centre for Diet and Activity Research (CEDAR) in Cambridge and the UK Centre for Tobacco Control and Alcohol Studies (UKCTAS), a network of 13 universities (12 in the UK and 1 in New Zealand). We are also building capacity in health informatics research through the Farr Institute, which comprises four nodes across the UK. BUILDING GLOBAL NETWORKS To support our ambition to accelerate translational research at our Centres and increase the reach of our network, we have entered into a new funding partnership with the Spanish Association Against Cancer Scientific Foundation (FC AECC), the principal cancer research charity in Spain, and the Italian Association for Cancer Research (AIRC), the principal cancer research charity in Italy. This partnership will capitalise on shared priorities across our research communities and will support our ambition to drive progress in translational research by building outstanding global networks. Our Accelerator Award will support development of high-quality resources including training programmes that could not be achieved in isolation, bringing together the best teams and resources to facilitate translational research and train the next generation of clinicians and researchers. OPENING OUR DOORS TO THOUSANDS Imagine you d not seen inside a research laboratory since school. Last year, thanks to your help, we hosted over 200 lab tours at our institutes and research hubs up and down the country. Welcoming the public to visit provides vital opportunities to engage with supporters, local communities and politicians about CRUK s world-class science. In October 2016, scientists at our Manchester Institute and colleagues in our Policy and Public Affairs team hosted a lab tour for members of Manchester City Council. The visitors learned about the city s leading role in lung cancer research and CRUK s policy work in tobacco control, both of which are important areas to help reduce the number of people dying from the disease in the future. Council Leader, Sir Richard Leese, commented, We are incredibly proud that Manchester researchers are leading the way in the fight against this awful disease. Manchester City Council is committed to playing its role in helping residents to reduce their risk of getting cancer. Hosting tours is a rewarding experience for our researchers. Dr Allan Jordan from the CRUK Manchester Institute said, Having the opportunity to meet with supporters, show how their donations are making a difference in our labs and thank them personally for their extraordinary efforts is a privilege. A recent guest remark highlights the impact of tours: What amazing work you re doing! What hope you re giving. Thank you doesn t seem sufficient but thank you anyway. Image: Manchester City Council leader, Sir Richard Leese, gets pipetting tips from John Weightman at the CRUK Manchester Institute 14 15

10 TACKLING HARD-TO-TREAT CANCERS FROM EVERY ANGLE In the three years since we pledged to increase research funding in cancers of unmet need, we have increased spend in our four identified priority cancers lung, pancreatic, oesophageal and brain, with particular success in lung and pancreatic cancer. We invested 85.8 million across these four disease types in 2016/17, more than doubling our spend since 2013/14. But our ambitions in tackling these hard-totreat diseases go far beyond funding research, as each of these intractable diseases has its own unique challenges. We have been working closely with the community to determine the critical scientific questions or identify gaps in infrastructure standing in the way of progress, with a view to taking proactive, bespoke approaches to each disease type. Activities have ranged from specialist symposia and conferences bringing the research community in these fields together, to looking at ways to fund large-scale international research initiatives. A second symposium on oesophageal cancer took place in spring 2017, followed by a workshop with key members of the international research community to identify priority areas for research. And with the long-term view of building a sustainable community working on each disease, it is encouraging that this year we have seen an increase in the number of career development awards focused on the unmet need cancers, particularly in brain tumours. In lung cancer, a notable highlight this year is a collaboration, through our partnership with the US Cancer Moonshot Initiative, which will see Caroline Dive at our Manchester Institute and Peter Kuhn s team at the University of Southern California apply their combined expertise and technology in circulating tumour cell analysis to study the blood of patients with early-stage lung (and bowel) cancer, to see if they can identify those who will relapse. A NEW ERA OF PRECISION As for all cancers, molecular stratification of tumours is key to our basic understanding of pancreatic ductal adenocarcinoma (PDAC), and its prognosis and treatment. Professor Andrew Biankin, at the University of Glasgow, is a leader in molecular analysis and next generation sequencing of pancreatic cancers: besides confirming known mutations, his work has uncovered new genes and pathways mutated at lower frequencies, some of which are potential therapeutic targets. He is lead investigator on PRECISION-Panc, an ambitious programme of research that seeks to uncover the molecular profile of individual patients with pancreatic cancer, to learn more about the disease and to facilitate patients entering clinical trials for treatments that match their tumour biology. CRUK is investing 10 million in this flagship initiative, to date our largest stand-alone investment in pancreatic cancer research. He also co-chairs Precision Promise, a sister programme to PRECI- SION-Panc, that will bring precision medicine to pancreatic cancer patients in the US. Andrew s aim is to pull together a knowledge bank about PDAC, taking in information not just from the US and the UK, but from many other partners around the world. His hope is that, eventually, a newly-diagnosed patient s tumour characteristics can be run against the knowledge bank database, enabling the best treatment option to be offered as part of a clinical trial: There ll be a day in the future, if we harmonise and align our methodology, when we can address specific issues through running international multicentre studies, he says, but for that, we ll have to better integrate research with the clinic. We want a patient to know when experimental medicine is the best option for them, and make sure that they have trials to enter. TARGETING THE MOLECULAR BASIS OF PANCREATIC CANCER IN THIS ARTICLE Andrew Biankin Regius Chair of Surgery and Director of the Wolfson Wohl Cancer Research Centre, University of Glasgow Paul Brennan Senior Clinical Lecturer, CRUK Edinburgh Centre Martin Humphries Professor of Biochemistry, University of Manchester Claus Jørgensen CRUK Career Development Award holder, CRUK Manchester Institute Improving the quality and quantity of research into cancers with the poorest survival rates remains a key priority across all aspects of our research activity from funding breakthroughs in biology, to growing a sustainable community of worldleading researchers. Here, we focus on two of the toughest cancers pancreatic and brain and share some of the exciting investments, initiatives and new research we re funding in the UK and internationally. TACKLING PANCREATIC CANCER Every year around 9,500 people are diagnosed with pancreatic cancer in the UK; only 1% survive their disease for 10 years or more. Surgery can significantly extend overall survival, but only 10 15% of patients are diagnosed early enough for surgery to even be an option. Other treatments only prolong life by a matter of months. Now the 11th most common cancer in the UK, new approaches are urgently needed to combat this devastating disease. From the work of Andrew and others, we know that the KRAS oncogene is mutated in % of PDACs, and has a frequent partner in crime: the MYC oncogene. Amplification of MYC in PDAC makes the tumours more aggressive, and, as in many other tumour types, MYC expression is critical for KRAS-driven tumour maintenance. Recently, it s been shown that MYC regulates so-called super-enhancers clusters of DNA protein complexes that coordinate the expression of large banks of genes critical for specifying cell identity and behaviour. Continued on next page Gerard Evan Professor of Biochemistry, University of Cambridge Richard Gilbertson Director, CRUK Major Centre in Cambridge, University of Cambridge Steve Pollard CRUK Senior Research Fellow and Group Leader, CRUK Edinburgh Centre Nicole Sodir Postdoctoral scientist, University of Cambridge 16 17

11 Q & A Q & A INSIDE THE DREAM TEAM Continued from page 17 NOT-SO-BLIND DATE What s it like working in the Transatlantic Pancreatic Cancer Dream Team? We asked Dr Nicole Sodir, a postdoc in Gerard Evan s lab. How has being part of the Dream Team collaboration helped your work? The Dream Team consists of oncologists and scientists from different backgrounds, all working together to tackle the same disease. This has allowed me to establish wonderful new collaborations with institutions, in both the UK and the US. What s the thing that excites you most about the Dream Team s work? PDAC is devastating, but using novel approaches, our aim is to transform it into a non-lethal and manageable disease. The Dream Team has amazing commitment and courage in its approach, always thinking outside the box. Will you be going to the US as part of the collaboration? I m travelling to the Salk Institute in San Diego as part of our Dream Team collaboration with Ron Evans. We plan to identify enhancers that are regulated by MYC activation using state-of-the-art techniques such as ChiP-seq and GRO-Seq that have been established in their lab. Who have you met so far? We re collaborating with Ron Evans and Tony Hunter at the Salk Institute and Josh Rabinowitz at Princeton University. I have met or skyped with students and postdocs from both places and it has been a delight working together. Meeting our patient advocates, cancer survivors from the US and the UK, has affected me the most. It is fascinating and humbling to hear their perspectives on what we do; I was touched by their great drive to fight the disease and to help others. They are always so encouraging; they keep me on the right track to make a difference. The Transatlantic Pancreatic Cancer Dream Team is funded by CRUK in partnership with Stand Up To Cancer and the Lustgarten Foundation. This may be how MYC can reprogramme cells at the flick of a switch. Because of its importance, MYC is one of the lead molecules being studied by the Pancreatic Cancer Dream Team, funded through a partnership between CRUK, Stand Up To Cancer (SU2C) and the US Lustgarten Foundation. Led by Professor Gerard Evan at the University of Cambridge, Professor Daniel von Hoff at the Translational Genomics Research Institute in Arizona and Professor Ronald Evans at the Salk Institute for Biological Sciences in California, the Pancreatic Cancer Dream Team aims to map super-enhancer hotspots in pancreatic cancers. They hope to understand how MYC hacks into the normal regenerative programme of the pancreas, driving relentless proliferation and, eventually, pancreatic cancer. Read more about Gerard s work on page 21. One year in, Gerard has found the collaboration immensely rewarding: The notion of looking at transcriptional changes would probably not have been something we d have gone for in our own lab, as we didn t have the necessary expertise, he says, so this was, and is, a game-changing opportunity for us and, we hope, for pancreatic cancer patients. TARGETING THE MICROENVIRONMENT One of the hallmarks of PDAC is extensive desmoplasia the formation of rigid fibrotic tissue or extracellular matrix, wrapped like a corset around the tumour. In some PDACs, as much as 90% of the tumour mass comprises non-tumour cells, and this stromal tissue shapes the tumour, both literally and metaphorically, toughening it up by starving it of oxygen and nutrients, and impeding treatment by reducing the access of drugs and immune cells. These stromal and tumour cells talk extensively to each other. Dr Claus Jørgensen, at the CRUK Manchester Institute, made the crucial discovery last year that oncogenic KRAS ramps up tumour cell signalling by coercing the stroma into feeding paracrine signals back to the tumour. And this communication extends into mechanotransduction too where cells sense their rigidity and that of their surroundings and convert that information into signals that control behaviours such as proliferation and invasion. Building on this, Claus has set up a collaboration with Professor Martin Humphries at the University of Manchester, who has made fundamental discoveries about the basic mechanisms of cell adhesion, to determine how stromal rigidity drives proliferation. Adhesion has evolved over hundreds of millions of years to control cell fate it s not simply a way of sticking cells together, says Martin. They will be studying how the adhesion nexus a cluster of receptors, extracellular matrix fibres and cytoskeletal polymers works as a sensor of stromal rigidity in PDAC, and hope to unpick exactly how desmoplasia forces proliferation under unfavourable circumstances, thereby accelerating tumour progression. TACKLING BRAIN CANCERS CRUK s spend on brain tumour research has more than doubled in the last five years. But growth since the launch of the Research Strategy in 2014 has been modest, suggesting more needs to be done. Brain cancer remains a challenging area in which there is limited research activity. To address this we held an international workshop in 2016 with a panel of expert leaders in the field. The meeting identified key research areas seen as crucial for the progress of brain tumour research and improving patient outcomes. We are now looking at ways to highlight these questions to the research community and to fund research to address them. Like pancreatic cancer, glioblastoma, the most aggressive form of brain cancer, is intractable and rapidly lethal. Though thankfully rare, with around 2,300 cases in England each year, survival is low with less than 5% surviving for at least five years. Clinician scientist Dr Paul Brennan, a recent Pioneer Award recipient, works on the frontline of glioblastoma, combining his work as a consultant neurosurgeon at Edinburgh s Western General Hospital with research at the CRUK Edinburgh Centre. When it comes to brain cancer, being a surgeon is peculiarly frustrating: This is a disease that can t be cured surgically. In the brain, there s no natural containment barrier; glioblastomas spread quickly along the normal white matter tracts, so removing the mass isn t curative, he explains. Eventually I d hope only to offer surgery to people with no alternative. Frustratingly, at the moment, that s everyone. Paul s Pioneer Award relies on a collaboration with two colleagues at the CRUK Edinburgh Centre Dr Dirk Sieger, who models brain cancer in zebrafish, and Dr Asier Unciti- Broceta, a medicinal chemist. Asier s work on palladium catalysts drives the project, and came to Paul s notice during a thesis committee meeting for one of Asier s students: I remember thinking that although this is a pure chemistry PhD and I don t understand the aromatic chemistry, I do understand how this would be applicable to brain tumours, Paul says. Glioblastomas tend to recur at their original site, implying that, post-surgery, residual cells remain. The Pioneer Award will be used to study the potential of implanting inert palladium beads at the time of surgery, and then treating patients with a prodrug that the palladium catalyst will activate. We should be able to give people a higher concentration of the drug and avoid some of the side effects, Paul says. They hope to develop prodrugs that work in Dirk s zebrafish glioma model, providing proof-of-principle evidence needed to scale up the project and take it into pre-clinical development. DEVELOPING RESEARCH RESOURCES Moving the brain cancer field forward will require the development of communal research resources to mine the knowledge gleaned from patient cell lines and samples, something that Dr Steve Pollard, also at the CRUK Edinburgh Centre, is passionate about. As well as having his own glioblastoma research programme, Steve is the PI for the Glioma Cellular Genetics Resource (GCGR), funded by CRUK in 2016 through an Accelerator Award. The GCGR will be a centralised resource for the generation, cataloguing and curation of glioblastoma cell lines, accessed via an open source database. Genome editing tools and novel engineered patient-derived cellular models will also be on offer Steve s already receiving plenty of requests for the CRISPR tools he s developed in the last year for modifying target genes of interest. TAKING A GLOBAL VIEW International cooperation is vital for rare cancers, where national patient numbers are frequently too low to permit meaningful studies, and this is especially so in the challenging field of paediatric brain tumours. Professor Richard Gilbertson, at our Cambridge Centre, believes that the availability of big data means that the global community can now work together in a more purposeful way: Next generation sequencing has allowed us to look into the biology of childhood cancer in a way we ve never done before, he says. It s like looking for keys in a dark room. What next generation sequencing has done is switched the light on so you can see the keys. You don t necessarily know what lock the keys fit but at least you ve found them. The tumour transcriptome has meant that paediatric brain cancers are now beginning to be stratified, but Richard says the challenge is to transfer this knowledge into the clinic: We now know, for example, that in medulloblastoma there are four distinct subgroups, one of which does really well and should probably be spared radiotherapy. There are things we re armed with now that will make an impact, and I have a lot of hope for the next five years. MAJOR ADVANCES In his own lab, Richard has had a long-standing preoccupation with the paradox that tissues grow faster during childhood than at any other time, and yet childhood cancers are so rare: If you have a tissue with this massive mitotic process going on there has to be a mechanism in there to stop it becoming malignant, In what he believes is the most significant work of his career, CRUK-funded work from his lab published last year in Cell showed this to be true: stem cells that give rise to adult cancers are about seven-fold more sensitive to generating cancer than paediatric stem cells. Major discoveries draw people and resources into a field, and cause a build-up of momentum that pushes the field forward. Up until now, such advances have been few and far between in the cancers identified by CRUK as unmet needs. Now, though, thanks to the influx of new blood synergising with the expertise and dedication of long-term researchers, those discoveries are starting to come; and as some of the work profiled here shows, the consequences may be profound, not just for single cancers, but for the whole spectrum of disease. We ll be investing in targeted funding to address these challenges. Find out more at cruk.org/unmet-need Professor Martin Humphries and Dr Claus Jørgensen, both based in Manchester and working together to study the adhesion nexus, discuss the fundamentals of good collaboration How did you two meet? Martin: Caroline Dive at the CRUK Manchester Institute introduced me to Claus. From then, the idea to work on the pancreas as a model for stromal signalling was largely influenced by him. His focus on the communication between cells and my focus on what s happening inside cells are highly complementary. Claus: The extracellular matrix and tissue stiffness is a huge thing in pancreatic cancer, and I d become interested in it but didn t have the time to do anything about it. We have a common interest in addressing this problem. Do you have any tips for collaboration? Martin: Real collaboration is where both sides need each other s intellectual input to solve a problem. That requires people to get on with each other if you don t get on with the person, it s difficult to develop a working relationship you enjoy. You have to respect your collaborator don t ever collaborate with somebody just because you can. Claus: When you pick a collaboration it s important to be honest with yourself you need to have a fundamental interest in the area and you ve got to genuinely trust the people you re working with. Otherwise it ll become a distraction rather than anything useful. What are the benefits so far? Martin: Collaborating with someone from a different background is beneficial because it can be disruptive, and anything that s disruptive to the way you think is good. Claus: Discussing science with Martin is a real benefit it takes me out of my comfort zone, which is where you can start connecting the dots. Martin s very open, honest and straightforward there s no agenda. We have a common goal and a common interest, and I m very excited for the future

12 Image: Dave Sims HACKING INTO NORMALITY DAVE SIMS: A FAMILY UNITING AGAINST CANCER There are so many areas of CRUK research which rely on the involvement of patients in studies and trials. Here, one family share their story of why and how they got involved. Mark Sims was 15 when he was first diagnosed with melanoma in When it came back 12 years later, it spread and became incurable. A doctor from near Bristol, Mark signed up to be part of our PEACE study, which will help us understand more about the late stages of cancer. He was an enthusiastic volunteer for CRUK, and was given a Flame of Hope award for his work. Mark died in January His twin Dave, 29, a doctor living in London, shares Mark s story on behalf of their parents, Chris and Sue, brothers Matt and Paul and Mark s fiancée, Georgie. Mark always thought about others more than himself. Even in his last days, he was worried about not being able to reply to people who d messaged him on Facebook. Everyone liked Mark. He was very easy to get on with and had a lot of friends. He realised that his experience of getting cancer so young, and the fact he was a doctor, would resonate with people. When Mark s doctors asked him about taking part in the PEACE study, we knew it would be something he d want to do. The study gave him another opportunity to help people. The tissue he donated, before and after he died, will help scientists learn about how cancer develops, particularly in the later stages. It s a great contribution to research. He wanted to do as much as he possibly could to make sure that, in 20 years time, another Mark Sims doesn t have to go through the same thing that he did. When Mark found out how serious his diagnosis was, he accepted it. He remained hopeful, but realistic. He wanted to do the best he could in the time he had. As well as raising money for research, it s really important to my family to raise awareness of melanoma. One of my main motivations for sharing Mark s story is to encourage people to take care of their skin. We are all really proud of everything Mark did. He inspired us. It s always going to be difficult without him, but the difference he s made to other people does make it a little bit easier. A NATIONAL POST- MORTEM TISSUE COLLECTION PROTOCOL (THE PEACE STUDY) This Award, led by Professor Charles Swanton at the CRUK UCL Centre and the Francis Crick Institute, will support the longitudinal collection of biological samples from patients with primary brain or metastatic cancer across the UK, including after their death. Sample collection will comprise tissue, blood, cell-free DNA and circulating tumour cells. The consortium will: Coordinate and standardise sample collection across the network Create a digital pathology hub from the samples Train clinical researchers in autopsy pathology This will create a unique resource of samples, supported by clinical annotation, to investigate through research initiatives such as understanding the evolution of cancer, intratumour heterogeneity, mechanisms of resistance, as well as identification of prognostic and diagnostic markers. Currently Sir William Dunn Professor at the University of Cambridge, Gerard Evan has focused his research on the MYC oncogene. His lab has recently started working on pancreatic and lung cancer, drawn in part by the excellent mouse models available. Here, Gerard discusses a new way of viewing cancer that has major implications for our understanding of the disease, and how to treat it. There are two questions in biology how and why? Both are important: the how addresses how the nuts and bolts of a biological process are hooked up with each other. The why question is the one that British science has always been very good at addressing why are things the way they are and why do they work the way they do? As a cancer biologist, my version of this question is simple: why is it that cancers of a particular tissue or cell type share a remarkably consistent histological phenotype so consistent, in fact, that we use it as a primary diagnostic tool? I always tried to understand biology for what it is: a set of evolved processes rather than a purposefully constructed machine. Thinking this way sheds a very different light on cancer because cancer is generally a late-life, post-reproductive disease. Hence, its impact on our reproductive fitness is negligible. We therefore have to view the properties and behaviour of cancers, and of our bodies responses to it, as a subversion of a process that is important for survival and reproduction namely, our amazing ability to repair our bodies when they get damaged. Viewed through this lens, it makes perfect sense that cancers of a particular tissue all look similar to each other. Although the oncogenic mutations that drive cancers are very diverse, they all do basically the same thing: they hack into the resident regenerative engine of each tissue type. Many drivers but only one car. These regenerative engines differ from tissue to tissue because each tissue type has its own unique structure and function, and so requires its own distinct programme to rebuild it when damaged. Take pancreatic cancer, for instance. A major function of the normal pancreas is to GERARD EVAN make digestive enzymes. When the normal pancreas is damaged, the body has to deal with a leaky bag full of digestive enzymes, able to wreak havoc on any nearby cells and tissues. To counter this threat, areas of injury are rapidly walled off by dense connective tissue, termed desmoplasia. Now, desmoplasia is not only a hallmark of a regenerating pancreas but also of pancreatic adenocarcinoma. So, we think pancreatic cancers look the way they do because they are hacked versions of the normal pancreatic regenerative programme. Damage to other types of tissue is repaired in other ways. For example, lungs are exposed to the outside world so lung damage is most commonly associated with infection. To combat infection, an enhanced blood supply is needed to pump the damaged region with lymphocytes and other protective cells. After the damage has been contained, the lung tissue needs to be rebuilt, but in a different way to the pancreas as its structure and functions are totally different. Hence, if we postulate that lung cancers are driven by a corrupted version of the regenerative process specific to lungs, we end up with a coherent explanation for why lung and pancreatic cancers look so different, despite sharing many oncogenic driver mutations. Using transgenic mouse models in which we can reversibly switch on and off the pivotal RAS and MYC oncogenes in either lung or pancreas, we ve shown two really important things that support our hypothesis. First, as soon as you switch on RAS and MYC in each tissue, you see tumours arise immediately that, from the outset, have the signature characteristics of each cancer type. In the lung, the tumours explode with blood vessels but little desmoplasia. In the pancreas, the tumours immediately resemble highly pancreatic adenocarcinomas in which 90% of the mass is not even tumour cells but desmoplasia. The same drivers but different engines. Second, and most encouragingly, because we build off-switches in our driving cancer genes, we have been able to address what happens to lung and pancreas tumours when we switch off MYC. The answer is that both kinds of tumour rapidly regress. This is intriguing since a similar thing happens in the regeneration of normal tissues. The idea we re working on now is that shutting down oncogenic signalling is essentially a trigger for a dominant wound resolution programme, which prunes the excess and aberrant tissue in the cancer and remodels it back to where it was originally. Cancer therapies essentially work by invoking a normal physiological process involved in wound repair. Why does this matter to our eventual aim of curing cancer? The current dogma is that each cancer in each patient is different and, even within an individual patient's cancer, there is huge heterogeneity amongst the component cells. Hence, treatment will require expensive personalised therapy tailored to each patient. By contrast, if we start from the observation that cancers are actually pretty similar in terms of the way they look and behave, then perhaps this implies the existence of shared vulnerabilities common to all patients with a particular type of cancer. We re really fired up by the possibilities this idea of impersonalised therapy, if you like offers for the future. The payoff is potentially colossal and my intuition tells me we re on the verge of some really exciting insights

13 In our 2014 Research Strategy we included an intention to facilitate a major shift in early detection and diagnosis research. We made an ambitious commitment to invigorate this field, stimulating research interest, building capacity, forging new partnerships, and actively supporting a community for early detection research sees a further increase in our investment, with significant new funds being made available by CRUK specifically for early detection science. What are the developments so far in this area, and what promise do they hold for the future? IN THIS ARTICLE Sarah Bohndiek Lecturer in Biomedical Physics and Junior Group Leader, CRUK Cambridge Institute Caroline Dive Professor of Cancer Pharmacology and Senior Group Leader, CRUK Manchester Institute Sadik Esener Director, Center for Early Detection Research, Knight Cancer Institute, Oregon Health and Science University CATCHING CANCER CER EARLIER We know that cancer is easier to treat, and causes patients to suffer less and live longer, when it is detected early. Yet for decades, whilst treatments for cancer have made revolutionary steps forward, early detection research has made limited progress, presenting a persistent scientific and clinical challenge. As a result, most cancers are still diagnosed at stage 3 or 4, when the prognosis is poorer and the treatment is often more severe. Now, with advances in technology starting to open up new research paths, our investment and commitment can help push this important field forward. We recognise that cracking this area could be a major player in achieving our aim to see 3 in 4 patients survive cancer within the next 20 years. WHAT IS EARLY DETECTION? We define early detection as the detection of cancer, or pre-cancerous states, at the earliest possible point at which an intervention might be made in order to lead to a better patient outcome. As Dr Ian Walker, Director of Clinical, Population and Early Detection Research at CRUK, states, In terms of survival, early detection science is one of the biggest things you can do. Take the example of bowel cancer caught at stage 1, it has a 95% survival rate at five years, yet at stage 4 this is around 8%. If we can catch cancers earlier, it will have a significant impact on survival rates on a scale that is very difficult to achieve through drugs alone." However, there are big challenges. Currently, we don t understand the cellular and molecular biology that occurs as cells become dysregulated and then cancerous. We don t know what we need to detect, how to avoid over-detection, or how to distinguish lethal and non-lethal disease. We don t have adequate models of early disease, which has delayed the progress. We need better combinations of omics and analytic platforms to identify and validate biomarkers of early disease. We need improved systems biology approaches to bring data into biological context. We need novel technology, including sensors, biochips and nanotechnology, to improve how we image and detect cancer, and we need multidisciplinary teams to develop the technology and ultimately to implement it in the appropriate clinical context. These are all big issues, and CRUK is making a significant commitment to early detection research to start to unravel them. We are working across our UK network to drive new activity in the area, as well as establishing international partnerships to start building a wider early detection community. And in 2017 we will announce major new funding specifically dedicated to supporting early detection research. CAMBRIDGE EARLY DETECTION PROGRAMME One current major area of investment is the CRUK Cambridge Centre Early Detection Programme, launched in This multidisciplinary programme brings together world-class researchers from a wide range of areas, and is co-led by clinician scientist Professor Rebecca Fitzgerald and physicist Dr Sarah Bohndiek. Rebecca s own work in the field of oesophageal cancer is a flagship example of early detection research. Her team developed a tiny sponge on a string, the Cytosponge, which is swallowed to sample cells from the whole oesophagus, and a simple lab test to analyse this. The cells are analysed with an antibody to check for Barrett s oesophagus, a condition that can be a pre-cursor to oesophageal cancer. As Rebecca says, We are now at the exciting stage of starting a large clinical trial in GP surgeries, the BEST3 trial, which is the final step in determining whether the Cytosponge antibody (TFF3) test is effective enough to be introduced into mainstream practice. As most oesophageal cancer is currently diagnosed at a late stage, the Cytosponge could provide a powerful new tool to improve early detection at the stage of Barrett s, offering GPs a cost-effective and minimally invasive first step of investigation. Rebecca s team is now working to develop the lab tests further, so that they not only diagnose Barrett s, but also distinguish between those Barrett s patients at low and high risk of cancer progression. Rebecca s close colleague and co-director of the Early Detection Programme, Sarah, comes from a very different field. I m a physicist by background, but now focus on how we can improve imaging techniques for early detection and evaluating cancer progression. For example, standard endoscopy replicates only what our eye could see if we were able to look inside the body. This struggles to pick up early abnormalities, so we re developing novel endoscopic devices that bring additional contrast for subtle early changes. One example is applying coherent light where the waves travel in unison as this is distorted when it hits tumour tissue compared to normal tissue. Studying the light distribution may prove to be a valuable tool in assisting earlier detection. Thanks to CRUK funding for early detection, the Cambridge team is expanding. As Rebecca explains, We now have three dedicated early detection research labs, with two more planned this year. It s an incredibly exciting time. Recently setting up his new lab, Dr Daniel Munoz-Espin joined the department last September, having moved from the Spanish National Cancer Research Centre in Madrid. His work is another example of the multidisciplinary nature of the field: My research focuses on developing nanotechnologies able to target pre-malignant tumours, both for early detection and early therapy. NANOTECHNOLOGY Daniel s work is looking at the origin of lung cancer and, in particular, the role of senescent cells, damaged or stressed cells that can no longer replicate. In the long-term, it s thought that accumulated senescent cells can lead to malignancy in the nearby cellular environment. Interestingly, cellular senescence is emerging as a feature of pre-malignant lung tumours and so could be a property with potential use in early detection. Daniel is working with silicon nanoparticles 100nm in size, and has developed the technology to load these up with active substances that can specifically target senescent cells. It works because in normal cells, the nanoparticles are internalised and then simply secreted. But in senescent cells, the coating is digested inside the cell, releasing the active substance. Using a fluorescent tracer as the active substance means any senescent cells light up, providing a powerful tool for early detection. Excitingly, the same technique also has potential in early therapy, because the nanoparticles can be loaded with active substances that target and kill the senescent cells. As Daniel explains, We ve now validated the tools in mouse models of pulmonary fibrosis and tumour models, showing that we can use nanoparticles to both detect and eliminate senescent cells. Our innovative treatment results in therapeutic activity, including reduction of tumour size. The next steps are to take this technology to mouse models of lung cancer and to human tissues. It is hoped that, in the long term, this research could lead to patients with a smoking history having a test for senescent cells. If they show accumulation in one area, early therapy could treat this, eliminating damaged cells and so stopping lung cancer before it even develops. LIQUID BIOPSIES At the CRUK Manchester Institute, Professor Caroline Dive is also working on lung cancer, and has become internationally renowned for her work on liquid biopsies detecting cells or particles in the bloodstream that could act as reliable signals for cancer. As Caroline says, Up until very recently, our work has been looking at circulating tumour cells (CTCs) as agents of metastasis, causing cancer to spread around the body in patients with more advanced disease. But now, we are turning our attention to how useful this technology could be for early detection. Continued on next page 5-year survival rate for bowel cancer when caught at stage 1 vs 8% when caught at stage 4 % IN THIS ARTICLE Rebecca Fitzgerald Professor of Cancer Prevention, MRC Cancer Unit, University of Cambridge Daniel Munoz-Espin Senior Research Associate, Hutchison MRC Research Centre, University of Cambridge Ian Walker Director of Clinical, Population and Early Detection Research, CRUK 22 23

14 Continued from page 23 The big question is how early on CTCs are sent out, and the hope is that they could be a very useful red flag for early detection. In an exciting new venture, Caroline is joining forces with Dr Phil Crosbie, Consultant in Respiratory Medicine at the University Hospital of South Manchester (UHSM). Phil has been part of the team that conducted the first ever UK-pilot to bring mobile computed tomography (CT) scanners to the public, allowing smokers and former smokers to receive free lung checks in shopping centre car parks. Funded by Macmillan Cancer Support, and led by clinician Dr Phil Barber at UHSM, the Manchester Lung Health Check pilot showed a dramatic benefit for early diagnosis: 80% of lung cancers picked up through mobile screening were at the potentially curable stage 1 or 2, compared with less than 20% of normal lung cancer diagnoses. The next stage of the pilot aims to assess 1,000 people in summer 2017, and Caroline s collaboration will now add another element to the study. Running in parallel to the CT scans, her team will take blood samples, which will be searched for CTCs and other particles such as nucleic acids and microrna. If CTCs are present as an early sign of cancer, they are going to be extremely rare, so we ll use high definition single cell analysis to ensure we don t lose any. If the blood tests show positive markers, they could provide a powerful, non-invasive tool for early detection. Caroline is hopeful this area holds huge promise, There are times in your career when you take stock and think where can my research make the biggest impact? This is a big turning point for me now, shifting to really focus on early detection, with the aim to develop a minimally invasive test for early cancer detection. The idea of a simple test that could reliably pick up signs of cancer before it takes hold is a clear goal of early detection research. As Ian states, If we could develop new blood tests to detect cancer before patients even develop symptoms, survival benefits could be huge. Taking this further, the ultimate aim for early detection would be to identify biomarkers that warn a cancer is first starting to develop, catching it at a pre-cursor stage. One avenue of our research that may take us a step closer is using the huge biobank originally built up for the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This was a CRUK-funded study that assessed screening tests for ovarian cancer, and involved a huge cohort of 200,000 healthy volunteers, collecting longitudinal blood samples from a quarter of them, and following up which volunteers went on to develop cancer. To have annual blood samples leading up to the clinical presentation of cancer is an incredibly valuable resource, and these data are now being combed for biomarkers. The priority cancers in this study are colorectal, lung, oesophageal and pancreatic. CRUK, Cancer Research Technology, and the biotech company Abcodia joined forces to form the Early Diagnosis Consortium to achieve this. They enlisted the help of three leading omics companies, with specific expertise in proteomics, microrna, and tumour auto-antibodies. The aim is to identify biomarkers that have consistently altered expression prior to cancer diagnosis. The results from years of this work are expected in 2017, with the best biomarkers then being taken forward. OUR AREAS OF FOCUS IN EARLY DETECTION EARLY & PRE-CANCER BIOLOGY An improved understanding of early tumour development is essential. This includes defining lethal vs non-lethal cancers. SYSTEMS BIOLOGY Novel approaches are required for understanding interactions within cells, between cells and with the early tumour microenvironment. COLLABORATION Combining the expertise and experience of academia, clinicians, industry, patients and multidisciplinary fields, in the UK and globally, will help solve our biggest problems. MODELS OF EARLY DISEASE Better models of early disease are urgently needed to inform our understanding of early tumorigenesis. MARKERS & INFORMATICS Assays and analytics for identifying biomarkers and integrating results will reveal the detectable signatures of early disease. NOVEL TECHNOLOGY Sensors, probes, nanotechnology, imaging; new technology will change how and when we detect cancer. GLOBAL COLLABORATION The ambitious nature of the Early Diagnosis Consortium led CRUK to seek out expertise globally and form new alliances. This need for a global approach will be crucial to advance the early detection field. Following the launch of our Research Strategy in 2014, we formed a partnership with the Knight Cancer Institute at Oregon Health and Science University (OHSU), a first of a kind collaboration for early detection. The Knight Cancer Institute is an ideal partner: it has been a pioneer of precision cancer therapy and, thanks to a philanthropic investment of $1 billion in 2015, is now establishing a new, largescale early detection programme. Dr Sadik Esener, a nanoengineer by background, has recently taken the helm as the new Director of the Center for Early Detection Research. He s enthusiastic about the partnership with CRUK. Early detection research holds huge promise, but it is still at a very embryonic stage, and it is such a big and complex problem that collaborations between institutions are going to be of crucial importance. With the aim of building a new community for the field and invigorating ideas, the partnership includes an annual joint conference, the second of which will take place in Cambridge in September This will draw researchers together and aid the development of a global, multidisciplinary network of early detection experts. To support and encourage collaborative research, we are developing schemes, in partnership with OHSU, to fund UK and US-based researchers. Sadik agrees that one major area ripe for collaboration will be the hunt for biomarkers, but he doesn t underestimate the challenge. It is like looking not just for a needle in a haystack, but for a special type of hay in a haystack. As Sadik identifies, One of the greatest challenges for early detection research is not only finding early warning signs that cancer is starting to develop, but identifying which of those alarms need following up with more tests and treatment and which we can safely ignore. This is the flipside of the early detection coin: the risk of causing overdiagnosis and unnecessary worry and intervention. THE RISK OF OVERDIAGNOSIS To really make progress in early detection, we need to understand how to tell apart early benign changes from lethal ones. This question is so crucial that we made it one of our Grand Challenges for 2016, with a multi-million pound award available to advance research that would distinguish between lethal cancers that need treating and non-lethal cancers that don t. A multinational team, led by Dr Jelle Wesseling of the Netherlands Cancer Institute in Amsterdam, was successful in securing this award, co-funded with the Dutch Cancer Society, and will address this challenge in the context of breast cancer. Breast lesions known as ductal carcinoma in situ (DCIS) can sometimes develop into cancer, but a large proportion of DCIS never develop into the disease, and we currently can t tell the difference. The Grand Challenge team aims to find biomarkers that identify which DCIS patients are at high risk of developing cancer, and which are not. By combining tissue samples and clinical data from thousands of patients, the team hopes to come up with the answer that will help women with DCIS avoid the burden of unnecessary treatment. This award is another sign of our commitment to early detection research, and the progress that we hope will be made in the coming years. Read more about this team and the award on page 31. A NEW FRONTIER Whilst the journey into early detection research is just at its beginnings, it holds incredible promise. From devising nanoparticles that can flag up and kill pre-cancerous cells, to hunting through millions of blood samples for biomarkers, to harnessing the physics of light for better imaging, early detection is a diverse, multidisciplinary field, with ground-breaking potential. It is an area with significant challenges, but also a reward-rich field that could bring real impact to cancer prognosis and mortality. The announcement of new funding specifically for early detection, which will build to an investment of 20 million per year, is designed to set us firmly on the path to success. Ian remarks, This is new funding, specifically for early detection. We are showing our commitment to this important new area of cancer research, which we hope will bring rewards that change the field forever. Find out about our opportunities in early detection research, including funding available, at cruk.org/earlydetection RAISING A GLASS TO EARLY DETECTION In December 2015, The British Museum opened its doors to an exclusive evening of glamour in aid of CRUK. Dr Sarah Bohndiek and her team were at the event to showcase their work into early detection. Transforming the museum to host a chic soirée, Sarah and her group used fun activities to engage the guests. But while the cocktails they were serving may have looked like drinks you d find at a swanky bar, they were in fact science demonstrations in disguise. One activity involved shining a laser beam through a glass of water, gradually adding milk to show guests how it increases the scattering of light. This simple demonstration helped explain how they are developing cutting-edge new endoscopy techniques using light scattering to detect oesophageal cancer sooner. At the very earliest stages, changes in the tissue microstructure that are invisible to the naked eye can be detected with these new methods. These cocktail-style activities provide a tangible insight into the research of Sarah s lab, helping to bring to life how funds are spent. Joanna Brunker, a postdoc in Sarah s lab involved in demonstrating the activities, reported: It was an excellent opportunity for us to share our research with CRUK supporters, as well as an interesting evening in a unique setting! Engagement activities like these are vital to inspire our supporters and the public to continue to donate to CRUK. They also provide an opportunity to thank them for their generosity and to demonstrate how their donations are making a difference. Image: Researchers from Sarah Bohndiek's lab serving cocktail science demonstrations 24 25

15 GRAND CHALLENGE IN THIS ARTICLE Ed Harlow Professor of Cancer Biology, Harvard University Rick Klausner Former Director of the National Cancer Institute (NCI) and Chair of CRUK s Grand Challenge Advisory Panel David Lane Chief Scientist, A*STAR, Singapore A GLOBAL MOVEMENT AGAINST CANCER In October 2015, CRUK launched a completely new and different type of funding scheme Grand Challenge with the aim of bringing together the world s greatest scientific minds to catalyse a revolution in how we prevent, diagnose and treat cancer. Here we celebrate our four exceptional teams that, 18 months later, have been awarded a total of more than 70 million in the first round of the initiative. Grand Challenge was set up to stimulate and inspire teams around the world to try and tackle some of the most persistent, tenacious problems that face the entire cancer community explains Dr Rick Klausner, Former Director of the US National Cancer Institute, and Chair of the CRUK Grand Challenge Advisory Panel. And the response was a triumph recalls Rick. Applications came in from 57 teams across 25 countries and the panel had the unenviable task of whittling this down to a shortlist of nine. These were some of the most exciting proposals we d ever seen, and it left us with a problem we had to find ways to fund more than one. We looked at how we could bring together a package of funding to do this, by involving the Dutch Cancer Society (KWF) and with the support of a generous philanthropist from the US who came on board as well. They shared our excitement about the overwhelming calibre and potential of these new collaborations, says Rick. Thanks to these two partnerships, we have been able to fund four teams this year, investing more than 70 million. SUPPORTING BIG IDEAS One of the great successes was to see proposals that simply could not have happened otherwise. The size of the Grand Challenge awards they are the largest cancer research grants in the world was certainly a key enabling factor for teams. It s a privilege being able to explore these questions in this way, says Professor Sir Mike Stratton from the Wellcome Trust Sanger Institute, who is leading a team tackling the mutational signatures challenge. These are almost fantasy ideas in our area of science. Things we might conceive of that we would love to do, but weren t sure we d ever actually have the means to do because of the sheer scale. Dr Jelle Wesseling, from the Netherlands Cancer Institute, is leading a team to differentiate potentially lethal from non-lethal ductal carcinoma in situ (DCIS). This requires a truly international endeavour, he says. We need well annotated, large sample series with adequate follow-up. Most DCIS studies are small and underpowered and, as a result, virtually nothing is known about DCIS biology. BUILDING A GLOBAL MULTIDISCIPLINARY COMMUNITY It s not the just the scale that makes Grand Challenge unique. The scheme is open to anyone internationally to apply, from any discipline, including commercial partners. And we were delighted to see an application led by chemist Dr Josephine Bunch from the UK s National Physical Laboratory (NPL), including both academic and industry co-investigators. She heard about Grand Challenge on BBC Radio 4 s Today programme, and her interest was piqued by the challenge of developing a 3D map of a tumour. I was excited to hear the scale of ambition, she recalls. I heard the problem and knew straight away that the techniques we ve been pioneering at NPL could make a massive difference. In Grand Challenge we are looking for something new, says Advisory Panel member Professor Sir David Lane, and I loved that Josephine s team is truly multidisciplinary. It s coming from a different sphere, where the central tenet is to create something and share it with everybody. Josephine s team is one of two we re funding to tackle the challenge of building a 3D map of cancer, a challenge set in the context of more than a decade s research that has vastly improved understanding of tumour heterogeneity. This has led to the widely held belief that tumours must not be thought of as individual cells but as a tissue with different components. The idea of the 3D map challenge was to dissect that tissue and understand its structure, explains Professor Ed Harlow, Professor of Cancer Biology at Harvard. We asked teams to rise to this challenge and they ve done it. We have no idea what we ll learn, but we ve got to jump in. A FLEXIBLE APPROACH The flexible nature of Grand Challenge funding is hugely important for tackling challenges of this scale, and this is certainly true for the second 3D tumour map team, led by Professor Greg Hannon from the CRUK Cambridge Institute. His team will be developing entirely new technologies and pushing the capability of existing ones. At this point it s impossible to know which will be the frontrunners and how the team will need to spend funds towards the latter stages of the grant. We ve structured our project a little differently from others, explains Greg. It s a big project, and you can t predict its course over the next six or seven years, so we ve built in a year where we ramp up, and we hire the right people, which is probably the most important determinant of success. Then we ll wait until we get further down the line to decide how to scale up. Our funded teams are now embarking on the first of five, or more, years of making their Grand Challenge vision a reality. In February 2017, we brought them together in London, where they had the chance to share their plans, exchange knowledge and discuss synergies and opportunities for collaboration. We thoroughly enjoyed meeting the other teams at the launch and hearing about their plans, says Josephine. We have started thinking about how we could work with the other teams and have already had some early conversations to start planning some joint work. These awards aim to stimulate people to think about problems differently, get together, discuss ideas and, as teams, be able to achieve more than the sum of their individual parts, says Rick. This is just the beginning. We want this to be the start of a global approach, a unique community, which will collectively redefine the way we think about cancer. Meet the teams on the next page We re looking for the next worldleading teams to tackle the latest Grand Challenges. Teams can be led from the UK or overseas. Find everything you need to apply at cruk.org/grandchallenge INTEGRATING THE PATIENT EXPERIENCE Patients and people affected by cancer have been involved in Grand Challenge since the moment it began. From feeding into what the research challenges would be back in 2015, to co-writing funding guidelines, reviewing research applications, and interviewing teams on their plans to involve people affected by cancer. For the first time, CRUK required applicants to include patient representatives as part of their team. Our patient advocates influenced ideas of how ultimately we might want to use the technology; this broadened out the applications beyond our original thinking, recalls Professor Greg Hannon. Patient representatives in all teams attended key meetings and have been part of ongoing conversations. I see that continuing throughout the project, says Professor Sir Mike Stratton. It wasn t a one-off event or series of events, it s a true collaboration. They challenged us around the language we use, and what patients expectations and hopes are. In addition to patient advocates being an integral part of each team, CRUK also formed a Grand Challenge Patient Panel to review all applications and feed in to final award decisions. Peter Rainey, who chairs this Patient Panel, says Only time will tell what Grand Challenge delivers, but great strides have been made in working collaboratively, thinking creatively and increasing the level of ambition among the research community. Awareness of the role that can be played by individuals affected by cancer in the research process has been significantly raised. Image: CRUK panel meeting in progress 26 27

16 MEET THE WINNING TEAMS WE DON T JUST WANT TO BUILD THE MAP, WE RE SEEKING TO DERIVE SOME FUNDAMENTAL NEW BIOLOGICAL INSIGHTS ABOUT CANCER Greg Hannon Lead PI: Josephine Bunch Lead PI: Greg Hannon TEAM MEMBERS National Physical Laboratory: Josephine Bunch, Ian Gilmore AstraZeneca: Simon Barry, Richard Goodwin CRUK Beatson Institute: Owen Sansom CRUK Cambridge Institute: Kevin Brindle Francis Crick Institute: Mariia Yuneva Imperial College London: Zoltan Takats Queen Mary University of London: John F. Marshall The Institute of Cancer Research: George Poulogiannis Patient advocates: Kelly Gleason, Harry C. Hall CREATING A GOOGLE EARTH FOR CANCER Dr Josephine Bunch is based at the National Physical Laboratory (NPL), the UK s National Measurement Institute, which is also home to the National Centre of Excellence in Mass Spectrometry, the technological firepower behind the team s approach. They plan to generate a map of a tumour at the metabolic level, by layering information obtained using a range of multiscale molecular imaging technologies. No single method can measure everything that you want to within a tumour, so we need to bring in a whole host of different techniques, Josephine explains. Some operate under vacuum conditions, others at atmospheric pressure, some use lasers, some use ion beams, some use charge solvents and some use surgeons knives. The team will need to find a way to bring these to bear on the same sample to build up the levels of molecular detail needed, and then accurately register this information spatially back to the tumour sample. It s very important that this work, and particularly this level of investment, delivers methods that are reliable and can be used by other laboratories and so we will be making efforts to standardise our work flow, Josephine explains. But it s not just about technology development. By building a team that includes co-investigators from AstraZeneca as well as renowned academic cancer biologists, Josephine wants to ensure that the technology answers several biologically and clinically relevant questions: How does metabolism relate to key cell types, tumour types, genotypes? How does metabolism relate to activation of key pathways? What are the pre-clinical models teaching us? How do our new generation of metabolism-targeting therapeutics impact the tumour? There is still much we don t know about how metabolism is altered in tumours versus normal cells, she says. Our team is a collective force of physicists, chemists and biologists, all coming together to gain new insight into these fundamental processes and develop new and better ways to diagnose and treat cancer. IMAXT: IMAGING AND MOLECULAR ANNOTATION OF XENOGRAFTS AND TUMOURS For Professor Greg Hannon, Grand Challenge gave him the opportunity to take an idea he had been mulling over and investigate it further. About two and a half years ago, when I was in New York, the neuroscientists there were using a tool called serial two-photon tomography to look at signalling states in the brain, and that got me thinking that none of us really know what a whole tumour looks like. So he started a project to look at what they could learn from tumour architecture, and spent time working out stain protocols, and which tissue to deal with first. Then the Grand Challenge call launched, including 3D tumour mapping: The level of funding, and the ability to bring together the right people, made me realise the project could actually be something much more meaningful than I had imagined was possible. The team s approach involves taking alternating physical and image sections of cancers using serial two-photon tomography which can be stitched back together to create 3D renderings of a tumour. Then, using a combination of analyses single-cell sequencing, imaging mass cytometry and multiplexed error robust fluorescent in situ hybridisation (MERFISH) they will identify and molecularly annotate each cell. We hope to collect 20,000 plus pieces of information on every cell in a tumour, explains Greg, so we needed to invent an entirely different way for people to interact with the information. Using virtual reality we can present many more dimensions of information than you can on a piece of paper, and it s immersive, so it creates a level of focus that is otherwise difficult to achieve. In addition to technological innovators Greg s team includes leading cancer biologists and clinicians who are hungry to learn more about tumour behaviour and tumour-host interactions. We don t want to just build the map, we re also seeking to derive some new basic biological insights. TEAM MEMBERS CRUK Cambridge Institute: Greg Hannon, Shankar Balasubramanian, Dario Bressan, Carlos Caldas, Simon Tavaré Harvard University: Xiaowei Zhuang Massachusetts Institute of Technology: Ed Boyden Súil Design: Owen Harris University of Cambridge: Nicholas Walton University of British Columbia: Sam Aparicio University of Lausanne: Johanna Joyce University of Zurich: Bernd Bodenmiller Patient advocates: Elaine Chapman, Lynn Dundas 28 29

17 Scientists from 25 countries applied to round 1 of our Grand Challenge CRUK AND THE DUTCH CANCER SOCIETY HAVE ESSENTIALLY BOUGHT DCIS GLOBALLY UNDER ONE UMBRELLA. IT S GOING TO LEAD TO JOINED-UP THINKING AROUND THE WORLD Jelle Wesseling Lead PI: Mike Stratton Lead PI: Jelle Wesseling TEAM MEMBERS Wellcome Trust Sanger Institute: Mike Stratton, Peter Campbell International Agency for Research on Cancer: Paul Brennan King s College London: David Phillips Los Alamos National Laboratory: Ludmil B. Alexandrov University of California San Francisco: Allan Balmain Patient advocates: Mimi McCord, Maggie Blanks MUTOGRAPHS OF CANCER We have an incomplete sense of what the causes of cancer are, explains Professor Sir Mike Stratton from the Wellcome Trust Sanger Institute, whose team intend to use the power of genomic sequencing to reveal mutational signatures, and use these as a lens to look for the unknown, preventable causes of cancer. The team will collect 1,000 cases each of five cancer types: renal, oesophageal (squamous and adenocarcinoma), bowel and pancreatic, plus normal tissue and blood samples, as well as epidemiological information about potential exposures. All samples will go through the Sanger Institute s mutation signature analysis pipeline, to be compared between regions. They ll also generate mutational signatures using known or suspect carcinogens in animals and organoids, taking advantage of the expertise of Professors Allan Balmain at UCSF and David Phillips at King s College London. The resulting catalogue of mutational signatures could help identify the causative agents of those signatures seen in the patient samples. Mechanistic studies are a key part of this, explains Mike. Take a risk factor like obesity, where we know it causes cancer, but do not have a good understanding of the mechanism. We ll be able to correlate BMIs of all patients with the mutational signatures, so we can start to uncover the mechanisms with this approach. The final part of the puzzle is forward-looking, says Mike: We want to look at what s happening in normal cells initially liver, lung, pleura, kidney to see what the levels of exposure are in those tissues. But those tissues are hard to biopsy, so we ll be exploring the extent to which mutational signatures can be developed in blood, with a view to monitoring exposures of known carcinogens across populations. PRECISION: PREVENT DUCTAL CARCINOMA IN SITU INVASIVE OVERTREATMENT NOW Dr Jelle Wesseling s team is tackling an urgent unmet clinical need the significant overtreatment of ductal in situ carcinoma (DCIS) and requires a large collaborative effort to do so: There are only three large cohorts of DCIS in the world right now, Jelle explains, and they are from the Netherlands Cancer Institute (NKI), Birmingham in the UK, and MD Anderson in Texas. One of the first questions the team will address is the genomics of DCIS. As Jelle states: This is something that no other study has had the power to do. They brought in the expertise of Dr Serena Nik-Zainal from the Wellcome Trust Sanger Institute to see if they can unveil a genetic clue about which cases of DCIS go on to become invasive breast cancer, and which cases of DCIS recur. The team will take the insights generated from this stage into functional studies, with Dr Andrew Futreal at MD Anderson investigating the tumour microenvironment and the immune profile, and Professor Jos Jonkers at the NKI taking on the challenge of developing a mouse model of DCIS something that has never been achieved before. The biggest challenge is this high risk, high impact in vitro and in vivo validation work we re planning to do says Jelle. If we can find markers that distinguish DCIS that invades from DCIS that doesn t, and can validate these, then we have an opportunity to intervene in aggressive DCIS. Our goal is to change clinical practice but to do so very much based on understanding the biology. CRUK and the Dutch Cancer Society have essentially bought DCIS globally under one umbrella. It s going to lead to joined up thinking around the world. Research co-funded with the Dutch Cancer Society TEAM MEMBERS Netherlands Cancer Institute: Jelle Wesseling, Jos Jonkers, Esther Lips Duke Cancer Institute: Shelley Hwang University of Birmingham: Daniel Rea University of Texas MD Anderson Cancer Center: Andrew Futreal, Alastair Thompson Wellcome Trust Sanger Institute: Serena Nik-Zainal Patient advocates: Deborah Collyar, Marja van Oirsouw, Donna Pinto, Hilary Stobart, Ellen Verschuur, Maggie Wilcox 30 31

18 Population research has a fundamental role to play in CRUK's ambition of 3 in 4 people surviving cancer by 2034, particularly in the areas of early diagnosis and prevention. To make sure we help drive the population research we need, there s been a quiet revolution taking place in our approach to funding it. are shortlisted, four members of each team are invited to a Joint Applicant Meeting, before submitting their full proposals. It s a great opportunity to meet up and do some face-to-face planning, but there s more: instead of using the occasion to check out the competition and work out how to beat them, participants are invited to discuss each other s proposals with a view to improving them all. They re also given an opportunity to meet the CRUK staff who ll be shepherding their applications towards the award panel, to ensure that everyone knows how to present their ideas in the best possible way. CATALYSING A STEP CHANGE IN POPULATION RESEARCH Over many years, we have funded some of the world s best population researchers, leading to changes in prescribing regimens and clinical practice, and the introduction of screening programmes. But our researchers told us that there is still huge untapped potential: if they had the time, space and flexibility to come together and collaborate, they could make the UK a global hub for population research. The snag? There was no recognised funding mechanism they could use to develop the necessary infrastructure to run big, collaborative, international projects and no existing population research Centre of excellence. Last year, to meet this challenge, we launched the Catalyst Award. Competing for a grant of up to 5 million over five years, teams had to show that their proposals, as well as being novel and innovative, were collaborative and sustainable, with a commitment to training and mentoring early career researchers, the research leaders of the future. As Professor Robert Strausberg, Chair of the Catalyst Award Panel, says, It s a great opportunity for international scientists from diverse disciplines, such as surveillance, early detection, prevention, and clinical research, to build connectivity with those they would not ordinarily interact with, in order to facilitate big impact research. Unsurprisingly, the scheme is attracting huge amounts of interest: for the first round, 56 different groups and institutions applied from 10 countries; in 2017, five shortlisted teams, comprising 22 groups from seven countries, are currently preparing their final applications, with a decision due in November. As well as providing a unique way of meeting a substantial research need, the Catalyst Award offers applicants a very different experience from the norm. If their Expressions of Interest For those accustomed to keeping their cards close to their chests, the idea of spilling the beans to the competition may be disturbing, but Dr Fiona Reddington, Head of Population, Prevention and Behavioural Research at CRUK, thinks that fears of being scooped are groundless: The ideas are so ambitious that the expertise needed can t be replicated, she says, so nobody s going to get their project pinched. Even if people are critical, it s helpful, she adds: Some of the brightest minds in population research are there, and you have an opportunity to pick their brains. They ll see the potential weaknesses in your proposal that the committee will inevitably grill you on. The long-term aim of the Catalyst Award, to create the nucleus of a virtual centre for population research, will allow the many cohort studies in the UK, and eventually internationally, to be rationally combined and shared. Traditional cohort studies, where participants typically complete lifestyle-based questionnaires over a number of years, are changing drastically. Nowadays, biological and phenotypic data are also collected, and cohort studies represent a rich data resource to generate and test hypotheses, and to identify and validate biomarkers. Backed up by the revolution in big data collection and processing, such studies mean that population research can be better integrated into discovery and clinical research, creating a genuine two-way flow of information: data from normal and patient cohorts will inform our understanding of the molecular basis of sickness and health, which can then be used to develop early detection and prevention measures. Bob Strausberg thinks that the Catalyst Award will be influential in driving this change: I envisage that the Catalyst Award will one day be looked back on as a transformational scientific endeavour that made a difference for people everywhere. Find out about the first team funded through our Catalyst Award on the next page Find out more at cruk.org/catalystaward IN THIS ARTICLE Fiona Reddington Head of Population, Prevention and Behavioural Research, CRUK Robert Strausberg Executive Vice President for Research, Ludwig Institute for Cancer Research and Chair of CRUK Catalyst Award Panel 32 33

19 Image: Willie Hamilton and Fiona Walter AND THE WINNER IS... CANTEST: OFFERING THE RIGHT PATIENT THE RIGHT TEST, AT THE RIGHT TIME, AND IN THE RIGHT SETTING Fiona Walter, Principal Researcher in Primary Care Cancer Research at the University of Cambridge, and Willie Hamilton, Professor of Primary Care Diagnostics at the University of Exeter, are joint PIs on the first Catalyst Award project: CanTest a 5 million venture aimed at investigating ways of bringing new and improved cancer diagnostic tests to GPs. Here, Fiona tells us about the CanTest team s plans. WHAT IS CANTEST? The Catalyst Award asked for a paradigm shift. For us as GP cancer researchers, the paradigm shift is to gather the evidence that s currently lacking to change the way diagnostics are delivered in primary care, so that patients will either have a more timely provisional diagnosis of cancer, or an exclusion of cancer. As an example of why this needs to happen, for colorectal cancer, only about 6% of people getting a rapid specialist referral are diagnosed with colorectal cancer. Therefore, the vast majority of these patients may have been unduly worried about possibly having cancer, and many colonoscopies are undertaken with a negative result. Against the background of the financial concerns of the NHS, we need to use our specialist and GP care much more cleverly. The first part of the project is providing a solid evidence base about which diagnostic tests can be used safely, accurately and cost-effectively for patients in a community setting. We want to build up our multidisciplinary evaluation expertise to form a conduit so we have sustainable methodological approaches for evaluating not just current tests, but future tests as they come out. When exciting discoveries are made, we need to ensure there are researchers to translate and evaluate them so they can be used accurately and safely in primary care diagnosis. So our second objective is to nurture the workforce of the future by establishing an international School for Cancer Detection Research in Primary Care. We ll train and support a new generation of scientists from a variety of backgrounds it ll be an educational melting-pot to rapidly expand the field internationally. WHAT DOES IT MEAN FOR PATIENTS? This is about more diagnostic tests for patients so they can be quickly reassured if they haven t got cancer, and have the appropriate tests and referrals if there is a high chance that they do. Ultimately we will very quickly, in 3 to 5 years, be able to reduce later diagnosis and poorer outcomes for patients with some cancers. It s the biggest investment there s ever been in primary care cancer diagnosis and treatment, and in effecting change for the patient. And of course we re not just talking about cancer. A patient usually presents with one of between 50 and 100 common symptoms yet there are around 8,000 diseases which we have to identify. We ll be helping our patients with any of these diseases if we can do more diagnostics in primary care. WHO DO YOU HAVE IN THE CANTEST TEAM? We are lucky to have a group of people who bring specialist understanding to our team of GP cancer researchers. We ve got behavioural scientists, health economists and statisticians involved, and they ll help us understand more about the patient safety and cost effectiveness aspects. We can also learn a great deal from others around the world. In Europe, we will be working with colleagues from Denmark and Holland who have healthcare systems similar to ours, but we re also working with GP colleagues from Australia and the US, both of which have very different healthcare systems to the UK; we can learn a great deal from them about some of the tests we think will be of value to the NHS, as they are already widely used in those countries where GPs don t act as gatekeepers for specialist care. Our international colleagues are equally keen to develop the evidence base for some of the tests they use, as some can result in overdiagnosis and over-treatment. This is one of our major concerns that you might diagnose people who are not at risk of dying of their disease. An important example comes from thyroid cancer, where there s increasing evidence that tests are picking up cancers that don t need treatment. I VE BEEN A GP FOR ABOUT 30 YEARS. CANTEST ARISES FROM THAT EXPERIENCE FEELING THAT WE CAN ALWAYS IMPROVE THE WAY TO BEST MANAGE OUR PATIENTS Fiona Walter DEMYSTIFYING THE COLONOSCOPY: LIVE Diagnosing cancer early can save lives. So it s crucial we use new ways to demonstrate its power to the public. In a world first, in January 2017, we broadcast a live 90 second TV advert from inside the human body to demystify a common procedure to find and remove early signs of bowel cancer: the colonoscopy. In partnership with Channel 4, we showed the removal of two bowel polyps from Philip McSparron, under the expert care and guidance of Dr Sunil Dolwani, live from University Hospital Llandough in Cardiff. Colonoscopies involve inserting a flexible tube with a camera and small loop into the bowel to remove the polyps, a vital procedure as it can prevent the disease from developing. The advert was viewed by over 1.6 million people, and obtained huge media coverage, reaching 54% of the UK public. Sunil played an instrumental role, from initial conversations with Philip, to guidance on the messaging and shaping of the live TV broadcast. He explains: This project was the combination of a wonderful patient, a great team and an important message. If it relieves anxiety around colonoscopies, then we have achieved something. And he has a note of encouragement to others: As cancer researchers we always want to share our passion with the public and patients I would encourage any researchers to get involved in similar projects so we can help the public understand better what we do and its importance. Image: Screenshot from our live TV advert showing the removal of polyps from the bowel 34 35

20 IN THIS ARTICLE Kevin Lee CEO, Bicycle Therapeutics Heike Lentfer Head of CRUK Biotherapeutics Development Unit, CRUK As our Centre for Drug Development celebrates its 25th birthday, we recognise the unique role CRUK plays in supporting early studies of anti-cancer therapeutics. Above: Research in the lab today Below: Archive photo from the Formulation Unit Herbie Newell Emeritus Professor, Newcastle University Ruth Plummer Clinical Professor of Experimental Cancer Medicine, Newcastle University Malcolm Stevens Emeritus Professor, University of Nottingham COMPLEX, INNOVATIVE AND NOVEL: A RECIPE FOR SUCCESSFUL DRUG DEVELOPMENT We look at some of the major achievements over the last 25 years, how the landscape of drug development has evolved and the impact our work is making internationally. As we enter the next quarter century of the charity s support for drug development, we re well placed to support the increasing breadth of therapeutics and are excited about the future potential for developing new treatments to improve the outlook for cancer patients. A BLEAK HISTORY For anyone unlucky enough to have been diagnosed with cancer in 1980, prognosis and treatment were very different from today. Cancer therapy relied on surgery, radiotherapy, and adjuvant chemotherapy with cytotoxic drugs, and whilst some of these treatments were very effective (and are still in use now), their side effects could be horribly toxic. The commercial arguments for making new anti-cancer drugs weren t very strong; cancer was a terminal illness, and there wasn t much profit in making drugs that patients would only take for a few months before they died. The first steps towards understanding the molecular basis of cancer were being taken, but the era when drugs targeted against particular molecules could become billiondollar blockbusters was yet to dawn. BREAKING DOWN BARRIERS BETWEEN BENCH AND BEDSIDE Many of the classic cytotoxic chemotherapy drugs, such as vincristine and cisplatin, had been discovered in academic labs, and in the UK the Cancer Research Campaign (CRC, one of the precursor charities to CRUK) funded three major drug discovery labs at the Institute of Cancer Research in London, the Paterson labs in Manchester, and Aston University in Birmingham. However, there was a big barrier between the lab bench and the clinic: promising candidates had to get from pre-clinical studies into Phase I and II trials designed to demonstrate safety, dose, and efficacy before most drug companies would be interested, and the logistics the facilities for bulk synthesis, toxicology, formulation and early clinical trials management were missing. To address these challenges, a funding committee was set up in 1982, the Phase I/II Clinical Trials Committee. Chaired by the dynamic and inspirational medicinal chemist Professor Tom Connors, the committee comprised key players involved in anti-cancer drug design, together with the clinicians who sought to use the new agents. Once the committee approved a project, our Formulation Unit, established by CRUK at the University of Strathclyde, got the drug into a form suitable for clinical use and manufactured supplies; the CRC-funded Clinical Trials Data Centre at Charing Cross Hospital helped develop and manage the Phase I/II trial protocol and collect the trial data, and pre-clinical toxicology testing was undertaken. Potential drugs, many of which, as first-in-human compounds, would have been considered too risky a commercial proposition for a drug company, sped through the programme. Continued on next page 36 37

21 Continued from page 37 TEMOZOLOMIDE: THE BRAIN TUMOUR SUPERSTAR Temozolomide was synthesised by Professor Malcolm Stevens and his team at the University of Aston, and was an early success for the Phase I/ II Clinical Trials Committee. Now the international standard of care for treatment of glioblastoma, in 2008 sales figures exceeded $1 billion. Here, Malcolm reflects on the work that led to his team s discovery. We didn t have any particular idea where we were going it was unfettered interesting research that eventually led to something very worthwhile. But we didn t know what that worthwhile was going to be when we gathered at Aston in the 1970s. There was no particular moment in time when temozolomide was discovered there was work that I did as a PhD student, serving my apprenticeship, and my early days as a lecturer up in Edinburgh where we investigated the properties of molecules that were rich in nitrogen. That was the secret of our ultimate success making compounds with multiple nitrogen atoms. They tend to be rather easy to make, which is a good thing, and they have interesting properties from a chemical and from a biological perspective. We realised when we d made the family of compounds that eventually became temozolomide that they were likely to have some exciting biological properties. Until then, all the compounds we d made were biologically inert, and it was only around that time the early 1980s when we were making interesting molecules. And because of funding from the CRC (a predecessor charity to CRUK), we had the ability to test the compounds. We were able to do the synthetic chemistry, the toxicology work, and could manufacture formulations of the drug. When we were researching temozolomide, we weren t supported by any major pharmaceutical companies, so the obvious place to go was the CRC s Phase I/II Committee. Exciting early work convinced the committee of the potential for the treatment, so they decided to fund the clinical trials on temozolomide. I don t think there was ever a eureka hats-in-the-air moment, but I guess we expected that something was going to work. After all, we re scientists, we think that we ve done our side of the bargain the preclinical work and why should we be surprised if something beneficial happens in the clinic? The number of new drugs tested by the CDD in cancer patients The number of first-in-class drugs tested by the CDD i.e. completely new types of drug BIRTH OF THE CRUK CENTRE FOR DRUG DEVELOPMENT By 1992, the Phase l/ll Clinical Trials Committee had acquired a reputation for fast tracking compounds into the clinic, with 32 drugs tested, and one, temozolomide, showing exciting activity against glioma. The nature of the drugs was changing too: targeted therapy was now the buzzword, and the committee was considering proposals to test biological agents such as monoclonal antibodies, as well as rationally designed small-molecule drugs. So that drugs could be taken into commercial development with as little delay as possible, a new expert resource was set up to ensure that all trials met the international standards of Good Clinical Practice. Under its first director, Dr David Secher, the Drug Development Office (DDO) the precursor to today s CRUK Centre for Drug Development (CDD) undertook to manage and coordinate development of all the drugs approved by the Phase I/II Clinical Trials Committee, and the data management team was moved from Charing Cross Hospital to the DDO. In 1998 the DDO established the New Agents Committee, which took over the role of the Phase I/II Clinical Trials Committee in considering new applications. In 2004, with the arrival of the EU Clinical Trials Directive, the DDO s role became even more critical. Prior to 2004, academic clinical trials were conducted under light touch DDX (Doctors and Dentists Exemption) rules, which assumed these two groups would run trials that were in the best interests of their patients; however, the new EU regulations were far more stringent. Whilst the DDO was already complying with established good clinical practice (GCP) quality standards, the requirement for the preparation of detailed scientific information in the form of Investigational Medicinal Product Dossiers (IMPDs) signalled a need to increase the scientific expertise in the DDO. The DDO, renamed the Centre for Drug Development (CDD) in 2015, now stands as a fully integrated, multidisciplinary development function that is globally unique in the non-commercial sector. EXPERT NAVIGATION IN A COMPLEX LANDSCAPE Today, led by Dr Nigel Blackburn, the CDD, staffed by 120 people, has a portfolio of around 25 drugs in development. The CDD works in close collaboration with the researchers, scientists and clinicians in our UK-wide Experimental Cancer Medicine Centres (ECMC) Network, providing specialist expertise on every aspect of preclinical and clinical development for a portfolio of increasingly complex drug candidates. Once new projects pass the stringent scientific review of the New Agents Committee, which also factors in assessment of novelty and likelihood to deliver patient benefit far in to the future, a multidisciplinary CDD team assembles to design and deliver pre-clinical studies and clinical trials in close collaboration with experts in our ECMC Network. It s the CDD s proud boast that they ve never failed to get regulatory approval for a drug submitted to the UK s regulatory body, the Medicines and Healthcare Products Regulatory Agency (MHRA). Continued on next page RUCAPARIB: TARGETING DNA REPAIR Inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) kill BRCA-deficient tumours, and have significant activity in single agent and combination therapy. Professor Herbie Newell, of Newcastle University (with Hilary Calvert, Nicola Curtin, Barbara Durkacz, Bernard Golding, Roger Griffin and Ruth Plummer), was part of the team responsible for making the PARP inhibitor rucaparib. In December 2016, the FDA fast-tracked rucaparib (Rubraca ) into the clinic to treat women with advanced ovarian cancer who have received two or more prior chemotherapies and whose tumours have a BRCA gene mutation. Here Herbie explains the start of the story. In the late 1980s, temozolomide, a DNA-methylating agent, was the drug of the moment. We reasoned that a PARP inhibitor should make temozolomide, as well as some other drugs and ionising radiation, more active by inhibiting DNA repair. There was lots of scepticism from pharma as they said a PARP inhibitor wouldn t be a standalone drug and would increase toxicity; consequently there was no major commercial interest. Nevertheless, in a collaboration between the Cancer Research Unit and the School of Chemistry, we established a drug discovery group in Newcastle in 1990 to make and test PARP inhibitors. Rucaparib was subsequently identified in collaboration with Agouron and Pfizer GRD, and is now being developed and marketed by Clovis Oncology. The critical breakthrough for PARP inhibitors was the recognition of single agent activity in cells defective for homologous recombination repair, as found in BRCA-deficient tumours (reported independently in Nature in 2005 by two UK teams). With the help of the CRUK New Agents Committee (NAC), rucaparib went into Phase I trials in 2003, and went on to stimulate high levels of commercial interest in PARP inhibitors in multiple companies. The FDA approved rucaparib in December 2016, having previously identified it as a breakthrough drug. In 2003, Professor Ruth Plummer, now the chair of the NAC, wrote the prescription for the first patient in the world to be treated by rucaparib, the first ever cancer patient to be treated by a PARP inhibitor. It was always clear we had a drug that did something. We have some patients whose scans are currently clear and have been for some years now. It s fantastic really great. The patient from our first trial doesn t even come to clinic now he s been discharged! A PATIENT S PERSPECTIVE ON RUCAPARIB Susan Ross was first diagnosed with ovarian cancer with a BRCA gene mutation 10 years ago. Here she explains her experience of being part of a clinical trial of rucaparib (Rubraca ) at the Northern Centre for Cancer Care in Newcastle. Early in 2015 I was told the ovarian cancer had returned and unfortunately an operation was not possible. I was facing the prospect of having chemotherapy again. Previously I had three rounds of chemotherapy and four operations, so knowing what treatment was going to entail, my heart sank. I thought Do I really want to go through this again? My consultant organised a BRCA gene mutation test, which showed I was a BRCA2 mutation carrier. I was then offered the opportunity to go on a clinical trial of this new treatment rucaparib, and I grabbed it with both hands. My care is overseen by Dr Yvette Drew, and I attend the unit every three weeks to be monitored, and discuss any worries with the nurses and doctors. I ve been taking rucaparib as part of this trial since December 2015 and it s the best I ve felt in 10 years, both physically and mentally. With the help and support of all the staff, it feels like I ve got my life back. Being part of a clinical trial means I m monitored very closely. I am so thankful for all those who have been involved in the development of rucaparib and for making this clinical trial possible. Being part of a clinical trial is an opportunity to help make a difference, help cancer patients in the future and hopefully find a cure for this awful disease. I d do it again in an instant. Image: Susan Ross with her partner Paul Appleby 38 39

22 AST-VAC2: A FIRST-IN-CLASS MANUFACTURING CHALLENGE Clinical Development Partnerships The Clinical Development Partnership (CDP) scheme aims to increase the number of new treatments for cancer patients by taking more novel oncology agents into clinical development. CDP brings promising anti-cancer agents, which companies are otherwise unable to develop, into clinical trials. BT1718: FIRST-IN-CLASS THERAPY FOR SOLID TUMOURS In December 2016, CRUK, Cancer Research Technology (CRT), and Bicycle Therapeutics announced their collaboration to trial a first-inclass drug in patients with advanced solid tumours. Together with Dr Udai Banerjee, Chief Investigator for the trial, our CDD is sponsoring and funding the first-in-human Phase I and Phase IIa clinical trial for BT1718, a bicyclic peptide conjugated to DM1, an existing anti-cancer therapeutic that kills cells by inhibiting microtubule formation. Bicyclic peptides are small molecule drugs which have pharmacology similar to monoclonal antibodies providing targeted delivery of highly potent cytotoxic drugs, but their low molecular weight allows them to penetrate tumours far more efficiently. In this case, the peptide portion of BT1718 binds with high affinity to Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) which is highly expressed in many solid tumours, including triple negative breast cancer, sarcoma and non-small cell lung cancer. Bicycle Therapeutics has the right to license the results of the CRUK trial in return for successbased milestone and royalty payments to CRUK as well as an equity stake in the company to reflect CRUK s value-add to the broader Bicycle platform. This relationship is an example of a situation where one plus one is greater than two, says Dr Kevin Lee, CEO of Bicycle Therapeutics. Our excitement for our lead molecule BT1718, our broad pipeline behind BT1718, our technology platform, and its potential to transform outcomes for patients was shared by CRUK. It is clear that by combining forces we can deliver potential benefit to patients more rapidly than we could by working alone. We greatly value our partnership with CRUK for many reasons, Kevin continues, especially the access the partnership gives us to CRUK s in-depth and complementary expertise and to its clinical network and infrastructure. CRUK s investment, as well as the breadth of data we expect will be generated, is beyond what we would have been able to accomplish on our own. Continued from page 39 A RECIPE FOR PRESENT AND FUTURE SUCCESS Not surprisingly, the portfolio managed by the CDD has changed considerably over the years. Nowadays, the majority of CDD projects are collaborations with industry, forged through the innovative Clinical Development Partnerships scheme. The agents under investigation have also changed drastically. Now, more than half of the CDD portfolio are biological drugs vaccines, antibodies, radiopharmaceuticals, cell therapies, viruses and recombinant proteins a development that would have astonished the pioneers in the 1980s. The CRUK Biotherapeutics Development Unit, now located in a new state-of-the-art building opened in 2010, undertakes the manufacture of these highly complex biological drugs for early phase clinical trials. At CRUK we are also tackling the challenge of how to run trials of combination therapies. THE UNDERLYING PHILOSOPHY OF THE CDD HAS REMAINED THE SAME TO BRING BENEFIT TO PATIENTS IN NEED OF NEW MEDICINES Frequently, ideal drug partners belong to different companies, and there has been little appetite for joint testing. Commercially-sponsored trials involving drugs paired with radiotherapy have also been a rarity. Through the Combinations Alliance, a joint initiative between CRUK, the ECMCs and a growing number of pharmaceutical collaborators, combination ideas involving novel or marketed drugs, radiotherapy and/or chemotherapy are trialled in the ECMC Network. Currently, 14 trials are open with six more being set up five of these trials are radiotherapy combinations and one an immunotherapy combination. Throughout all this change, the underlying philosophy of the CDD has remained the same to bring drugs that otherwise might not have been developed into clinical trials, to bring benefit to patients in need of new medicines. Isolation and in vitro loading of dendritic cells with cancer antigens is a promising concept for immunotherapy. Dendritic cells can elicit an immune response by presenting cancer antigens such as telomerase (expressed by nearly all cancer cells but very rarely by normal cells) to the adaptive immune system, kick-starting a focussed attack on the tumour. To date, this approach has been limited by the requirement to individualise patient therapy. In a Clinical Development Partnership with Asterias Biotherapeutics, our CDD has developed an innovative laboratory-scale process to make it possible to manufacture a Good Manufacturing Practice (GMP) clinical drug product of this kind for the first time ever. The process employs human embryonic stem (ES) cells (rather than patient blood) as the starting material, which are expanded in number and differentiated into mature dendritic cells by adding various growth factors at key development stages. The dendritic cells are loaded with modified telomerase (htert) mrna so that the cells express suitably-short telomerase fragments, shuttled by the cell onto its surface for presentation to the immune system. The resulting vaccine is being made in the CRUK Biotherapeutics Development Unit, here Dr Heike Lentfer, the Unit s manager, explains some of the challenges. The journey starts from a single cryovial containing 10 7 human ES cells, which are expanded and differentiated into dendritic cells over a period of ~65 days and electroporated with htert mrna. By the end of the process, approximately 100 vials of drug product have been made, each containing 20 million cells enough to dose many patients. The manufacturing processes for creating living cell therapies at sufficient scale to supply clinical trials are still in their infancy. Our team has addressed many challenges, including maintaining rigorous cell culture and sterility standards during the two month manufacturing process, through to the development of new assays to make sure that dendritic cells are present in abundance. There were similar challenges for monoclonal antibody production 30 years ago, so we re optimistic that improvements will be made in scale-up and productivity. Asterias has helped solve problems throughout the technology transfer and manufacturing campaign, no matter what time of day it was in California a great example of a productive collaboration with an industry partner. Combinations Alliance The Combinations Alliance is a joint initiative between CRUK, the Experimental Cancer Medicine Centres (ECMC) network and pharmaceutical collaborators which aims to drive academia/industry collaborations to increase novel combination treatment options for people with cancer

23 INSIDE THE FRANCIS CRICK INSTITUTE After years of meticulous planning and design, in late 2016 Her Majesty The Queen officially opened the brand new Francis Crick Institute in London, the biggest biomedical research facility in Europe under one roof. Bringing scientists together from different disciplines to tackle the pressing health concerns of the 21st century, the new institute is now home to 1,250 scientists and a further 250 support staff. Here, we take a glimpse behind its doors and meet some of its new inhabitants. The Francis Crick Institute is huge, but it s also beautiful: sweeping curved roofs cover an imposing structure of glass, steel and concrete, with a frontage whose vast cathedral-like stained glass windows refract a rainbow of colours into the high-tech atrium. Inside, things only get more impressive. Standing in the entrance area feels like stepping into the space between two ocean-going liners; the five above-ground floors (a further four lie below) rise up on either side, joined by walkways floating across the gulf of the atrium. But walk up the central spiral staircase, or ride the high-tech lifts, and the impression of grandeur disappears. Collaboration spaces and work pods featuring comfy sofas and coffee machines give each floor a far more intimate feel. The labs and offices, laid out on either side of the atrium, are open-plan, with sight-lines extending across the whole breadth of the building, but they house familiar equipment, and are already gathering the reassuring clutter of scientific workspaces the world over. Beyond the grand exterior, what is life like at the Crick? Talking to the new inhabitants gives a flavour for how it feels to work in this amazing building. Whilst there are some of the inevitable teething problems that are to be expected when settling into a brand new facility there are issues with the glassware washing and ultrapure water, and the category 3 labs have yet to be commissioned things are running remarkably well given that the last groups moved from their legacy institutes [CRUK s London Research Institute (LRI) and the MRC National Institute of Medical Research (NIMR)] less than six months ago. The Crick was designed in concert with its future occupants, and the strategies for encouraging collaboration and mingling of the scientists are working well. All the offices are deliberately small, so everyone, including Director Sir Paul Nurse, meets in the communal areas. Monica Rodrigo, a staff scientist in Professor Steve West s group, thinks the Crick s layout is changing how individual labs function: On each floor there are booths and LCD screens so you can have impromptu meetings. Steve doesn t have meetings in his office any more, he just goes to a booth, she says. Dr Narin Hengrung, a postdoc with Dr Steve Gamblin, agrees: The NIMR in Mill Hill had very small and cut-off labs, and they were very crowded, he says. Here, the views and openness make it feel like you can wander over to another lab and see what they re up to. He s looking forward to finding out what everyone else is doing: Peter Cherepanov s lab works on something very similar to what I m trying to do, so it s really nice to have their expertise next to us. I don t know what most of the other BUSI- NESS The modernist facade of the Francis Crick Institute designed by HOK Architects OPEN FOR people on the floor do yet but that will come it s still early days. Esther Wershof, who s doing a PhD in Dr Paul Bates s lab, loves the fact that even the big boss has a tiny office you can see into, and there s no feeling of hierarchy. If I have an idea, she says, I feel I can just talk to whoever I like. I m doing a mini-project at the moment just because I bumped into somebody in the collaboration space and we realised we had common interests. There s still some degree of nostalgia for the legacy labs, especially from those coming from the labs in Mill Hill and the LRI s Clare Hall in Hertfordshire, which were far more rural. But they are also enjoying the compensatory benefits from their new central London location: There are more talks and high profile people coming here than we ever had at Mill Hill, says Narin, and lots of people go to talks at places like Imperial, where we d never have gone before. And the Camley Street Nature Reserve, only a short walk away, also offers some solace the West lab can be found eating lunch there on sunny days. What makes everyone most happy, however, is being able to access the rich opportunities offered by the Crick s state-of-the-art core scientific resources. With 14 in-house stateof-the-art science technology platforms, including electron and light microscopy, structural biology, next generation sequencing, mass spectrometry, bioinformatics and biostatistics, metabolomics and peptide chemistry, all run by permanent scientists who are acknowledged experts in their fields, the Crick is tremendously fortunate. As Monica endorses: Not everyone can be an expert in everything. Now, if you have an idea for, for example, a screen, you don t have to figure out how you re going to do it on your own; you can talk to someone in the screening facility. That really accelerates research because you just deal with the results and look at what s interesting. It s too early to demonstrate the impact of the Crick, but all the ingredients for success are in place: great people, amazing facilities, and a collaborative, non-hierarchical ethos are already making the institute one of the most attractive places in the world for top-class medical researchers looking to push the boundaries of knowledge. Esther, whose mathematical background makes her an exemplar of the Crick s multidisciplinary appeal, summarises the general sentiment: I feel hugely lucky to be here I can t think of anywhere better to work, she says. For a young researcher, to be surrounded by really good scientists is a mixture of daunting and inspiring I come in every day and I think I d better earn my place! Interior atrium at the Francis Crick Institute IN THIS ARTICLE Narin Hengrung Postdoctoral researcher, Francis Crick Institute Monica Rodrigo Principal Laboratory Research Scientist, Francis Crick Institute Esther Wershof PhD student, Francis Crick Institute 42 43

24 A MIXING POT OF IDEAS: WORLD-CLASS IMMUNOLOGY Professor Caetano Reis e Sousa was awarded the 2017 Louis-Jeantet Prize for Medicine for his outstanding contributions towards our understanding of how the immune system senses pathogen invasion and tissue damage. His latest in a long list of accolades, the Jeantet is Europe s most prestigious prize for bioscience research. Here, Caetano shares his thoughts on the move into the Crick, where he is a Group Leader, and the work currently going on in his lab. When the building was being designed and we were told about the collaboration spaces, and how they d bring people out to talk to one another, some of that came across as a little bit contrived. However, it really is happening you do see a lot more of other people, you bump into them and talk about all sorts of things, including science. Most importantly, people in different labs are talking to one another more. The fact we have so many great people doing so many things in the building is facilitating research somehow information just gets transmitted. Someone in my lab doing Drosophila work who wants to do some clever mutants involving conditional knockouts found that Jean-Paul Vincent is one of the world s pioneers, so his lab has been helping us set it up. Another person is interested in protein precipitation of RNA; she discovered that Jernej Ule is a world expert, so she s gone to talk to someone in his lab. My lab s work is going very well, particularly considering that we ve only been here for six months. My research is centred around dendritic cells, the body s professional antigenpresenting cells we study their ontogeny and function. We re currently excited about cancer immunology as it s likely that some patients who don t respond to immunotherapy treatments have insufficient numbers of primed T cells, which is a big problem. The idea is that naive T cells aren t encountering tumour antigens, and so can t be activated. That s led to a resurgence of interest in exploring the role of dendritic cells in kick-starting the anti-tumour immune response. One way that tumours evade the immune system is by producing prostaglandin E2 (PGE2), quite different from other routes that target immune checkpoints. We ve found that PGE2 can decrease dendritic cell infiltration of tumours, which might help explain how the T cell response is impaired: if there are no dendritic cells to process and present tumour antigens, the T cells are blind to the tumour. We already know that tumours infiltrated by dendritic cells have a better prognosis data from mouse and man show that dendritic cell presence elicits a good immune response, and correlates with survival across different cancers. Now we re trying to work out how to increase dendritic cell numbers in tumours; we think there s an exciting opportunity for therapeutic intervention. Previously at the LRI, there was understandably a strong emphasis on using cancer as a model, so there are a lot of people at the Crick who are interested in cancer. But we re also finding people who ve come from NIMR, who weren t necessarily looking at cancer before, but are now identifying synergies with their research, and vice versa. There are so many interesting parallels between different diseases, for example cancer and infections, and we now have more opportunity to explore these options. It s not just hype that being more integrated brings benefits it really does. From CRUK s perspective, the Crick is a very worthwhile investment: they re getting the expertise of the whole institute. Read more about Caetano s Jeantetwinning research in his Commentary in EMBO Molecular Medicine (doi: /emmm ) BEHIND THE SCENES: PIONEERING HUMAN STEM CELL RESEARCH Dr Kathy Niakan is a Group Leader at the Crick. In 2016, she became the first person in the world to gain regulatory approval to edit the genomes of human embryos for research. For this, Kathy is in TIME 100, TIME magazine s annual list of the world s most influential people. Here, Kathy reflects on her recent move into the Crick and gives a flavour of the painstaking work that goes on in a world-leading human stem cell lab. I would say that the UK is the world leader in human embryo and stem cell research. A lot of that is due to the pro-active legislation, which provides a protected space where you can focus on developing tools that enable you to address really important questions in human biology. Being in the Crick has significantly increased our ability to collaborate with clinicians. We re working with nearby clinics much more directly and rapidly than we could in the past. It s a two-way learning process: they have embryologists interested in basic research who we can learn from as they re experts in certain aspects like handling embryos. And this can only mean one thing faster progress. My interest is in how we start off as a one-cell embryo and the subsequent events that distinguish the cells from each other as they multiply. Increasing our understanding of this fundamental area of biology will, we hope, help uncover pioneering new ways to tackle infertility, miscarriages and developmental disorders, as well as support the development of new therapies using stem cells. We know a little about the molecular mechanisms in the mouse, but in the human we know very little the more we compare the two, the more we see how different they are. The classic developmental regulators abundant in the mouse zygote are absent in humans, and vice versa. It would have been so easy if molecularly they had been similar, but they re fundamentally different at this stage. Unfortunately, we don t always have the tools readily available to enable us to test whether insights found in model organisms translate in humans. For example, it wasn t clear whether CRISPR, which we successfully use to edit genomes in mice embryos, could be used in a human embryo. There were no optimised protocols, so we ve spent almost a year optimising every single one of the parameters and developing new technologies. We ve been testing them in any cellular context we can, so before we do anything with even one human embryo, we ve developed the best methods we can. Overcoming technical challenges will hopefully enable us to use this technology to address fundamental questions, such as how are the first lineages specified in humans, how do these early cells diverge in their fate and function at this critical stage of development. It s a really hard choice for IVF patients to decide what to do with excess embryos, so it would be disrespectful to them to not use that precious material in absolutely the best way we can. LABORATORY OPERATIONS & INFRASTRUCTURE Jo Payne: Head of Laboratory Infrastructure I manage the teams doing all the behind the scenes stuff that keeps the science going glass-washing, media, the freezer farm, the fly facility, and the equipment care team. If we re doing it right, you shouldn t see very much of us! Much of our activity is in the basement, and we need to find a way of getting out more and mixing with the scientists, not just formulating on our own. I was involved in designing the facilities here; mostly they re working as we planned, which is really satisfying. It s been amazing seeing it from zero when it was a building site through to this complete institute now. Grace Davies: Fly Facility Technician It s pretty awe-inspiring coming to work here. My main job is to keep the flies alive, but I ve started injecting DNA constructs into them now as well, which I m finding really interesting. The lab can be used by everyone working with flies, so there are about 60 scientists coming in and out, and it s a really friendly atmosphere. Emily Lau: Laboratory Operations Being here is how I imagine being in a spaceship would feel, especially the basement you see all the offices made out of glass, and past that there are the big NMR machines, it s like something out of a film. I m quite new and I do find the scientists a bit intimidating, but they re all really friendly. 600,000 vials for food for fruit flies made yearly 21,000 items of scientific equipment are tracked, along with a further 9,000 power packs/cables 13,000 litres of L Broth made each year 6,500 litres of liquid nitrogen are stored in the bulk gas compound, together with the same volume of CO 2 12,000 litres of sterile distilled water made each year Each year, media prep makes 75,000 poured microbiological plates o F There are C freezers, and 600,000 vials in the Cryostore 10,000 litres of phosphate buffered saline made each year Around 750,000 items of glassware are washed every year 44 45

25 IN THIS ARTICLE Mark Bodmer Chief Scientific Officer, Evelo Biosciences Michael Burns Assistant Professor, Department of Biology, Loyola University Chicago Hani El-Nezami Associate Professor, School of Biological Sciences, University of Hong Kong The microbiome has been a buzz word for years because of its association with a number of diseases, from obesity to Crohn s disease. Now some researchers from around the world believe there may be a link between cancer and the microorganisms that call our body home which, if true, will open up a host of new opportunities to understand and tackle the disease. We take a look at what s happening within this rapidly developing field and ask some of its leading figures if they think it will live up to the hype. In November 2016, Dr Jennifer Wargo stood in front of an audience in Liverpool to speak about two things with no immediately obvious connection faeces and skin cancer. The Associate Professor from the University of Texas MD Anderson Cancer Center was closing the National Cancer Research Institute s conference by presenting results from her study examining more than 100 faecal samples from people with advanced malignant melanoma. Soon the connection became clear the patients whose cancer responded well to certain new cutting-edge immunotherapies had more diverse and different types of bacteria in their gut. Our research shows a really interesting link that may mean the immune system is aided by gut bacteria when responding to these drugs, said Jennifer. Jennifer s study builds on the hypothesis that by altering gut bacteria you might improve a person s response to immunotherapies, increasing the numbers who could potentially benefit from these new cancer drugs. Her results reinforce earlier mouse studies, although the bacteria are different. And it appears that the benefits may not be limited only to response to these drugs, with other studies showing that feeding certain bacterial species to antibiotic-treated or germ-free mice receiving treatment can also reduce a dangerous side effect from the treatment the inflammatory bowel condition, colitis. This research highlights a rapidly developing new avenue in cancer exploration that focuses on the human microbiome, the complex ecosystem of thousands of different microorganisms that call our bodies home. Imbalances in the microbiome (or dysbioses ) have already garnered a lot of interest in the medical world as a potential player in numerous conditions, from inflammatory bowel disease to multiple scelorosis, diabetes (type 1 and type 2), allergies, asthma, obesity and even autism. AN EXPLOSION OF INTEREST Attention on cancer and the microbiome is coming from several directions: first, from the research community clearly demonstrated by the fact that between 2005 and 2015 the number of published articles on the topic increased by nearly 2,000%. The media have also leapt on the bandwagon, capturing the public s imagination with reports of its potential for preventing and treating various diseases by targeting and rebalancing our microbiomes. And results from early studies like Jennifer s have spurred industry to back research into live biotherapeutics (or probiotics), with several start-ups backed by heavy investment. Even some big pharma companies, such as Bristol- Myers Squibb and Roche, are moving into the microbiome immuno-oncology space. Researchers are also actively exploring what role the microbiome might play in the development of cancer, and their early findings make interesting reading. The microbiome appears to differ between people with cancer and those without, and the disease can develop in a healthy mouse after transferring the microbiome, via a faecal transplant, from another with colorectal cancer. Several species of bacteria are also potentially connected with cancer, with researchers finding them in higher proportions in people with the disease. This opens up intriguing possibilities that a certain microbiome may be a risk factor in developing cancer or could be used as a new diagnostic tool. Jennifer calls the science potentially game changing for cancer. We have made tremendous advances in cancer treatment over the decades, with personalised medicine and immunotherapy that target components of the tumour cells. The next era we are entering is to understand not only the tumour but other parts of the individual, such as interactions with the immune system and the scaffolding in the surrounding tissues that counts towards the development of cancer and how it responds to treatment, she says. This is a whole new aspect of cancer therapy. Could we predict responses? Could we treat cancer more effectively by modulating the microbiome? Or prevent it altogether? That s why it s exciting. But looking behind the scenes, a number of important challenges still remain for researchers in the field particularly around teasing out which changes to the microbiome are meaningful, if any, and, not least, distinguishing between cause and effect. The latter is indeed a very big caveat, as researchers are yet to properly establish whether changes in the microbiome contribute to cancer onset and progression, or whether the changes seen are a consequence of the disease. Hypothetically, this perhaps isn t such a big jump as there are already well-known microbes that can cause cancer, such as Helicobacter pylori and human papillomavirus (HPV). But as Professor Paul O Toole, Professor of Microbial Genomics at the APC Microbiome Institute at University College Cork, notes, the scientific community has been criticised for hype before. He says: It s important to make clear that these are association studies; there is no causal link. Sure some research hints at causation, but such studies have been done in mouse models, which can t be replicated in humans. The solution, he says, is to study people and follow their microbiome over a long time, comparing it between people who develop cancer with those who don t. But many others within the community are becoming more confident that there is indeed a connection. A 2013 opinion piece in Nature Reviews states: Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis. (doi: /nrc3610) And while the evidence continues to stack up, many researchers believe the potential mechanism is through our resident microbes influence on the immune system, with their abilities to dial up or dampen down inflammation as well as to manipulate the capabilities of our immune cells. For instance, it has been known for years that inflammation is central to the development of colorectal cancer, but there have been question marks over its source and now fingers are pointing towards the microbiome. But the relationship is complex, with some studies suggesting certain bacteria can promote tumour growth while others appear to inhibit it and, in some cases, they might even switch roles in different cancers. At the moment, there are simply too many moving parts we don t understand enough about which species is doing what, how they change over time and how they interact to know what role they play in disease and what we might be able to target. And we need to relate any results seen in laboratory animals with what actually happens in patients. Despite the challenges, the potential is enormous and is continuing to fuel the current flurry of interest. As Paul conveys, The microbiome is a plastic environmental factor. If it is found to be an additional determinant of cancer then we can modulate it. That s exciting. Continued on next page IN THIS ARTICLE Paul O Toole Professor of Microbial Genomics, APC Microbiome Institute, University College Cork Jennifer Wargo Associate Professor, University of Texas MD Anderson Cancer Centre Emese Zsiros Assistant Professor of Oncology, Roswell Park Cancer Institute 46 47

26 EXCITING RESEARCH Continued from page 47 Some recent findings exploring the role of the microbiome in cancer 2011 Studies identify that Fusobacterium is found more often in colon cancer tissues than healthy tissue University of Michigan researchers show that transferring the gut microbes from a mouse with colon cancer to those with no microbiome sees them develop two times more tumours than mice receiving microbes from a healthy mouse Researchers at the European Molecular Biology Laboratory predict the presence of colorectal cancer from the abundance of bacterial species in stool samples, with about the same accuracy as a blood test NYU Langone Medical Centre find that people whose oral microbiome includes Porphyromonas gingivalis, linked with gum disease, have a 59% greater risk of developing pancreatic cancer compared to those who do not Researchers from Kumamoto University in Japan find that people whose oesophageal tumours test positive for Fusobacterium nucleatum have poorer survival chances Researchers at the University of Texas MD Anderson Cancer Center show that people whose malignant melanoma respond to immunotherapy have more diverse and different types of gut bacteria compared with non-responders. % of the body s microbial mass is in the gut, which is why it s the most well-studied OPPORTUNITIES ABOUND Indeed, the opportunities are considerable, with the scope to change our approach to cancer treatment sparking a lot of interest. At the end of 2016, a new Phase II clinical study started at Roswell Park Cancer Institute in the US, with backing from Merck & Co. This is one of the first human trials looking for links between the microbiome and response to immunotherapies. The team will evaluate how well 40 ovarian cancer patients respond to a combination treatment of the immunotherapy drug pembrolizumab (Keytruda ) and two other cancer drugs, bevacizumab (Avastin ) and oral cyclophosphamide (Cytoxan ). Then, the researchers will analyse their blood, tumour, stool, vaginal and skin microbiomes to identify any associations with clinical outcomes and tumour response. The study will extend the work that has already been carried out looking at the influence of the gut microbiome and highlights the variety of research angles being investigated to improve immune defences against cancer, says the study s principal investigator, Dr Emese Zsiros of Roswell Park Cancer Institute. Indeed, for scientists exploring drug responses, this opens up a possible new treatment paradigm whereby patients microbiomes are checked before treatment and then modulated, if needed, to enable the best drug response. Benefits could also come through using live medicines or probiotics to modify a person s resident microbial communities. Uncovering this tantalising possibility, last year a team in Finland and China carried out a study feeding mice with a microbial cocktail called Prohep for a week before injecting them with liver cancer. Their results were astonishing the weight and size of tumours in the microbially treated mice were reduced by 40% compared with control mice without the probiotic, with the team showing that it works by promoting an anti-inflammatory environment in the gut and liver. Dr Hani El-Nezami, associate professor of biological sciences at the University of Hong Kong and lead author of the study, is excited by their results. He says, We had not expected such a significant impact and we are now exploring even better cocktails for study. We now also want to investigate how humans will respond to this bacterial cocktail. Start-up companies are also getting in on the microbiome immuno-oncology therapeutic opportunity. One such firm is Evelo Biosciences, which is developing the next generation of immunotherapies to treat cancer and inflammatory diseases. The company plans to begin first-in-human testing of its products monoclonal microbials in early 2018, says Evelo s Chief Scientific Officer, Mark Bodmer. The oncology products are orally-delivered single strains of microorganisms that induce a systemic anti-tumour immune response with the potential to treat to treat melanoma, non-small cell lung cancer, renal and bladder cancer. The products exert a systemic immunomodulatory effect via the lumen of the gut. This can be either alone or in combination with current immunotherapies. What has become increasingly clear is that naturally occurring monoclonal microbial strains act through the gut to modulate systemic immunity for an anti-tumour effect, says Mark. It s still early days, he adds, but the new tools and a new appreciation of the microbiome has opened up a massive area of biology with scope to develop new types of therapeutics for patients. Meanwhile, others are spearheading early investigations into using the microbiome in cancer diagnostics. For example, in 2014, a team at the University of Michigan found that identifying differences in gut microbiome data alongside known clinical risk factors improved their ability to differentiate between healthy people and those with colorectal adenomas and carcinomas. And a team of Canadian researchers is studying the potential of using the breast tissue microbiome as a biomarker in cancer diagnostics and in determining individual risk. SO IS IT REALLY THE NEXT BIG THING? From a patient s point of view, research into the microbiome holds great promise for tackling cancer from many different angles: identifying who is at increased risk, earlier diagnosis, and new and improved treatments with fewer side effects. It could also open up simple new interventions to help prevent the disease from ever occurring, such as promoting a healthy microbiome through the diet. But, while the excitement continues to build, we need to be mindful that research into cancer and the microbiome is very much in its early days with a host of questions that still need answering. Dr Michael Burns, an Assistant Professor at Loyola University Chicago studying the cancer microbiome, notes two phases for research: characterisation and functional testing. We are currently in the characterisation phase. We have to determine what microbes and how many of them Iain are present Foulkes, in CRUK cancer patients before we can try to understand exactly what these microbes are doing. Once we nail this down, and it s by no means trivial, we ll have targets to start investigating function. The first phase is critical to identify the differences, and the second is needed to identify which of these are actually biologically and medically relevant. So it s still too early to say where the current buzz around this area will ultimately lead. But the rewards that it could open up for patients mean that it s something to keep a close eye on particularly if the balance of evidence confirms that a causal link does indeed exist. Achieving that and the ability to modify one environmental risk factor, not to mention improving the efficacy of current drugs, could transform the whole approach to cancer. With 1 in 2 people in the UK now likely to develop the disease, new findings are critical. Microbiome research is turning heads, but will it deliver all that it promises? Only time and research will tell. THIS IS AN INTRIGUING AREA OF RESEARCH WHICH OFFERS A LOT OF PROMISE BUT ALSO MANY UNCERTAINTIES. THIS IS WHY WE VE IDENTIFIED IT AS ONE OF THE QUESTIONS IN THE NEXT ROUND OF OUR GRAND CHALLENGE AWARD Iain Foulkes, CRUK 48 49

27 INVESTING IN THE FUTURE HOW OUR FELLOWSHIPS MAKE A DIFFERENCE IN THIS ARTICLE David Adams Group Leader, Wellcome Trust Sanger Institute, Cambridge Noor Gammoh CRUK Career Development Fellow, CRUK Edinburgh Centre In the last 10 years, CRUK has invested over 150 million in fellowships, funding a diverse community of researchers, across a wide range of disciplines. Our fellowship schemes include a range of options designed to support long-term career progression, and are recognised for providing much more than the security of the funding. Our fellowships support home-grown talent as well as attract promising scientists from around the world. We fund across a wide range of research areas and at all career levels, supporting renowned researchers at the top of their fields, as well as helping promising early career researchers to become the leaders of the future. We believe this early career support is crucial in cultivating the next generation of scientists who will bring real impact to the field. Dr David Adams, a world-renowned researcher at the Wellcome Trust Sanger Institute, started his early research on a Career Development Fellowship (CDF). I think the ability that first CRUK fellowship gave to work on a long-term vision was what really appealed to me. The six-year fellowship is different to a normal three-year cycle of grant funding. It gives you the support and freedom to chase the big ideas, and have the time and resources to evolve that. Our strong community is a big part of why our fellows testify that our career support is unrivalled. We host networking events that allow our junior fellows to rub shoulders with world-leading researchers. Our scientific meetings provide opportunities to share ideas and learn from the best, and we actively help our fellows to forge new connections and collaborations. As David puts it, the network of researchers CRUK draws together and the interactions they encourage is just incredible. We also provide mentoring opportunities to enable our fellows to gain advice from more experienced researchers, and we assist all our fellows to do a lab management course to improve skills needed to set up and run a lab. Dr Noor Gammoh currently holds a CRUK CDF, having moved to the UK in 2014 to pursue her research career, and emphasises this important aspect of CRUK fellowships: I get invaluable support and advice from my mentor. No matter how much training you ve had before, starting your own lab is a big step, and I think having that outside window someone who knows the challenges, but is not closely related to your work can have a really positive effect. I can reflect with them on how my research is progressing, and the areas I need to develop, as well as get practical advice on new areas like managing finances. Our fellowship schemes offer flexibility, with funding designed to support a range of career pathways, including both clinical and non-clinical careers, and over long-term career progression. Our early career options for non-clinicians include the Career Development Fellowship (CDF), open to postdocs and early career researchers, and the Career Establishment Award (CEA), to help researchers who already have a tenured position to set up as new group leaders. Both awards provide six years of funding to help researchers establish themselves and their science. For clinicians, the Clinician Scientist Fellowship is available to researchers with less than three years' postdoctoral experience, and the Advanced Clinician Scientist Fellowship for those with more than three years experience. Both schemes offer funding over five years. Our two awards for the most senior researchers the Programme Foundation Award and Senior Cancer Research Fellowship are open to both clinicians and non-clinicians. The Programme Foundation Award is for researchers already salaried at a host institution, and the Senior Cancer Research Fellowship for those without existing salary support. These awards support the most experienced researchers to establish or further develop their own independent research group. As David testifies, With CRUK it is about long-term funding that allows you to pursue your own long-term vision. My initial CDF really allowed me to establish myself, I then went on to be awarded a Senior Fellowship, and in 2016 I was awarded a CRUK Programme Award. It s that long-term support that really allows you to meet your goals and produce research with real impact. Here three researchers from different fields and at different stages of their careers recount their experiences of CRUK fellowships. Dr Serena Nik-Zainal qualified in medicine, trained as a medic and then specialised in clinical genetics. She has recently been awarded a CRUK Advanced Clinician Scientist Fellowship (ACSF) to further her research into the mutational signatures of primary cancers. My interest in research led me to pursue a PhD and postdoc, which by chance took me into the area of cancer genetics. I started looking at patterns of mutational signatures that arise as cells become cancerous, caused by factors such as smoking, ultraviolet light, or DNA repair defects. CRUK is extremely supportive, welcoming and positive. They take the time and effort to understand you and your science and what it needs to progress, and they really listen to you. The five-year award gives me the ability to spread my research wings and explore a much more sophisticated understanding of mutational signatures. One of my aims is to try to understand the mechanisms that actually cause these signatures. At the moment it s like having a photo of a landscape, where you can see the mountains and rivers, but can t tell how they were formed. We can see the mutations, but don t know how they ve arisen, such as by sunlight, smoking or a genetic defect, so we want to gain a better knowledge of this. The fellowships provide a great level of autonomy and flexibility, which is very powerful to advance research. I m now also part of a team funded by the incredible CRUK Grand Challenge it s another example of how CRUK is prepared to think differently, fund differently, and provide support in ambitious ways, to achieve real results in cancer research. I m so proud to be a part of that. Continued on page 53 of our Junior Fellows go on to obtain senior fellowships or grants from major biomedical funders MILLION awarded by CRUK in fellowship and career support awards in 2016 Find out about CRUK support for research careers at cruk.org/ leaders-of-tomorrow % 50 51

28 PAVING THE WAY CRUK CAREERS AND FELLOWSHIPS SENIOR RESEARCHER / LEADER ESTABLISHED INDEPENDENT RESEARCHER EXPERIENCED POSTDOCTORAL RESEARCHER EARLY STAGE POSTDOCTORAL RESEARCHER PhD PRE PhD CAREER LEVEL Postdoctoral Research Bursary ~ 35k (up to 2 years) PhD Studentships in Institutes & Centres Predoctoral Research Bursary ~ 25k (up to 1 year) Advanced Clinician Scientist Fellowship ~ 1.7m (over 5 years) Clinician Scientist Fellowship ~ 1.2m (over 5 years) Clinical Research Training Fellowship For clinical academics only For clinical and non-clinical researchers. Funding pays salary FUNDING AVAILABLE Senior Cancer Research Fellowship ~ 2m (over 6 years) Career Development Fellowship ~ 1.5m (over 6 years) Population Research Postdoctoral Fellowship Salary (3 years) Programme Award Support Different levels of support Programme Foundation Award ~ 1.5m (over 6 years) Career Establishment Award ~ 1m (over 6 years) Clinical Trial Fellowship ~ 50k/yr (up to 3 years) For clinical and non-clinical researchers with salaried positions Other support / positions available Senior Group Leader in Institutes Junior Group Leader in Institutes Research Travel Award < 10k (flexible length) Continued from page 51 Originally from New York, Dr Doryen Bubeck completed her PhD in biophysics at Harvard, before coming to the UK as a postdoc at Oxford University. She now leads a group at Imperial College London, supported by a CRUK Career Establishment Award. Her research merges cryo-electron microscopy and x-ray crystallography to investigate membrane proteins. My CRUK award provides six years of funding to help develop as a new group leader. It s this security and support that means I m now leading a team of researchers to make breakthroughs in one of the most significant medical challenges we face today. I think CRUK provides an extraordinary opportunity for its fellows. They foster a sense of community for researchers working towards a common goal. CRUK s mentorship scheme has also been an important resource as I embark on this new challenge of running my own group. As scientists we ve been trained to think critically, to problem solve, and to be creative with our ideas. But we ve not always been trained to manage, provide direction, and perhaps most importantly, motivate a team. I've found this mentorship opportunity to be invaluable. The results of this level of support can be seen in the science. My proudest achievement, besides balancing my career with being a new mum, is uncovering how an immune pore called the Membrane Attack Complex is formed. These pores can punch holes in cancer cells and only now, with work done in my lab, can we see this complex in 3D and determine at a molecular level how it works. The award from CRUK has enabled me to realise my goal of leading an internationally competitive research team, committed to understanding how the immune system can be targeted to fight cancer. Originally from Chile, Dr Sergio Quezada was a postdoc at the Memorial Sloan Kettering Cancer Center in New York, before moving to the UK to take up a CRUK Career Development Fellowship at University College London. He has recently been awarded a Senior Cancer Research Fellowship and has a growing worldwide reputation for his cellular and molecular work in the field of immunotherapy. Applying for the CRUK Career Development Fellowship was definitely the best decision I ever made. I was drawn to it initially because it offered six years of funding and I wanted that level of security to follow my own path of research. For me, the fellowship is about so much more than just the funding. From the very beginning CRUK takes good care of you. The amazing community of scientists, collaborators, and support it offers seems unmatched to me. The fellowship gives you the freedom to innovate, explore your research and take it in new directions. I believe the best scientific results come from having that freedom. I have now been awarded a Senior Cancer Research Fellowship to pursue my work in lung cancer. These fellowships are different to funding just for a specific piece of research or an individual. They allow you to build a team that all start at the same time, hiring postdocs and technicians, and building that team over the long-term, giving continuity to the whole research group. None of this would have been possible without that first CRUK fellowship. It allowed me to settle and establish myself, with the six years of absolute support and freedom that produced real results. I ve become very attached to CRUK now. They have given me a level of support and funding that means I am achieving everything I ever wanted to do. WHERE SCIENCE, ART AND LITERATURE COLLIDE Inspiring new audiences to take action for CRUK means taking our research to unexpected places. The Hay Festival of Literature and The Arts is an internationally-renowned gathering in a small Welsh town, bringing together the world s greatest poets, writers, comedians and thinkers to exchange views and share ideas. The Festival has a growing programme of science sessions, and in 2016 this included three events delivered in partnership with CRUK. One session featured Dr Sergio Quezada as part of an internationally renowned panel discussing the potential for immunotherapy to revolutionise cancer treatment. The sold-out session, kicking off with thought-provoking introductions from the three panellists, led to a lively discussion amongst the audience and panel members about this fascinating area of research. Sergio thoroughly enjoyed the experience: Talking about science at a literature festival is amazing. You get to interact with the public and have to prepare a really lay presentation which offers a simple explanation to your very complicated work. What an experience I would do it again many times over! Around 200,000 people attend the Hay Festival over the course of the week, and this particular session received national press coverage in both The Sun and Daily Mail. The partnership was an excellent way to raise our profile and share our world-class research with a new audience. Following that success we ve now been invited to deliver more cancer research debates and discussions at Hay Festival Image: Sergio Quezada and panel at The Hay Festival

29 OUR PRIZE WINNERS At CRUK we award prizes to members of the research community to recognise their outstanding achievements. Our awards support and celebrate the incredible work, dedication and scientific innovation of those at the forefront of advancing our ability to prevent, detect and treat cancer. FUTURE LEADERS IN CANCER RESEARCH PRIZE Our Future Leaders in Cancer Research Prize recognises those with great potential at the early stages of their research careers. Winners must have produced research of international importance within 10 years of receiving their doctorate. In 2016 the quality of nominations was incredibly high, and so the panel took the decision to award the maximum three prizes for this category. Dr Georgios Lyratzopoulos, a CRUK Clinician Scientist Fellow working at University College London, has produced world-class outputs in key areas of population health research. His research has provided large-scale evidence for the influence of psychosocial factors in early diagnosis, highlighting the importance of ongoing community campaigns about cancer symptoms. His work has allowed a better appreciation for diagnostic timeliness in cancer patients presenting to their GPs with symptoms, and his discoveries have been highly influential, providing a roadmap to guide future early diagnosis strategies and investment. Dr Florian Markowetz, a senior group leader at our CRUK Cambridge Institute, has, over the last seven years of his career, been on a quest to integrate genomics and imaging. His research is giving us unprecedented insights into the evolution of the cancer genome and its interaction with the tumour microenvironment. Florian has collaborated closely with clinicians to create novel quantitative assessments of histopathological images, whilst jointly analysing genomic aberrations in tumours. He has pioneered approaches to link genetic heterogeneity of tumours to clinical outcomes and has demonstrated how rigorous analysis of evolutionary patterns can predict progression-free survival in ovarian cancer. Florian is a true champion for research reproducibility and data sharing. He is leading the way by making the software developed in the lab freely available as a research tool for others many having been downloaded thousands of times. Dr Andrea Sottoriva, a Group Leader at The Institute of Cancer Research, has a passion for applying mathematical and computational methods to solve biological problems. He has pioneered the development of novel models based on understanding cancer evolution from a solid mathematical perspective, and his models have the potential to forecast the future course of disease in individual patients. His fresh perspective has revolutionised how data is generated and used in order to achieve maximum patient benefit. Andrea has transformed a wealth of existing publicly available data into intelligible information detailing a new way to interpret cancer genomic data from single tumour biopsies. We were extremely saddened by the passing of Jane Wardle in 2015, a pioneer in the fields of prevention and early diagnosis. In recognition of Jane s esteemed research career and lifelong devotion to the field, we launched the Jane Wardle Prevention and Early Diagnosis Prize. This prize recognises a researcher at any stage of their career who has produced world-leading research in the fields of prevention and early diagnosis. We were delighted to award the first prize to Dr Jo Waller, a CRUK Career Development Fellow working in the fields of epidemiology and public health at University College London. Jo trained and worked with Jane between 1998 and 2015, and like her mentor, Jo is committed to training junior colleagues, and has a reputation for being approachable and generous with her time. Jo has made substantial advances in our understanding of women s attitudes to cervical screening and HPV vaccination identifying the psychological challenges facing women who receive a positive HPV result through screening. Jo works to ensure that her findings lead to a real impact on cervical cancer prevention and early diagnosis in the UK and beyond. In particular, Jo s research has directly influenced the Cervical Screening Programme in England. Our Pontecorvo prize is awarded to CRUK-funded students who have produced outstanding PhD theses and made the greatest contribution to scientific knowledge in their field. In 2016 the prize was awarded to Dr Nicholas McGranahan, an outstanding young scientist at University College London and the Francis Crick Institute. Nicholas is now a postdoc with Professor Charles Swanton, who describes him as a rare breed due to the interdisciplinary nature of his work. With parallel interests in mathematics and cancer biology, he completed his PhD in Cancer Bioinformatics at UCL s centre for interdisciplinary research in the medical and life sciences. Nicholas s most striking contributions have been through his development of major new insights into mechanisms of cancer branched evolution and genomic instability. He has helped to set novel directions for TRACERx a multi-million pound programme and our largest single investment in lung cancer research. CRUK 2017 Research Prizes closed in March and winners will be announced in November. Nominations for 2018 awards open in November Check out cruk.org/researchprizes to find out more. JANE WARDLE PREVENTION AND EARLY DIAGNOSIS PRIZE PONTECORVO PRIZE THIS WORK WOULD NOT HAVE BEEN POSSIBLE WITHOUT THE GENEROUS SUPPORT FROM CRUK Dr Nicholas McGranahan RECOGNISING EXCELLENCE IN COMMUNICATING SCIENCE TO THE PUBLIC: EDD JAMES In 2015, Dr Edd James, Associate Professor in Cancer Immunology at the CRUK Southampton Centre, won the CRUK Inspiring Leadership Research Engagement prize for his enthusiasm in communicating science to the public. What set Edd apart are the creative methods he uses to bring complex science topics to life, using innovative, fun, interactive activities. So, it s no surprise that he put his prize money towards developing his most ambitious engagement activity to date. Edd is working with his local Research Engagement Manager and the Winchester Science Centre to create an arcade game that teaches players about immunotherapy. The idea is that the player is recruited as a killer T-Cell says Edd. They will be shown a letter sequence corresponding to the amino acid sequence of a known cancer antigen. They ll then be shown pictures of cells with letter sequences and will have a short time to decide whether it s one of the cells they are looking for and whether to kill it, or whether to save it much like our immune system has to do. If they kill a healthy cell by accident the game is over. Built in the style of a 1980s arcade unit, with neon lights and flashing buttons, the game will generate instant nostalgia; but the underlying message is a serious one. We want to show just what a difficult job the immune system has to do Edd continues, and how research into the way it interacts with cancer aims to make our own bodies more effective at recognising and fighting the disease. Image: Edd James 54 55

30 Qualifies in medicine at the University of London, then completes training in medicine and oncology in London and Australia. Appointed to the Chair of Medical Oncology at the University of Glasgow, Stan sets up a state-of-theart early stage clinical trials unit. Moves to The Institute of Cancer Research (ICR) in London, establishing the Drug Development Unit. Retires from the ICR, but remains an active advisor to many organisations. de Bono, his team was also the first to show the potential of abiraterone for prostate cancer patients and to take it through to approval. MAKING AN IMPACT ON PEOPLE S LIVES HONOURING Stan is also an exceptional mentor and a role model. He has been instrumental in the education of a new generation of medical doctors who closely interact with lab scientists. He says, At one point, you could have got the whole community of UK medical oncologists around one table. Now, I can look at a map and feel proud that I ve helped people s careers in cities all across the UK. He adds, One of the best things you can do as you get older is to look back and think there are younger folk to carry on who can do it better! Our Lifetime Achievement Prize recognises individuals who have demonstrated a career-spanning commitment to the fight against cancer. In 2016 we awarded the Prize to Professor Stan Kaye, an extremely deserving winner who has made exceptional advances in the field of medical oncology that have had a major impact on people s lives. OF TRANSLATIONAL RESEARCH A LIFELONG PASSION Stan s interest in oncology was sparked while training as a doctor at Charing Cross Hospital in the 1970s, working with Ken Bagshawe who he describes as one of the godfathers of medical oncology. He witnessed the astonishing curability of the advanced cancer choriocarcinoma in young women and feels privileged to have been there at such an exciting time when many of the key drugs, such as platinum, were being used for the first time. He says, There were young men with testicular cancer, which was usually fatal, and all of a sudden we were curing them too. In 1985 he moved to the University of Glasgow, where he set up a new state-of-the-art early stage clinical trials unit. Embedding his specialist interest in ovarian cancers, he founded the Scottish Gynaecological Cancer Trials Group, with some key results highlighting another of his career themes tackling the challenge of drug resistance. Stan explains, Before it became fashionable, we were collecting blood samples to understand why some people do better than others. That is now widely appreciated and almost all trials will now have some sampling of blood or tumours to understand why subgroups do better or worse. KEY INGREDIENTS FOR SUCCESS In Scotland, Stan was one of the first clinical cancer researchers to demonstrate the importance in translational research of the link between the laboratory and the clinic. He believes that to succeed you need a critical mass of people, hospital support, and support from an academic institute. He says, to do really high-quality cancer research that will make a difference to patients you have to have top class lab bench scientists working alongside doctors, and he cites examples of Paul Workman and Allan Balmain from his time in Glasgow. He also emphasises, it really does matter that its bench to bedside and back again with material collected in the clinic going back to the lab. In 2000 he moved to The Institute of Cancer Research in London, where he established the Drug Development Unit now one of the largest and most successful in the world. One of his group s most notable achievements was their pioneering work to develop the new PARP inhibitor, olaparib, which they demonstrated as an effective treatment for women with BRCA mutation-associated ovarian cancers. Stan says, Once every 10 years or so something comes along that really changes treatment for a subgroup of cancer patients. Within a few months of taking it into the clinic, it was clear that it was making a difference you could see the cancer shrinking. The drug was approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in 2014, with recent results suggesting that double the number of patients may benefit than originally thought. Led by his eventual successor as Head of the Drug Development Unit, Johann According to Stan, the toughest part of being an oncologist is losing patients but at the same time, this also motivated him to make improvements. Recently, he received a letter from a patient s daughter. She told me her mother had just enjoyed her 80th birthday party, which was also the 5th birthday of her youngest grandson. And she wanted to let me know how key it was for her mother to enjoy that we d given her an extra five years. His advice is, It s important to remember who you re treating and why you re doing the research some of the humanity can be easily forgotten when you re dealing with the science. HOPE FOR THE FUTURE Stan officially retired from his role at the ICR in 2014, but he s not stopping yet. He says, I m now involved in health services research. We can make a difference by changing pathways and finding ways to diagnose cancer earlier. He also remains an active advisor to many organisations. Stan s many outstanding contributions to the care and treatment of cancer patients and to the conduct of cancer research in the UK and internationally makes him a very worthy winner of our Lifetime Achievement Prize. Describing how he felt when he heard he had won, he says, I was flattered, but a little anxious as I didn t feel I deserved it. I know people who have won the Award before they are giants in terms of science, people who have made great contributions. Reflecting back over his career, Stan says: If I had my time again, there is nothing else I d rather have done. Professor Stan Kaye (right) receiving his Lifetime Achievement Prize from CRUK Chief Clinician, Professor Peter Johnson IF I HAD MY TIME AGAIN, THERE IS NOTHING ELSE I D RATHER HAVE DONE Stan Kaye 56 57

31 BEHIND At CRUK we run more than 40 funding schemes in a wide range of different disciplines, each with a specific purpose and remit and, as a result, requiring different application processes from those that ask for an anonymous outline, to those that require a preliminary interview with an expert review panel. But although the application process might vary, all our schemes have one thing in common they are designed to ensure we fund the highest quality, internationally competitive science, judged through a fair, robust and transparent process. This is no easy task, given the diversity and CLOSED DOORS AN INSIGHT INTO OUR FUNDING COMMITTEES breadth of scientific applications we receive. And we couldn t achieve this without the expertise and commitment of our research community, who sit on our panels and committees and participate in our independent peer-review. Here are the perspectives of three people with a different behind-the-scenes view of our funding process. We welcome expressions of interest from leading scientists, clinicians and health policy specialists who are interested in joining our community of committee and panel members. Find out more about eligibility and how to apply at cruk.org/joina-committee THE APPLICANT THE SCIENTIFIC COMMITTEE MEMBER THE PATIENT REPRESENTATIVE Postdoctoral fellow Dr Alice Forster successfully applied for a Cancer Prevention Fellowship in This was the first grant I had applied for so I had to learn a lot about the process. I started thinking about my application about six months before the submission deadline, and had a supportive group of collaborators who reviewed early drafts. As an early career researcher it can be intimidating sharing your ideas with senior staff, but their input was so important to shaping the application. I felt that the more I could address the comments of internal reviewers, the more I would be prepared to deal with peer reviewers comments. After submitting my application, it was sent for peer review. The next stage was my interview with an expert review panel, made up of four senior cancer prevention scientists alongside three CRUK staff observers. My interview was a relatively pleasant experience. The panel were friendly, and interested in my research. And thanks to having two mock interviews in advance, I felt prepared and able to respond to their questions. The most helpful part of the process was having a single point of contact at CRUK. I felt comfortable asking any questions they were very supportive, and I got the impression that they wanted to facilitate funding researchers. I would encourage anyone applying to get in touch with the relevant CRUK contact to discuss their proposed project with them. Since being awarded the Fellowship, I ve been involved in cancer prevention conferences, and even spent some time seconded to the CRUK Policy Research Centre to learn about how research is translated into policy. Medical oncologist Professor Ruth Plummer sits on CRUK s Science Committee and Clinical Research Committee and is Chair of CRUK s New Agents Committee (NAC), which selects new anti-cancer treatments for early clinical trials. It s a huge honour to be asked to chair a CRUK committee, and it s a fascinating role. My day job means I see patients who don t have any treatment options and are prepared to take an experimental agent and these are the patients we recruit to the Phase I studies funded through NAC. It s a good grounding for me, seeing novel agents coming through and knowing that, by also sitting on Science Committee, I ve got an idea of the science that s ongoing in the background and some of the new developments that might come through. NAC is a good-humoured committee, and as Chair I try and make sure that people who come in to present their trials ideas they ve worked incredibly hard on feel comfortable, even if there are probing questions. We re very involved with the Centre for Drug Development (CDD) staff. This is the team that will ultimately take the projects forward, as many of the studies are run through the CDD, and there s a world of experience and advice available there. Often the proposals that don t do well at the committee are those where the applicants haven t talked to CDD first. There are often situations where you think a proposal is good but there s a critical part missing. With NAC we have the option of giving a preliminary score and providing feedback to support applicants submitting a revised application. Or if a project s really exciting, we may be able to fund an initial stage, and review progress. Mat Baker is a member of CRUK s Prevention Expert Review Panel. After many active years at the consumer-research interface, following his wife s death from cancer, he became interested in helping to develop a research portfolio that engages with the challenges of cancer prevention and health inequalities. Most of the research proposals that come before the panel are exciting in one way or another, and I am continually impressed by the sheer weight and quality of thought that is being applied to reducing cancer risk at a population level. I have a background in social sciences, which means I m aware of some of the methodological challenges that a successful proposal must overcome, but I m careful not to get preoccupied with methodological detail. The other panellists are all worldclass experts in this area! My role is to establish the public and community benefit that would flow from a proposed study, and to gauge whether a study is placing realistic expectations on its participants. Studies are often flawed if there has been little or no consultation with representatives of the relevant population. I see public involvement of this nature as being necessary for a well-grounded and viable study. The panel discussions are particularly stimulating I m always impressed by the expertise, care and thoroughness with which applications are considered and the thought that goes into the provision of feedback to applicants. Most of all, I appreciate the opportunity to assist in the development of an important research portfolio, and to contribute points that may be of concern to patients and other lay people. The patient voice, I believe, is invaluable

32 MEASURING THE IMPACT OF RESEARCH Evaluating the broader societal impact of research is increasingly important for research funders. But what is the best way to do this? And how should we work with the research community to ensure we know our research is bringing the greatest possible impact to cancer patients? IN THIS ARTICLE Jonathan Grant Assistant Principal, Strategic Initiatives and Public Policy, King's College London Andrew Knowles Senior Research Evaluation Manager, CRUK George Santangelo Director, Office of Portfolio Analysis, US National Institutes of Health (NIH) Rachel Stirzaker Director of Strategy, CRUK We know the research we fund is world class, but is it curing cancer? That s the 386 million question (the amount CRUK spent on research in 2016/17). We have an ambition to accelerate progress and see 3 in 4 people survive cancer by But is our strategy on track to achieve this ambition? Enter the world of research impact assessment. CRUK is plugging into this evolving area to link the activity we fund to eventual patient impact, explains Rachel Stirzaker, CRUK s Director of Strategy. It is really important to us to fund exceptional cancer research and to support the community that delivers it. But our mission is to drive real patient impact. Everything we do must feed into that. A BRIEF HISTORY OF RESEARCH IMPACT ASSESSMENT Impact assessment involves plotting a path from input right through to patient impact (see diagram). The concept is not new, but is increasingly important for funders. There is a need for society to hold research funders and organisations undertaking research to account, says Professor Jonathan Grant, Assistant Principal for Strategic Initiatives and Public Policy at King s College London. We have a duty to make research effective if we are using taxpayers and donors money. Research impact and its assessment has moved up the science policy agenda, Jonathan says, and now plays a strong role in the UK s Research Excellence Framework (REF), which determines university funding. Changes introduced in 2014 mean the impact of research beyond academia now accounts for 20% of the overall assessment, which has changed the conversation around research funding and impact, making it more mainstream and visible. The REF pushed people to really consider the impact of their research, says Andrew Knowles, Senior Research Evaluation Manager at CRUK. However, REF s impact assessment hasn t been without its critics, with claims including extra admin time for reporting. Lord Stern s 2016 review contained recommendations for future REF exercises, which were generally well received. These included retaining peer review as a key assessment tool, supported by appropriate metrics and data, and the introduction of institutional level impact case studies to better showcase interdisciplinary research. As Dr George Santangelo, Director of the Office of Portfolio Analysis at the US National Institutes of Health (NIH), points out, impact assessment is an evolving process, involving learning from past experiences and collaborating with the research community. LAYING THE FOUNDATIONS In 2014, we joined Researchfish, an online platform that enables us to capture research outputs and outcomes directly from researchers and link them with inputs. Andrew describes Researchfish as a tool that helps collect a wealth of information on the research CRUK funds. Aware of the risk of creating more admin for researchers, we worked closely with many funders, including Research Councils UK, to agree a shared set of questions for the platform. We re still learning what works, Andrew says. But lessons from REF and Researchfish have evolved our thinking on impact assessment. In just three years, Researchfish is providing us with a great deal of new insight that we wouldn t have previously collected or analysed. While Researchfish provides a granular view and is generating a better knowledge of outputs, we know there is more to be done to monitor and measure impact. As Andrew explains, We are currently at stage one: considering impact assessment, clarifying our objectives and starting a conversation with our research community so we can work together on stage two developing the tools and measures to gauge impact and the charity s progress. FINDING THE RIGHT MEASURES But figuring out what to do, and what not to do, is complicated. For starters, there are 16 different frameworks and models that already exist for assessing impact, according to a review published in 2015 in Health Research Policy and Systems (doi: /s ), and each has its own benefits and downsides. And understanding what to measure is critical. This is where working with the research community and learning from others is paramount. As Rachel notes, there is still a lot of work needed to develop the right metrics, but she points to the work being done by experts in the field that will help frame CRUK s thinking. The NIH s George Santangelo is one such expert. He is of the mind that traditional impact gauges used mainly because they are easy to measure, such as publications, citations and journal impact factors are flawed metrics, and he believes a more effective metric is needed. George and INPUTS What you need Funding ( ) Staff Equipment/ facilities PLANNED WORK Research projects his team have developed the Relative Citation Ratio, which looks at the citations of individual papers and the rate these are accrued, adjusted for different research disciplines, as a proxy of influence rather than impact. He is pleased with the buy-in from the community, but no one metric will capture impact, he notes. Instead, there needs to be a diversity of metrics which could include measuring translation into treatments, media mentions, patents, data sharing, reproducibility and quality based on human judgement and these need to be developed collaboratively with the research community. STRIKING A BALANCE Academic / Research community ACTIVITIES What you do Hundreds of scientists and research organisations also hold this view, criticising the reliance on the journal impact factor and signing the Declaration on Research Assessment (DORA). As a signatory of this Declaration, CRUK is committed to accurately measuring output and improving the ways research is evaluated. As Andrew reports, CRUK doesn t want to focus too much on publications. We want to take a wide-ranging approach, incorporating lots of data sources and a whole host of existing information, to develop a broad suite of metrics that work for CRUK at each stage of the impact pathway, Andrew says. Furthermore, Andrew and Rachel both confirm that expert review will stay as part of the suite because it remains key to ensuring that we continue to fund world-class research. TIME OUTPUTS What you deliver/ produce Publications Reports Prizes Patents Impact assessment pathway from input to patient impact. Adapted from CSIRO (Commonwealth Scientific and Industrial Research Organisation) We want to make sure our reporting is as simple and efficient as possible while still achieving high-quality data necessary for analysis. Sharing data between systems, universities and funders is one way to enable this, Andrew believes. Researchfish is aiming to improve interoperability between systems, with work so far focusing on publication records between institutions and funders a recent pilot study showed significantly reduced reporting times for researchers with this increased sharing of data. Researchers can also share information between their Researchfish account and their ORCID profile. KEEPING ON TRACK Measuring impact and doing it well is a necessity for CRUK. To be able to understand where we ve had impact, and where we could help to drive impact if we applied funding, has become central to our decision-making, says Andrew. We will continue to fund high-quality research, and building on learnings and collaborations to date, we will establish an appropriate suite of metrics for CRUK. Our supporters increasingly expect to understand how their money is helping to solve the cancer problem as part of their reason to donate; ultimately, our aim is to use our supporters money in the most effective and efficient way, helping the researchers we fund generate the greatest impact for cancer patients. INTENDED RESULTS OUTCOMES Awareness and use of your outputs Clinical guidelines Awareness of new diagnostics Training accessed Awareness / uptake of new techniques Wider society IMPACT Consequences of using your outputs Societal impacts Patients treated Getting closer to 3 in 4 people surviving cancer 60 61

33 THE LAST WORD THE CRICK IS JUST THE KIND OF MAGNET WE NEED TO ATTRACT THE BRIGHTEST MINDS Peter Johnson WHAT S NEW AND EXCITING THIS YEAR? In terms of science, immunology and immunotherapy continue to produce very exciting results, but the other thing I m really interested in is the microbiome. It is yet another layer of complexity that we re just beginning to understand: how the microorganisms that we live with can change the body s internal environment to help or hinder the growth of cancer, and how we might be able to manipulate this through alterations in diet. Our knowledge is still at a very early stage, but it is clearly an area that we need to explore, now that the tools for doing so are becoming readily available. Read more about the microbiome and cancer in our hot topic article on page 46. In our own research portfolio, I m keen to see how the PRECISION-Panc programme develops: there s a lot of expectation riding on it for patients with pancreatic cancer, an area where we badly need to speed up progress. Read more about this programme in our article on tackling pancreatic cancer and brain tumours on page 16. I m looking forward to seeing the outputs from our Accelerator Awards: we have made some big investments through these awards, and the early signs are that they are driving some superb science which should start to reach the clinic in the next few years. WHAT COULD CRUK DO MORE OF? We know that earlier diagnosis makes a huge difference to the chances of surviving cancer, which is why we are putting an increasing emphasis on this right across the board, from our work with the Royal College of General Practitioners to help hard-pressed GPs access diagnostic services more rapidly, to examining new technologies that might be able to detect Peter Johnson, CRUK s Chief Clinician, reflects on his highlights from the last year and what s exciting on the horizon. cancers at a much earlier stage. We need to look for opportunities to accelerate progress in everything from behavioural research to microscale detectors, to make sure we are doing everything we can. WHAT DO YOU THINK THE IMPACT OF THE CRICK WILL BE? The Crick is a world-class institute that s going to be a great asset, not just to discovery science but to many fields of medicine, both in London and across the UK. I am looking forward to seeing how we can maximise the value of this great project for cancer research in the coming years. We must ensure that we continue to attract the brightest minds to the UK, now more than ever, and the Crick is just the kind of magnet we need for this. YOU VE PREVIOUSLY MENTIONED THE CHALLENGES OF CLINICAL ACADEMIC CAREERS WHAT DEVELOPMENTS ARE YOU SEEING IN THIS AREA? I am encouraged by the progress we re making in supporting clinical academics, despite many and varied challenges. We funded a record number of Clinician Scientist Fellows in the last year they are such an impressive group of people, brilliant minds, and so motivated to make a difference to patients at the same time as pursuing the best science. I hope we can keep up the pace and really put the UK at the forefront with the work that our clinical academics are doing at the interface of science and medicine. This is so important for patients and the good of the healthcare system. We know that the NHS is under more pressure than ever before, but this is just the moment when we should invest in the next generation to lead the cancer treatment workforce of the future. YOU VE BEEN IN THIS CRUK ROLE FOR A YEAR NOW, COULD YOU EXPLAIN HOW YOU THINK OF YOUR ROLE? My job is not to drive research in a particular direction, but rather to try to ensure the scientists doing the most innovative and impactful research are supported, enabling them to tackle big ideas and ambitious projects. Whilst such research spans the whole spectrum from bench to bedside, a large part of our commitment at CRUK, and a personal passion, is to continue to fund the best discovery science and blue skies research, to make sure we have a strong base on which to build our translational ambitions. HOW BEST CAN CRUK ACHIEVE THESE OBJECTIVES? In my travels round the country meeting our funded researchers and clinicians, I ve been pleased to discover that, on the whole, they feel we re doing a pretty good job. We ve built a community where people feel they ll be listened to if they have concerns or suggestions, or simply need a little flexibility in the system, and where they feel confident that our scientific objectives are shaped after consultation with them. Scientifically, there s enthusiasm for our Centres and Institutes, and for the way in which we re networking them to leverage our resources, both human and technical. It s important that CRUK remains a convenor of the best research and brightest researchers, irrespective of nationality. Science is all about open borders and free movement, and I m proud to say that our scientists and clinicians are a truly international bunch. We boast an array of nationalities that signals the high calibre of our science we have facilities, infrastructure, and people as good as anywhere in the world. Karen Vousden was appointed as CRUK s Chief Scientist in Here Karen reflects on her first year in the role and the challenges ahead. IS INTERNATIONAL COLLABORATION A PRIORITY? In cancer research, we re seeing more and more opportunities for really meaningful international collaboration, and I m very excited by the possibilities we ve uncovered for funding teams of people worldwide. I believe CRUK has the vision, flexibility of approach and resources to make a real difference in an area where grant schemes are difficult to find. In order to get to grips with the big, complicated problems in cancer, we ve begun funding researchers worldwide, through initiatives such as our Grand Challenge, the Stand Up To Cancer/CRUK/Lustgarten Foundation Pancreatic Cancer Dream Team and our Catalyst Awards. We re also working with international partners, tackling the problem of early detection with the Knight Cancer Institute in Oregon, and working closely with the Dutch Cancer Society (KWF) to jointly fund one of our Grand Challenge awards and collaborate across other activities. In the years ahead, we will deepen our existing partnerships and are committed to exploring more opportunities for joint initiatives, both nationally and internationally. For example, one area of promise for cancer research is machine learning, and we are exploring interactions with the Farr and Turing Institutes in London to develop capacity in this area. WHAT DO YOU HOPE THE FUTURE HOLDS? I am confident that CRUK will continue to support the best work, strengthening its capabilities in emerging areas such as inflammation, metabolism and the microbiome, and taking smart risks to fund potentially transformative ideas. It will be my great privilege and responsibility as Chief Scientist to try and make sure that this happens. IT S IMPORTANT THAT CRUK REMAINS A CONVENOR OF THE BEST RESEARCH Karen Vousden 62 63

34 GET IN TOUCH ACKNOWLEDGEMENTS Here are some useful contact details and links if you want to get in touch with someone at CRUK about specific areas of our work. FUNDING AND RESEARCH For details on all our funding schemes and application deadlines, plus contacts for relevant funding manager: cruk.org/funding-schemes For the latest opportunities for researchers and updates on our research strategy and policies Sign up to our monthly Research Update newsletter by ing researcher. INVOLVING PATIENTS IN YOUR WORK Support and resources for researchers who want help with patient involvement in their work. PUBLIC ENGAGEMENT AND FUNDRAISING OPPORTUNITIES If you are interested in getting involved in promoting research in your area, get in touch with your local Research Engagement Manager. cancer.org.uk OUR POLICY WORK Help our policy team to identify the issues affecting the research community. PUBLICISE YOUR WORK We can help you get your work across to the media, our supporters and the general public. Your story could be featured on our science blog. This publication was only possible through the involvement, contribution and commitment of many individuals across the cancer and wider research community and at CRUK. Thank you to everyone who contributed. Project team: Charlotte Davies Katie Holt Editorial panel: Richard Bayliss Alice Forster Sean Lim Kevin Myant James O Connor Simona Parrinello Writers: Alison Halliday Katrina Megget Becky Opstad Joanna Owens Kathy Weston Contributors: David Adams Tamsin Ashton Jenny Bacon Mat Baker Rachael Barber Andrew Biankin Alexa Bishop Nigel Blackburn Mark Bodmer Sarah Bohndiek Tom Bourton Carrie Boyce Paul Brennan Sarah Brown Doryen Bubeck Lily Bull Josephine Bunch Michael Burns Ross Carruthers Ed Cervantes-Watson Flo Chan Sue Chua David Crosby Alastair Cunningham Laura Danielson Safia Danovi Grace Davies Annie Deck-Miller Caroline Dive Graydon Downs Yvette Drew Joe Dunckley Anna Durrans Hani El-Nezami Sara Ellis Alessia Errico Sadik Esener Gerard Evan Hayley Farmer-Hall Rebecca Fitzgerald Alice Forster Iain Foulkes Caroline Foxton Noor Gammoh Allison Gaw Richard Gilbertson Alison Glossop Jonathan Grant John Gregson Caitlin Hamilton Willie Hamilton Greg Hannon Ed Harlow Narin Hengrung Sandra Hirschberg Ben Hood Martin Humphries Edd James Peter Johnson Tim Johnson Claus Jørgensen Matt Kaiser Terry Kavanagh Stan Kaye Greta Keenan Lauren Kerr Rick Klausner Andrew Knowles Jenni Lacey David Lane Zahid Latif Emily Lau Kevin Lee Heike Lentfer Paul Maclean Kris Martindale Lyndall McLellan Sarah Mellor Jamie Meredith Sophy Meyers Tanya Moore Daniel Munoz-Espin Stephen Nabarro Herbie Newell Kathy Niakan Serena Nik-Zainal Karen Noble Paul O Toole Roz Onions Freya Parry Vaishali Patel Jo Payne Ruth Plummer Steve Pollard Sergio Quezada Peter Rainey Fiona Reddington Caetano Reis e Sousa Jo Reynolds Alan Rickinson Stefan Riley Monica Rodrigo Susan Ross George Santangelo Mathew Sargeant David Scott Katie Scott Kate Searle Lucy Shaw Dave Sims Tricia Smith-Carrington Nicole Sodir Malcolm Stevens Rachel Stirzaker Mike Stratton Robert Strausberg Sarah Sutton Charles Swanton Jess Vasiliou Karen Vousden Ian Walker Karen Walshe Fiona Walter Jennifer Wargo Alexis Webb Esther Wershof Jelle Wesseling Eleanor Wheeler Jon Wood Emese Zsiros Design and art direction: SomeOne. Funding graphics: Andy Kirk Cover image: Brendan Dawes Proofreader: Fern Bryant Printed by: Park Communications Image credits: Page 20 Dave Sims, Patrick Harrison Page the Francis Crick Institute Page 57 NCRI, Simon Callaghan photography Page 61 Impact pathway adapted from CSIRO (Commonwealth Scientific and Industrial Research Organisation) Registered Trademarks: Avastin is a registered trademark of Genentech Inc Cytoxan is a registered trademark of Baxter International Inc Erivedge is a registered trademark of Hoffman-La Roche Keytruda is a registered trademark of Merck Sharp & Dohme Corp Researchfish is a registered trademark of Research Fish Ltd Rubraca is a registered trademark of Clovis Oncology Inc Temodal is a registered trademark of Merck Sharp & Dohme Corp Zytiga is a registered trademark of Johnson & Johnson 64

35 Download a pdf at cruk.org/pioneering-research Copyright 2017 Cancer Research UK Cancer Research UK Angel Building 407 St John Street London EC1V 4AD Tel: +44 (0) cruk.org/science Registered charity number England and Wales: Scotland: SCO41666 Isle of Man: 1103