CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL

CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL

IN PARTNERSHIP WITH: 2 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL CONTENTS

INTRODUCTIONS 4

RESEARCH THEMES 8 Basic Science 10 Immunology 12 Drug Discovery 14 Early Detection and Pre-Invasive Disease 16 Tumour Evolution and Heterogeneity 18 Biomarkers 20 Clinical Trials 22 Radiation Biology/Radiotherapy Trials 24

INTERDISCIPLINARY RESEARCH 28 TRACERx 29

TRAINING 32 Exploiting Biomarker Expertise to Elucidate 34 Mechanisms of Resistance Revealing Genetic Differences that 35 Impact Patient Outcomes

FACILITIES 38

PARTNERS The University of Manchester 42 Cancer Research UK Manchester Institute 42 The Christie NHS Foundation Trust 42 University Hospital of South Manchester 42 NHS Foundation Trust Manchester Cancer Research Centre 42 UCL Cancer Institute 42 UCLH Macmillan Cancer Centre 43 UCLPartners 43

GOVERNANCE 46

3 INTRODUCTION FROM CANCER RESEARCH UK

Dr Iain Foulkes Executive Director Strategy and Research funding, Cancer Research UK

Over the last 40 years improvements in detection and treatment have revolutionised cancer medicine and we’ve seen survival rates double. Yet despite these advances, there remain groups for whom outcomes are particularly poor, including those with lung cancer.

Lung cancer is the second most of Excellence to provide strong research today that will save common cancer in the UK, with scientific leadership in the field, lives tomorrow. over 40,000 people diagnosed and to recruit and develop vital each year. It has one of the lowest expertise. rates of survival - fewer than 10% of patients survive five years after The first Centre, jointly based in diagnosis - and improvements Manchester and UCL, will have been limited in recent combine strengths across the decades. spectrum of lung cancer research with state-of-the-art technology. Growing the quality and quantity It will catalyse new approaches to of lung cancer research in the UK prevention, diagnosis and therapy is vital, and Cancer Research UK is to have the greatest impact. committed to increasing our investment and focus to meet the We believe our investment urgent need for progress. provides an ideal platform for making progress by building the We are establishing the Cancer long-term capacity, environment Research UK Lung Cancer Centres and infrastructure for lung cancer

4 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL WELCOME FROM THE CENTRE LEADS

Professor Caroline Dive Professor Charles Swanton Leader of the Clinical and Experimental Pharmacology Chair in Personalised Medicine at the UCL Cancer Institute group at the Cancer Research UK Manchester Institute and Consultant Medical Oncologist at University College London Hospitals NHS Foundation Trust

We are delighted to have been chosen as Cancer Research UK’s first Lung Cancer Centre of Excellence. The establishment of the CRUK Lung Cancer Centre of Excellence at Manchester and UCL brings together a unique range of internationally renowned scientists and clinicians within the field of lung cancer research. By building on this existing foundation, we will create an environment that catalyses imaginative and innovative lung cancer research.

Research within the Centre is re-emergent and advanced The establishment of the focused around eight disease through personalised CRUK Lung Cancer Centre of complementary and interacting therapy. These aims can only be Excellence at Manchester and research themes: Basic Science, realised through improved UCL recognises our strong track Immunology, Drug Discovery, knowledge of lung cancer record, expertise and ambition Early Detection and Pre-Invasive genetics, biology and tumour in all aspects of lung cancer Disease, Tumour Evolution and adaptation to therapeutic research. By working together, Heterogeneity, Biomarkers, intervention. we have a real and exciting Clinical Trials and Radiation opportunity to support advances Biology/Radiotherapy Trials. We We are committed to delivering in the prevention, diagnosis, aim to detect and diagnose lung an outstanding lung cancer treatment and care of lung cancer earlier; better predict risk training programme and building cancer; with our ultimate aim to of recurrence post-surgery; a world class centre of excellence improve outcomes for lung monitor disease non-invasively in lung cancer research. cancer patients. with biomarker testing and control

INTRODUCTION 5 6 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL RESEARCH THEMES

RESEARCH THEMES 7 RESEARCH THEMES

The CRUK Lung Cancer Centre of Excellence at Manchester and UCL brings together world class basic, translational, clinical and imaging research, with the overall vision of improving outcomes for lung cancer patients.

Our work is focused on eight together responsible for different disciplines; including key research themes: developing and implementing pathologists, medical and the overall research strategy. radiation oncologists, biologists, • Basic Science These themes are designed to chemists, physicists, • Immunology be both interacting and bioinformaticians and engineers • Drug Discovery complementary and to cover the – allowing us to expand our • Early Detection and full spectrum of cancer research, research interests into innovative Pre-Invasive Disease linking pioneering laboratory and exciting new areas of lung • Tumour Evolution studies to the implementation of cancer research. and Heterogeneity novel treatments for patients in • Biomarkers the clinic – with the overall aim of • Clinical Trials improving patient outcome and • Radiation Biology/ quality of life. Radiotherapy Trials Increasingly, projects are Each of the Centre’s research multidisciplinary, drawing on themes has joint leads based at the skills and expertise of Manchester and UCL, who are researchers from a range of

8 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL RESEARCH THEMES 9 BASIC SCIENCE

Dr John Brognard Professor Henning Walczak Leader of the Chair of the Centre for Signalling Networks in Cell Death, Cancer and Cancer group at the CRUK Inflammation at the UCL Manchester Institute Cancer Institute

At present less than 20% of lung cancer patients can be stratified for treatment with targeted therapies – patients with mutationally activated kinases such as EGFR or EML4-ALK. These patients receive significant benefit from targeted therapies aimed at inhibiting these kinases specifically. The inhibition of the activated kinase suppresses proliferation and, in some cases, promotes cell death.

genetic drivers of lung cancer and lung cancer therapy resistance, with a particular focus on mutations in components of survival pathways, and, on the other, to devise targeted therapeutic combinations that specifically induce programmed cell death by apoptosis in lung cancer cells.

Regarding the first approach, we use (i) bioinformatics tools Nevertheless, despite significant To do this, it is necessary to and structural modelling to advances in the development of uncover which cellular signalling evaluate the functional impact of targeted therapies for patients pathways are responsible for somatic mutations in novel or with lung cancer, many patients resistance to current and novel understudied kinases identified in are either ineligible or suffer the therapies, and how we can cancer genomic screens or drug consequences of the emergence overcome resistance more resistance screens, (ii) genetic of drug resistant disease. It is specifically and potently in dependency screens to identify therefore evident that more individual cancer patients. important genetically altered powerful targeted therapies, drivers of cancer or mediators of including combination therapies, The approaches we currently therapeutic resistance, and (iii) will need to be developed for take in Manchester and UCL are, mining of cancer genomic data successful lung cancer treatment. on the one hand, to identify portals to identify frequently

10 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL amplified kinases that harbour individual lung cancer patients. As pathological somatic mutations. such, we will investigate the “Basic scientific The overall goal of this approach is interplay between the molecular to identify common and alterations induced by targeting research is an convergent pathways utilised by survival pathways that are essential first step cancer cells to promote tumour upregulated in individual cancers in unravelling the growth and adaptation, which can with specific kinase inhibitory be therapeutically targeted. therapies and the triggering of the complex apoptosis machinery by targeted interactions that The aims of the second approach combination therapies. Finally, we promote cancer are (i) to determine the therapeutic will examine this interplay on the efficacy of novel pro-apoptotic biochemical, genomic and cell survival in targeted therapeutic proteomic level using human lung order to find new combinations in the most cell lines, primary human lung targets for advanced in vivo models of lung cancer cells and the most personalised cancer and (ii) to identify the advanced murine in vivo models mechanisms of resistance – and of lung cancer. treatments how we may be able to target specific to them therapeutically – that The Centre will draw on individuals and characterise cancers that emerge Manchester’s strengths in as resistant to even the most elucidating genetic drivers of lung their disease highly effective of these therapies cancer, with its special focus on characteristics.” by multilevel data analysis which kinases in survival pathways, and includes genomic, proteomic and UCL’s strength in devising novel tumour microenvironmental apoptosis based therapies for lung profiling. cancer, in order to develop a number of novel targeted Our ultimate aim is to determine therapies. how best to combine the inhibition of genetic drivers of lung cancer with targeted apoptosis inducing therapies in

BASIC SCIENCE 11 IMMUNOLOGY

Professor Tim Illidge Dr Sergio Quezada Leader of the Targeted Leader of the Cancer Therapy group in the Immunology Unit at Institute of Cancer the UCL Cancer Institute Sciences at The University of Manchester and Consultant at The Christie NHS Foundation Trust

Manipulation of the patient’s own immune system to target cancer has for the first time demonstrated significant clinical efficacy against metastatic melanoma, renal cell cancer and non-small cell lung cancer. Cancer immunotherapy will play a pivotal role in improving outcomes for patients with lung cancer.

conventional approaches. The interplay between the immune Centre will draw on the expertise system and intra-tumour of both institutions to incorporate heterogeneity and the relevance these components in a rational of different immune-modulatory and multidisciplinary bench pathways in the control of to bedside approach. anti-tumour immunity in human lung cancer. UCL is currently leading efforts to determine heterogeneity and the In a parallel and complementary potential impact of intra-tumour area of discovery, Manchester has heterogeneity in the clinical developed a number of tumour outcome of lung cancer patients. models to investigate the impact In this scenario, the immune of radiotherapy and system is likely to play an essential immunotherapy combination In order to improve the activity role, as the same genetic approaches. Complementary to of cancer immunotherapy in a instability that promotes tumour this, at UCL new ways to promote higher proportion of patients, progression might also generate tumour apoptosis are being a multifaceted approach, neo-antigens seen by the studied. Finally, we are using targeting not only the cancer immune system as non-self, thus expertise in cellular therapies to cell but also the tumour becoming potential targets of develop preclinical and clinical microenvironment and the activated immune cells. Several protocols for the genetic immune system, is likely to be research teams are bringing engineering of immune cells, essential to favour complete together the cancer and immune arming them with the necessary tumour eradication, alongside biology fields by investigating the tools to recognise the tumour and

12 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL to function within an and implementation of clinical immunosuppressive trials harnessing the immune microenvironment. response. “The multidisciplinary Tumour cell death induced by Through a multidisciplinary expertise within different agents will help reduce approach incorporating Manchester and disease burden whilst also acting preclinical and clinical research, as a personalised vaccine, we will establish a strong, UCL will drive allowing recognition of multiple continually growing and development tumour antigens and neo- successful translational cancer of even more antigens by the immune system. immunology programme for the In this context, incorporation of treatment of lung cancer. effective immune modulatory strategies immunotherapies capable of enhancing immunity that target not just should result in a long lasting, diversified and evolving layer of the tumour cell but protection against lung cancer. also the tumour We will engage in a collaborative microenvironment effort to use relevant mouse and the immune models of cancer to determine the best combinatorial system.“ approaches incorporating the activity of drugs inducing immunogenic cell death with immune modulatory antibodies.

The impact of such therapies will be tested in preclinical models of lung cancer alone and in combination with chemo, radio and immune modulatory agents in order to inform future design

IMMUNOLOGY 13 DRUG DISCOVERY

Dr Donald Ogilvie Dr Ian Waddell (Deputy) Head of the Drug Head of Bioscience within Discovery Unit at the CRUK the Drug Discovery Unit at Manchester Institute the CRUK Manchester Institute

The CRUK Drug Discovery Unit (DDU) at Manchester was established in 2009 following a strategic decision to increase small molecule drug discovery alongside the CRUK core funded research institutes in Manchester and Glasgow. We have opened and equipped a new laboratory and recruited a team of 28 biologists and medicinal chemists with a mixture of academic and industrial experience.

in lung cancer. The new CRUK Lung Cancer Centre of Excellence at Manchester and UCL will greatly enhance our interface with cutting edge research in lung cancer.

The Drug Discovery Unit team has been assembled from drug discovery scientists with an impressive track record of success having been involved in the delivery of over 50 clinical development candidates, 35 of which have progressed to clinical trials and 2, so far, to full registration. The proximity to The laboratory is underpinned by research and has provided an ideal basic, translational and clinical state-of-the-art bio- and chemo- environment for cancer drug research expertise has proved informatics platforms for drug discovery focused on unmet invaluable in the selection and discovery. The CRUK Manchester patient needs. Over 40% of the validation of novel cancer drug Institute is a centre of excellence novel targets that the DDU have discovery targets. One particularly for basic and translational cancer progressed have potential for use successful approach during

14 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL the last four years has been attrition, we need to identify new the provision of quality small targets and look forward to “Our Drug molecule tools to local attracting more lung cancer drug researchers for target validation target opportunities from the Discovery Unit studies. The DDU is also outward CRUK Lung Cancer Centre of will translate facing beyond Manchester and, as Excellence at Manchester and basic science well as working with other CRUK UCL. Principal Investigators in the UK, discoveries into we have secured several valuable novel preclinical collaborations with international candidate drug Pharmaceutical companies – molecules that AstraZeneca and GSK – and Biotech companies to progress can be tested in our projects. Most importantly, the clinic.” we have now built a robust drug discovery portfolio and have progressed two of these projects to the advanced, lead optimisation stage. Both of these targets have potential for therapeutic use in lung cancer.

Our ambition is to deliver preclinical drug candidate molecules for progression into the clinic. Given the historically high rates of drug discovery project

DRUG DISCOVERY 15 EARLY DETECTION AND PRE-INVASIVE DISEASE

Dr Richard Booton Professor Sam Janes Head of the Lung Cancer Chair in Respiratory Medicine Early Detection group in at UCL and Consultant at the Institute of Cancer University College London Sciences at The University Hospitals NHS Foundation of Manchester and Trust Consultant at University Hospital of South Manchester NHS Foundation Trust

Compared with other common malignancies, the prognosis for lung cancer patients is poor, with more than 75% of patients presenting with largely incurable advanced stage lung cancer. A new strategy is needed, aimed at detecting lung cancer earlier, treating in a lung sparing manner and preventing early disease by understanding pre- cancerous lesion development.

Understanding more about the early lung cancer to deliver for patient follow up, treatment key steps in early lung cancer effective lung sparing treatments and research biobanking across pathogenesis will allow the for pre-invasive (and very early both institutions. The new CRUK development of novel therapies invasive) disease, and to develop Lung Cancer Centre of Excellence targeting early pre-invasive quality assured management at Manchester and UCL will disease. This could possibly lead pathways for suspected disease expand the previously established to chemo-prophylactic therapies that facilitate rapid diagnosis. University College London in those most at risk. Finally, identifying patients at Hospitals NHS Foundation Trust highest risk of disease recurrence (UCLH) Lung Surveillance study Our research targets include post-radical treatment and that has led to an unsurpassed screening or surveillance of establishing a cross site quality collection of patients studied asymptomatic high risk patients assured tissue bank to support longitudinally, with lesion, blood and detecting and biologically personalised and precision and sputum samples collected interrogating pre-invasive lung medicine will be vital. from the same patients and cancer lesions to enable lesions over time, enabling mechanism directed Manchester and UCL already genetic mapping of lesion chemoprevention. We also aim to share clinical expertise in early progression or regression. better understand the clonal lung cancer detection and origins and tumour evolution of treatment; with shared protocols

16 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL Together we lead the CRUK evolution of squamous cell funded LUNG-SEARCH study cancer. In collaboration with the investigating the use of sputum, Sanger Institute in Cambridge, a “With more than auto fluorescence bronchoscopy large scale whole genome 75% of patients and CT in the early detection of sequencing programme will be presenting with lung cancer in high risk undertaken to examine the key populations. UCL was recently genetic features that lead to largely incurable awarded funding to examine the progression of pre-cancerous advanced stage feasibility of CT screening in a UK lesions. Exome sequencing will lung cancer, we population of lower be combined with methylation aim to develop socioeconomic status. and gene expression arrays to Manchester and UCL already distinguish the genetic and new tools for collaborate on several rapid biological markers of lesion early detection diagnosis and staging studies and progression compared to those of pre-invasive are co-applicants on the PEARL lesions that regress. Mechanistic trial – an early intervention study investigation of key genes that disease to improve on pre-invasive disease. UCLH predict progression will be patient survival.“ also leads the STREAMLINE whole examined with a view to body MRI diagnosis and staging determining biomarkers of trial. We have a critical mass of progression/risk, candidates for over 20 clinicians and scientists circulating biomarkers of lung working on early lung cancer cancer risk/detection and the pathogenesis and investigating development of novel therapies the role of stem cells in tumour targeting early lung cancer initiation and treatment. development.

We will develop the largest collection of samples from high risk individuals with pre-cancerous lesions enabling the clinical and biological delineation of the

EARLY DETECTION AND PRE-INVASIVE DISEASE 17 TUMOUR EVOLUTION AND HETEROGENEITY

Professor Caroline Dive Professor Charles Swanton Leader of the Clinical Chair in Personalised and Experimental Medicine at the UCL Pharmacology group at Cancer Institute and the Cancer Research UK Consultant Medical Manchester Institute Oncologist at University College London Hospitals NHS Foundation Trust

Modern technologies are increasingly revealing the tremendous diversity between cancers from different patients, despite similar characteristics under the microscope in the pathology department. Furthermore, in depth analysis of tumours from individual patients is increasingly revealing the diversity of genetic changes both within and between biopsies from the same tumour.

Such diversity both between and stratification within therapeutic microscopy, RNA interference and within individual tumours presents trials aimed at understanding the CRISPR genome editing difficulties for the modern era of changing landscape of the lung technologies, we are personalised medicine and the cancer genome in individual endeavouring to explore the development of new drugs. Of patients over time and exploiting functional basis of somatic even greater concern is emerging such changes for therapeutic changes identified within evidence that tumours with benefit. Between the CRUK individual cancer genomes, greater diversity have worse Manchester Institute and prioritised through bioinformatics clinical outcome and an increased University College London, we analyses. The Centre has close propensity for resistance to have access to world class links with industry and is common anticancer treatments. computing infrastructure and data developing a series of cancer storage. Our bioinformatics clinical trials aimed at identifying The Tumour Evolution and teams in London and Manchester key drivers of drug resistance in Heterogeneity theme is supported are developing new tools to lung cancer and targeting by a dedicated lung cancer next decipher the evolution over time tumours optimally, based on an generation sequencing facility of both non-small cell lung cancer understanding of the evolution of and a Good Clinical Practice (NSCLC) and small cell lung individual lung cancer genomes. (GCP) laboratory. We work on cancer (SCLC) genomes. In We will focus on the changing target validation and patient parallel, utilising high resolution dynamics of cancer cell diversity

18 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL during anticancer treatment to cell diversity, the Centre will develop improved understanding develop means to target diversity of the mechanistic basis for drug through pharmacologic “Our collaborative resistance and treatment failure. intervention. Through the multidisciplinary The Centre will study the infrastructure developed, the approach is mechanical processes within a Centre will provide the essential to better cancer cell that lead to differences pharmaceutical industry and between tumour cells and the academic clinicians with a understand ability of a cancer cell to tolerate personalised therapeutic service tumour diversity ongoing changes to its genetic enabling the evolution and so that new material. adaptation of tumours from clinical trial patient cohorts to be strategies that TRACERx (TRAcking Cancer studied in real time. Ultimately, it is overcome cancer Evolution through therapy/Rx), the hoped that such developments cells’ ability to lung cancer evolution longitudinal will improve precision cancer patient cohort study, will form a medicine approaches and the evolve and central component of studies clinical outcome for patients thereby evade focussed on tumour evolution suffering from lung cancer. treatment can be and intratumour heterogeneity. developed.“ The DARWIN (Deciphering Antitumour Response With Intratumour Heterogeneity) clinical trial programme will provide the clinical basis to explore the impact of tumour subclonal dynamics on drug response, acquisition of resistance to therapy and clinical outcome and develop sustainable links with pharmaceutical partners. Through a greater understanding of the processes that drive tumour

TUMOUR EVOLUTION AND HETEROGENEITY 19 BIOMARKERS

Professor Caroline Dive Professor Tony Ng Leader of the Clinical Chair in Molecular Oncology and Experimental at the UCL Cancer Institute Pharmacology group at the Cancer Research UK Manchester Institute

Successful delivery of precision medicine to lung cancer patients depends on robust biomarkers to define prognosis, determine optimal dose and select patients most likely to benefit. Our Centre has considerable strengths in biomarker science with strong research programmes in tissue, circulating and imaging biomarkers.

challenges associated with serial lung biopsy, we have developed an extensive portfolio of circulating biomarker assays. These include the enumeration and molecular characterisation of circulating tumour cells (CTCs), sensitive multiplex ELISA panels for angiogenesis and cell death biomarkers and a comprehensive ‘tool kit’ of approaches to assess circulating nucleic acids (cfDNA and miRNA). CTC profiling using advanced bioinformatics Clear synergies exist between via innovative clinical trials led algorithms for single cell analysis the Biomarkers and Tumour from within the Centre. will be used to evaluate Heterogeneity and Evolution heterogeneity and discover themes where our biomarker Our Centre has one of the largest biomarkers. In parallel, we expertise is being deployed within biomarker hubs in the UK run to established unique small cell lung the pioneering TRACERx protocol. Good Clinical Practice (GCP), cancer (SCLC) patient CTC derived Biomarker candidates emanating where biomarker data can be mouse models – termed CDX – from our Basic Science and used for clinical decision making generated at patient presentation Immunology themes will be according to EU regulations for and/or at relapse. Our new SCLC developed, validated and qualified clinical trials. Acknowledging mouse models now afford

20 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL unparalleled opportunity to detect onset of signal explore disease biology, transduction ‘rewiring’ processes interrogate mechanisms of drug early such that intervention can “Our strengths resistance, test novel therapeutics occur before drug resistance is in biomarker (integrating with other Centre fully developed. Tissue imaging research will themes) and develop tissue, based pathway analyses will be facilitate circulating and imaging coupled to in vivo PET and biomarkers for this disease for multi-parametric MR imaging, successful which as yet no targeted therapies underpinned by the development delivery of have made an impact. of new PET/SPECT tracers, for precision example against c-Met, that are Lung cancer imaging is a major being developed with our Cancer medicine for focus within our two aligned Research UK/EPSRC Cancer lung cancer CRUK/EPSRC Imaging Centres. Imaging Centres. We were the patients by Establishing imaging tools to first to publish methods for probe the molecular basis of motion corrected DCE-MRI providing robust cell-to-cell intra-tumour applied to lung imaging, we are biomarkers that heterogeneity to complement our leading development of Oxygen define prognosis, genomic studies represents a Enhanced MRI for imaging the determine optimal major step forward and is a goal of lung and we are exploring the the Biomarkers theme. Focussed relationships between Diffusion dose and select on druggable receptor tyrosine Weighted MRI and drug induced patients most kinases (e.g. EGFR, c-Met) and cell death. likely to benefit associated signalling networks, we are developing advanced In summary, the Biomarkers from specific biophysical techniques to theme will integrate the basic and treatments. “ measure protein-protein clinical research within our centre interactions (from the less than as we strive to improve patient 10nm through to 200nm outcomes with hypothesis driven, separation range by a biomarker guided clinical trials. combination of FLIM histology and superresolution) in tumour biopsies and CTCs from patients pre and post treatment with these targeted therapies. We aim to

BIOMARKERS 21 CLINICAL TRIALS

Dr Fiona Blackhall Professor Siow-Ming Lee Dr Martin Forster Dr Matthew Krebs (Deputy) Leader of the Lung Cancer Professor of Medical Clinical Senior Lecturer at Clinical Senior Lecturer in group in the Institute of Oncology at UCL and the UCL Cancer Institute and Experimental Cancer Cancer Sciences at The Consultant at University Consultant at University Medicines within the University of Manchester College London Hospitals College London Hospitals Institute of Cancer and Consultant at The NHS Foundation Trust NHS Foundation Trust Sciences at The University Christie NHS Foundation of Manchester and Trust Consultant at The Christie NHS Foundation Trust

Clinical trials are central to the introduction of novel treatments into the clinic and the development of better, more effective, standards of care. From a disease once deemed insensitive to chemotherapy, there now exist gold standard treatment regimens for the therapeutic management of lung cancer. With the central objective of improving patient outcomes, we aim to design and perform internationally competitive and practice changing clinical trials in lung cancer.

Manchester and UCL have been world leading in the conduct of seminal clinical trials. A pioneering study of gemcitabine and platinum helped establish the regimen as the standard first line treatment of advanced non-small cell lung cancer (NSCLC) in Europe. At the turn of the century, Manchester treated the first ever NSCLC patient with gefitinib, paving the way for a new era of personalised treatments in this disease, and UCL recently conducted the ET trial, the largest randomised prospective biomarker study of patients with advanced NSCLC.

Capitalising on a uniquely diverse large patient population,

22 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL Manchester and UCL both have way interaction between the well established Clinical Trials laboratory and the clinic. Through Units (CTUs) enabling us to our clinical and translational “Manchester drive research and establish research programme, we aim to and UCL have a large collaborative multicentre bring in the best new treatments strong heritage trials of the highest scientific for our patients through practice in clinical trials, excellence. The Christie in changing phase III trials. Manchester houses the largest which underpin early phase treatment unit in the the bench to world, with around 400 trials bedside delivery taking place at any one time, and UCL has one of the largest CTUs of innovative in the UK, developing and treatments conducting small and large scale that improve trials in lung cancer since 1978. outcomes for With the establishment of the lung cancer Centre, we have an exciting patients. “ opportunity to further implement biomarker driven early phase studies and continue to investigate the combination of radiotherapy, chemotherapy and targeted therapies in lung cancer. These studies will draw on expertise across all research themes within the Centre and will involve two

CLINICAL TRIALS 23 RADIATION BIOLOGY AND RADIOTHERAPY TRIALS

Dr Corinne Faivre-Finn Dr Ruheena Mendes Leader of the Radiotherapy Consultant at University in Lung Cancer group in College London Hospitals the Institute of Cancer NHS Foundation Trust Sciences at The University of Manchester and Consultant at The Christie NHS Foundation Trust

Radiotherapy plays an important role in the management of lung cancer, with over 50% of patients receiving this treatment modality at some point during their treatment. The Christie NHS Foundation Trust provides the largest radiotherapy service in the country – with around 600 lung cancer patients treated with radical radiotherapy a year – and, together with University College London Hospitals NHS Foundation Trust (UCLH), aims to form a cohesive and collaborative clinical and translational research group.

The core principle of the group benefits from expertise in several developed strong collaborative is to provide individualised disciplines within the field of links, enabling early phase trials radiotherapy treatment that oncology including clinical combining thoracic radiotherapy continually pushes treatment oncology, medical oncology, and mechanism based therapies. boundaries and thus leads to imaging, medical physics, There is also specific expertise and improved outcomes for lung radiobiology, circulating leadership in the multimodality cancer patients. Our research is biomarkers, proteomics and treatments for stage III non-small underpinned by state-of-the-art immunotherapy. This unique cell lung cancer (NSCLC) (MEKRT radiotherapy delivered routinely to combination of expertise and and isotoxic IMRT trials), limited our patients including 4DCT and experience has led to the disease small cell lung cancer FDG PET-CT planning, intensity development of the only (SCLC) (CONVERT trial), modulated radiotherapy, biomarker programme in the UK stereotactic radiotherapy for early including stereotactic that aims to predict response and stage NSCLC (lungTech trial) and radiotherapy, and online cone toxicity in lung cancer patients radiotherapy for mesothelioma beam CT verification. treated with radical radiotherapy. (PIT trial). In addition, Manchester The Radiotherapy departments and London will host the UK’s only Radiotherapy research in lung and Clinical Trials Units at The two high energy Proton Beam cancer is multidisciplinary and Christie and UCLH have Therapy Centres, with unique

24 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL opportunities to codevelop joint and collaborate on phase II/III radiation clinical research for radiotherapy trials to impact patients, including trials in locally standard of care and explore the “Radiotherapy advanced lung cancer and role of proton therapy in lung continues to mesothelioma. cancer and mesothelioma as an be the backbone active member of the National of many lung Our main aim is to position the Cancer Research Institute Clinical Centre as an international leader and Translational Radiotherapy cancer treatment in the field of lung cancer (CTRad) Proton Beam Therapy regimens and radiotherapy, working Research Group. practice-changing collaboratively within the areas of personalised therapy, trials to optimise theragnostics, combined delivery to therapies and proton therapy. The individual delivery of personalised, highly technical radiotherapy, including patients are key the evolution of the radiotherapy to improving pathway, should increase patient accuracy and precision of outcomes.“ treatments delivered. This involves interaction and facilitation with multidisciplinary research groups. Theragnostics – predictive models of radiotherapy response and toxicity including biomarkers based on population data – will also enable more individualised treatments. The advancement of early phase trials of combined radiotherapy will include novel agents such as immunotherapy. We will engage

RADIATION BIOLOGY AND RADIOTHERAPY TRIALS 25 26 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL INTERDISCIPLINARY RESEARCH

INTERDISCIPLINARY RESEARCH 27 INTERDISCIPLINARY RESEARCH

The strength of the CRUK Lung Cancer Centre of Excellence at Manchester and UCL will be the interaction of scientists within different research themes at both institutions, allowing us to expand our research interests into innovative and exciting new areas of lung cancer research.

One such project that already TRACERx – TRAcking Cancer Biomarkers, Tumour Evolution draws on the strengths and Evolution through therapy (Rx). and Clinical Trials research themes expertise of a number of the The trial brings together teams at both Manchester and UCL. Centre’s research themes is from across the Basic Science,

Radiation Biology / Radiotherapy Trials Basic Science

Clinical Trials Immunology

Biomarkers Drug Discovery Tumour Evolution and Heterogeneity Early Detection and Pre-Invasive Disease

28 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL TRACERx

The TRACERx – TRAcking Cancer Evolution through therapy (Rx) – study was launched in July 2013 by Cancer Research UK. This £14 million study spanning nine years aims to investigate how lung tumours evolve over time as patients receive treatment. Bringing together researchers from Manchester and UCL alongside a national network of research and clinical trials centres, it will recruit 850 lung cancer patients from across the UK.

the lethal subclone that results in the development of metastatic disease. This aspect of the study builds on work at UCL that has explored tumour evolution in both lung and renal cancers and shown that cancer subclones are spatially diverse.

Patients also have blood samples taken at each time point, to allow the assessment of circulating tumour cells (CTCs) and fragments of tumour genetic material, such as circulating free The project focuses on the Various analyses are carried out tumour DNA (cfDNA). genomic analysis of early stage on each sample in order to assess Researchers are exploring non-small cell lung cancer genetic intra-tumour whether genetic mutations can be (NSCLC) and its changing nature heterogeneity and its evolution detected in CTCs and cfDNA – over time. Patients with primary from diagnosis through the allowing the investigation of NSCLC, suitable for surgical disease course. These analyses tumour heterogeneity in a resection with curative intent, include both molecular pathology minimally invasive manner. will be potentially eligible for and next generation sequencing TRACERx. Each patient approaches to decipher tumour Clinical and genomic data is consenting to the program will genetic driver events that might be integrated to permit comparison donate their tumour tissue, targetable within the DARWIN between indices of intra-tumour resected during the course of program or other trials within the heterogeneity and drug resistance surgery, for high depth tumour Centre. Whole exome and clinical outcome. The sequencing of multiple sites of sequencing – detection of amount of data produced by the the disease. If the disease somatic point mutations, study – up to ~6 petabytes – offers recurs, further consent will be insertions, deletions and structural the opportunity to build an requested to analyse tumour changes in the tumour genome advanced cancer bioinformatics tissue from the recurrent site – will allow the construction of a infrastructure, linked with clinical of disease to establish how phylogenetic tree of the tumour trial implementation, across the the tumour has changed regions and lead to a greater country and develop national over time. understanding of the origins of cancer sequencing expertise.

INTERDISCIPLINARY RESEARCH 29 30 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL TRAINING

TRAINING 31 TRAINING FUTURE LEADERS IN LUNG CANCER RESEARCH

Training the next generation of scientists is at the heart of the CRUK Lung Cancer Centre of Excellence at Manchester and UCL. The Centre provides a comprehensive PhD postgraduate training programme, with a strong focus on lung cancer molecular biology, to develop clinical and non-clinical academics of the future.

The training programme covers a present the opportunity to work development courses encourage range of different technologies, closely with world leading intellectual and social interaction providing a substantial research scientists and clinicians, between students. The annual competitive advantage for whilst having access to state-of- CRUK Lung Cancer Centre of obtaining positions at the next the-art laboratories. Excellence Workshop also career level. Through the provides PhD students, clinical Manchester/UCL Clinical Each PhD student will have the fellows and postdoctoral scientists Research Training Fellowship opportunity to undertake core with the opportunity to hear about scheme, graduate students with training at both Manchester and world leading lung cancer clinical backgrounds will be UCL sites where joint supervision research, formally present their encouraged to pursue research in ensures a supportive environment work and receive constructive lung cancer related programmes. that encourages students to feedback from senior colleagues flourish as they move towards and internationally renowned The partnership enables us to becoming independent leaders in the field. offer challenging and stimulating researchers. projects in a wide range of lung cancer related research areas. Our An active seminar series and a unrivalled expertise and facilities wide range of skills and

32 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL TRAINING 33 EXPLOITING BIOMARKER EXPERTISE TO ELUCIDATE MECHANISMS OF RESISTANCE

“During a PhD it’s important to become a specialist in your specific area, but there’s always a danger of getting tunnel vision. Being able to meet researchers from across the Centre will give me a fresh perspective on my project. I’m really excited about working with scientists from different laboratories and perhaps even setting up future research collaborations.”

Louise Carter Clinical Fellow, CRUK Manchester Institute

I am in the third year of my PhD project investigating acquired resistance to chemotherapy in small cell lung cancer (SCLC) through the analysis of circulating biomarkers in Professor Caroline Dive’s research group at the CRUK Manchester Institute. SCLC has a high response rate to first line chemotherapy but unfortunately the cancer rapidly progresses and is usually resistant to further chemotherapy.

Utilising circulating tumour cells SCLC. The goal of this work is to (CTCs) isolated from the blood of identify potential mechanisms of patients prior to receiving resistance that could provide new chemotherapy and again drug targets, with the aim of following the development of improving patient outcomes. My relapsed disease, I am exploring studies on isolated CTCs dovetail the changes that potentially lead with the group’s recent to disease resistance. I am using development of SCLC CTC data generated from both derived mouse models where conventional sequencing and mechanisms underpinning drug next generation sequencing of resistance can be investigated at amplified DNA from single CTCs the functional level. to interrogate mutational hotspots, whole exome changes and chromosomal aberrations in

34 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL REVEALING GENETIC DIFFERENCES THAT IMPACT PATIENT OUTCOMES

“As someone who is involved in a big multicentre trial, it’s the collaborative nature of the Centre that most appeals to me. The fact that all the research themes interact with each other will allow me to study lung cancer from every angle.”

Mariam Jamal-Hanjani Clinical Fellow, UCL Cancer Institute

I completed my undergraduate training in Physics at UCL and went on to study Medicine, graduating in 2005. During my training as a specialist registrar in Medical Oncology, I was awarded a Cancer Research UK Clinical Research Training Fellowship for a PhD and am currently working in Professor Charles Swanton’s laboratory at the UCL Cancer Institute.

My research project involves determining whether the In order to understand the impact studying intratumour genomic aberrations, identified of tumour clonal heterogeneity heterogeneity and characterising using multi-region sequencing, upon therapeutic outcome and the genomic aberrations in can be detected in circulating-free how cancer subclones compete non-small cell lung cancer tumour DNA (cfDNA) in blood and adapt during tumour (NSCLC) by sequencing multiple samples collected from patients, evolution, I have been involved in tumour regions collected from and whether clonal as well as the development of the multi- primary lung tumours in patients subclonal mutations can be national centre study TRACERx eligible for resective surgery. This identified so that cfDNA may be (TRAcking Cancer Evolution project follows on from existing used for the detection of through therapy (Rx)). work in Professor Swanton’s intratumour heterogeneity - laboratory, which is beginning to offering a minimally invasive reveal the complexity of NSCLC method to monitor NSCLC evolution and intratumour throughout the disease course. diversity. My project also involves

TRAINING 35 36 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL FACILITIES

FACILITIES 37 OUTSTANDING FACILITIES SUPPORT OUR RESEARCH VISION

The CRUK Lung Cancer Centre of Excellence partners offer some of the best infrastructure and facilities in the UK for supporting basic, translational, clinical and imaging research into lung cancer. The wealth of cutting edge laboratories and clinical facilities enables pioneering studies into novel approaches to the detection, monitoring and treatment of the disease and the development of personalised medicine.

Laboratory studies are supported the CRUK Manchester Institute, a additional space for around 150 by state-of-the-art equipment gatedSTED microscope enables University researchers and 100 of and core facilities. Examination scientists to visualise cancer at The Christie’s research and of the genetic drivers and the molecular level. development support staff. molecular processes underpinning lung cancer Expansion of fundamental Translation of laboratory findings development can be explored research into cancer cell biology is into clinical benefit for patients is using a variety of methods. Just as being brought about through vital for improving outcomes and two examples, UCL is home to an ambitious investment. In the CRUK Drug Discovery Unit extensive RNAi library, allowing Manchester, the iconic new (DDU) in Manchester is well researchers to explore the effects Manchester Cancer Research equipped to focus on producing of individual genes in both mouse Centre building is due to open at novel anticancer agents. Bringing and human cancer cells, and at the end of 2014, providing together biologists and chemists,

38 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL the DDU takes molecular targets the use of samples in a wide world, with around 400 trials identified by groups looking at variety of studies and experiments. taking place at any one time, and cancer cell biology and, through UCL has one of the largest CTUs screening libraries, computer Extensive imaging facilities are in the UK, leading practice aided design and experimental available at Manchester and UCL. changing trials in lung cancer optimisation, aims to develop new In Manchester, the Wolfson since 1978. medications. Molecular Imaging Centre offers PET and MR imaging, including The Christie is also home to one Biobanking allows our researchers two research dedicated clinical of the world’s largest radiotherapy to easily access large numbers of PET scanners, two preclinical PET units, carrying out over 80,000 high quality biological samples cameras, a cyclotron, treatments every year. From 2018, from cancer patients. radiochemistry production UCLH and The Christie will Infrastructure for biobanking exists facilities, analytical and bioanalysis become the first centres in the UK at Manchester and UCL to enable laboratories and a 1.5T research to offer Proton Beam Therapy, coordination of sample collection MRI scanner. Elsewhere, there are following a £250 million and to integrate clinical partners two 3.0T clinical research MRI investment by UK government. with laboratory based users. The scanners and preclinical MRI This advanced form of UCL/UCLH Biobank stores a range equipment. In London, the radiotherapy spares much more of normal and pathological recently opened UCLH Macmillan of the surrounding healthy tissue specimens surplus to diagnostic Cancer Centre contains the UK’s and is particularly useful for deep requirements, whilst the MCRC first simultaneous PET-MR lying tumours. The development Biobank collects a sample ‘six scanner and across the UCL of the new Proton Beam Therapy pack’ – fresh frozen diseased and campus are major centres with centres offers the opportunity for normal tissue, formalin fixed other advanced clinical and existing and newly recruited diseased and normal tissue and preclinical scanners carrying out research expertise in radiotherapy, pre-operative blood and urine research into advanced medical physics and particle samples – from all consenting biomedical imaging and medical physics within Manchester and patients during surgery specifically image computing. UCL to be harnessed to investigate for research purposes. Biobanking and improve this cutting edge of circulating nucleic acids and Capitalising on a uniquely diverse treatment. isolated circulating tumour cells large patient population, (CTCs) is also now routine pre and Manchester and UCL have well post therapy within the MCRC. established Clinical Trials Units Both Biobanks have been (CTUs) providing a supportive, awarded ethical approval as patient focussed environment to Research Tissue Banks and have a host clinical research of the standardised consent procedure, highest scientific excellence. The which allows long term storage of Christie in Manchester houses the samples for future projects and largest early phase CTU in the

FACILITIES 39 40 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL PARTNERS

PARTNERS 41 PARTNERS DRIVING PROGRESS

The CRUK Lung Cancer Centre of Excellence at Manchester and UCL incorporates expertise from a number of different organisations, including The University of Manchester, Cancer Research UK Manchester Institute, The Christie NHS Foundation Trust, University Hospital of South Manchester NHS Foundation Trust, Manchester Cancer Research Centre, UCL Cancer Institute, UCLH Macmillan Cancer Centre and UCLPartners.

The University of Manchester development of novel therapeutic and community services that were A member of the Russell Group, approaches. formerly operated by Manchester The University of Manchester is Primary Care Trust. The trust is one of the largest universities in The Christie NHS Foundation home to the North West Lung the UK. According to the results of Trust Centre, which has an international the 2008 Research Assessment The Christie specialises in cancer reputation for respiratory Exercise, the University is officially treatment, research and medicine and offers specialist ranked best in the UK for cancer education, and is the largest lung cancer services. research. There are two hubs for cancer centre in Europe. As well cancer research within the as treating 40,000 patients a year University: the Faculty of Life from across the UK, its experts Manchester Cancer Research Sciences – home to the Molecular have been pioneering cancer Centre Cancer Group – and the Faculty of research breakthroughs for more The Manchester Cancer Research Medical and Human Sciences, than 100 years. The Christie Centre was formed in 2006 by which encompasses the Institute serves a population of 3.2 million The University of Manchester, of Cancer Sciences and the people across Greater Manchester Cancer Research UK and The Manchester Pharmacy School as and Cheshire, with 26% of patients Christie NHS Foundation Trust. It well as groups with expertise in referred from across the UK. has since been established as the cancer imaging and stem cell Based in Manchester with cancer research arm of the research. radiotherapy centres in Oldham Manchester Academic Health and Salford, The Christie is known Science Centre, which is a for many world firsts, which have strategic partnership between the Cancer Research UK Manchester impacted cancer treatment on a University and six NHS Trusts Institute global scale and it became the first across Greater Manchester. The Cancer Research UK UK centre to be officially Manchester Institute is a research accredited as a comprehensive The MCRC coordinates basic, institute within The University of cancer centre. translational and clinical cancer Manchester, and is one of five research across its partner research institutes core funded by organisations. The Centre is also Cancer Research UK. Research at University Hospital of South home to the MCRC Biobank, the Institute spans the whole Manchester NHS Foundation which has been set up to collect spectrum of cancer research, Trust human samples from cancer from programmes investigating University Hospital of South patients across Greater the molecular and cellular basis of Manchester is a major acute Manchester, and the Manchester cancer to those focused on teaching hospital trust providing Experimental Cancer Medicine translational research and the services for adults and children Centre.

42 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL UCL Cancer Institute imaging equipment, including the The UCL Cancer Institute was UK’s first PET-MR scanner. The established in 2007 and is the hub Centre is located across the road for cancer research at University from the UCL Cancer Institute and College London – it hosts the enables the expansion of patient majority of cancer research orientated and translational scientists and acts as the nucleus cancer research. for the UCL Cancer Research UK Centre and the UCL Experimental Cancer Medicine Centre. UCLPartners Particular areas of strength within An academic health science the Institute include stem cell partnership between higher biology, immunology and education and NHS organisations, immunotherapy, drug UCLPartners was established in development, viral oncology and 2009. It has since expanded and genomics and bioinformatics. now covers north east and north central London as well as parts of Hertfordshire, Bedfordshire and UCLH Macmillan Cancer Centre Essex. Serving a population of six The purpose built UCLH million people, UCLPartners Macmillan Cancer Centre brings together 100,000 health provides specialist cancer professionals and academics in treatment to University College order to translate cutting edge London Hospitals. Based at the research and innovation into Centre are outpatient and day care measurable health gain for cancer services and a dedicated patients in London and across teenage and young adult cancer the UK. service, as well as state-of-the-art

PARTNERS 43 44 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL GOVERNANCE

GOVERNANCE 45 GOVERNANCE

The management of the Cancer Research UK Lung Cancer Centre of Excellence at Manchester and UCL and the implementation of its strategy are supported by a number of boards and committees:

Cancer Research UK Scientific Executive Board

Centre External Scientific Management Advisory Board Group

Research Programme Management Committee

External Scientific CRUK Lung Cancer Centre of implementing the programme of Advisory Board Excellence at Manchester and work undertaken at the CRUK The External Scientific Advisory UCL, as well as overseeing the Lung Cancer Centre of Excellence Board (ESAB) is an independent governance, resource and and overseeing the Centre’s body carrying representation from financial arrangements of the training programme. international senior academics, Centre. clinicians and patient The committee actively manages representative groups. Meeting The Group manages the Centre the research themes, facilitating annually, the Board is tasked with on a day to day basis, as well as ongoing and coherent integration advising the CRUK Lung Cancer coordinating and regularly of projects to add value, as well as Centre of Excellence leads on the reviewing the progress and providing an internal peer review scientific strategy of the Centre success of the Centre’s research process for the Centre’s grant and its implementation. themes. applications.

Centre Management Group Research Programme The committee also oversees and The Centre Management Group is Management Committee identifies areas of potential charged with leading the The Research Programme collaboration both within and development and delivery of the Management Committee is outside the Centre. agreed research strategy for the responsible for developing and

46 CANCER RESEARCH UK LUNG CANCER CENTRE OF EXCELLENCE AT MANCHESTER AND UCL GOVERNANCE 47

ISSN 1479-0378 Copyright © 2014 Cancer Research UK www.cruklungcentre.org