College of Medical, Veterinary and Life Sciences GLASGOW COLLABORATIVE COLORECTAL INITIATIVE GROUPING AND STRATEGY

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1 College of Medical, Veterinary and Life Sciences GLASGOW COLLABORATIVE COLORECTAL INITIATIVE GROUPING AND STRATEGY

2 OUR GROUPING The Cancer Research UK Glasgow Centre is a partnership between the Beatson West of Scotland Cancer Centre, the CRUK Beatson Institute, NHS Greater Glasgow and Clyde and the Universities of Glasgow and Strathclyde. One cancer the centre has chosen to focus on is colorectal cancer and as part of this we have developed the Glasgow Collaborative Colorectal Initiative (GCCI), which is a collaborative grouping of experts in colorectal cancer research based in Glasgow, UK. The GCCI brings together individual groupings from within Glasgow University, the CRUK Beatson Institute and NHS Greater Glasgow and Clyde, all with a common interest in colorectal cancer. By combining our strengths in discovery, translational and clinical research we have the foundations to develop personalised treatment strategies for colorectal cancer patients in a true bench to bedside manner. The team is managed by a multidisciplinary collaborative grouping of translational scientists (Dr Joanne Edwards and Professor Donald McMillan), discovery scientists (Professor Owen Sansom and Dr Seth Coffelt), academic surgeons (Mr Campbell Roxburgh and Professor Paul Horgan) and oncologists (Dr Janet Graham). Since the initial formation of this collaborative grouping, the team has strengthened its academic resources by developing large comprehensive patient cohorts of linked clinical data along with extensive in vivo models and investing in state-of-the-art equipment for genomic analysis. The success of such an approach has been demonstrated in the research outputs that resulted in all members of the management team being returned in the 2014 REF. University Beatson Institute NHS

3 The aim of the GCCI is to better understand the determinants of short and long-term outcomes in patients with colorectal cancer. In particular, the relationship between the local and systemic inflammatory responses, tumour microenvironment and cell signalling is being examined with a view to taking such knowledge into the routine clinical management of colorectal cancer. Our collective aim is to develop novel treatment strategies to establish a personalised medicine approach for colorectal cancer. COLLABORATIONS University of Dublin Amsterdam Medical Centre Sørlandet Hospital Norway University of Sydney Memorial Sloan Kettering New York Dokkyo Medical University RESEARCH CENTRES RESEARCH FACILITIES Glasgow Polyomics NHS Research Scotland GGC Biorepository NHS GGC Safe Haven Beatson Institute of Cancer Research Sansom Group Coffelt Group Basic Science and Animal Models Wolfson Wohl Cancer Research Centre (UoG) RESEARCH GROUPS Edwards Group Biankin Group RESEARCH EXPERTISE Translational Science and Genomics OUTPUT AND AIM Precision medicine approach for Colorectal Cancer New prognostic and predictive tests New therapeutic strategies Improved outcomes and efficiency Greater Clyde and Glasgow NHS Horgan Group Graham Group Clinical Research and Clinical Trials Cancer Research UK BioClavis Medical Research Council (MRC) FUNDERS/INDUSTRIAL PARTNERS To achieve these aims strong academic collaborations have been established to utilise the expertise of the colorectal cancer community: Professor JP Medema and Dr Louis Vermeulen, AMC, The Netherlands Dr Christian Kersten, Sorlandet Hospital Norway Dr Marty Weiser, Memorial Sloan Kettering, USA Professor Keiran Sheehan and Dr Liz Ryan, University of Dublin, Ireland Professor Ishizuka and Kubota, Dokkyo Medical University, Japan Professor Stephen Clarke, University of Sydney, Australia The group also has a working relationship with the NHS Tissue Biorepository and Safe Haven, allowing access to important clinical trial specimens and data. Furthermore, an industrial partnership with BioClavis will give the grouping access to exciting new technologies to push colorectal cancer research forward.

4 RESEARCH EXPERTISE The GCCI has a wealth of expertise across discovery, translational and clinical science allowing us to quickly move from bench to bedside. The CRUK Beatson Institute hosting Professor Owen Sansom and Dr Seth Coffelt is a world-leading centre for basic colorectal cancer research. Their research focuses on the drivers of colorectal metastasis. Central to this work is the use of novel inducible models of colorectal tumourigenesis that allow the study of functions related to specific genes and inflammation. The Wolfson Wohl Cancer Research Centre is a state-of-the-art translational science facility hosting the teams of Professor Andrew Biankin, Dr Joanne Edwards and Mr Campbell Roxburgh. Their work focuses on linking genomics, the tumour microenvironment and signal transduction mechanisms to inform on response to therapy. Central to this work is large colorectal tissue microarrays allowing identification of clinically relevant prognostic and predictive biomarkers and a state-of-the-art genomics suite allowing assessment of the genomic landscape of the tumours. The Glasgow Royal Infirmary is a leading centre for clinical research hosting the team of Professors McMillan and Horgan. Their work has highlighted the importance of the systemic and local inflammatory response in colorectal cancer. This has led to the introduction of the Glasgow Prognostic Score (GPS) and Glasgow Microenvironment Score (GMS) as prognostic markers for colorectal cancer. Central to this work is the large clinical databases created by the team. The Beatson West of Scotland Cancer Centre is the second largest cancer treatment centre in Europe, serving a population of 2.6 million. The treatment centre has ECMC status and hosts the CRUK Clinical Trials Unit, providing access to colorectal cancer clinical trial specimens and data. Dr Janet Graham s team takes a lead on a broad portfolio of early and late phase colorectal trials within the centre. Beatson Institute of Cancer Research World renowned CRUKfunded centre for basic research into cancer development and progression GEM and xenograft models for colorectal cancer research Drug discovery programme to identify novel cancer therapeutics Expertise in cell function and signalling Wolfson Wohl Cancer Research Centre (UoG) State of the art centre for translational cancer research Large colorectal cancer tissue resources Polyomics and Genomic expertise Expertise in biomarker research Collaborative research between scientist and clinicians Greater Glasgow and Clyde Leading hospital-based centres for clinical cancer research Large clinical databases and tissue collection Access to NHS Research Scotland s GGC tissue Biorepository: colorectal tumour specimens such as the SCOT clinical trial Clinical expertise in colorectal cancer surgery and oncology

5 College of Medical, Veterinary and Life Sciences GLASGOW COLLABORATIVE COLORECTAL INITIATIVE RESEARCH DISCOVERY RESEARCH Research Interests Understanding the early changes associated with intestinal neoplasia to identify novel markers of disease and new targets for therapy The role of the APC gene in sporadic cancers The use of novel inducible mouse models of colorectal tumourigenesis to study the functions of specific tumour suppressor genes The study of the dichotomous roles of immune cells and how tumours control immune cell behaviour Understanding how immune cells participate in the metastatic process to develop new immunotherapies that counteract metastatic lesions Resources In vivo mouse models of colorectal tumourigenesis GEM models of consensus molecular subtypes and metastatic disease Orthotopic xenograft models Colorectal and immune cell lines Selected Publications Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau C, Verstegen NJM, Ciampricotti M, Hawinkels LJAC, Jonkers J, de Visser KE. IL-17-producing gd T cells and neutrophils conspire to promote breast cancer metastasis. Nature :345-8 Myant KB, Cammareri P, Hodder MC, Wills J, Von Kriegsheim A, Gyorffy B, Rashid M, Polo S, Maspero E, Vaughan L, Gurung B, Barry E, Malliri A, Camargo F, Adams DJ, Iavarone A, Lasorella A, Sansom OJ. HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. EMBO Mol Med 9: , 2017

6 TRANSLATIONAL RESEARCH Research Interests Assessment of tumour-associated inflammation and stromal infiltration as prognostic biomarkers The development of strategies to pre-operatively assess the tumour microenvironment The relationship between signal transduction and inflammatory response in relation to patient outcome The use of tumour signalling pathways to predict prognosis and response to therapy Development of a clinically translatable subtyping method based on histological analysis to classify patient by prognosis and predict response to therapy The use of genomics to evaluate RNA expression and DNA mutational landscaping of cancers to provide biomarkers to inform clinical trial design Characterising the genomic, transcriptomic and epigenomic aberrations in cancer, and extending this to a personalised model of cancer care, where molecular characteristics guide treatment decisions. Resources Established 274 stage I-III colorectal cancer patient tissue microarray with matched clinical data from Glasgow Royal Infirmary Established 750 stage I-IV colorectal cancer patient tissue microarray with matched clinical data from Western Infirmary and Stobhill hospitals from (MSI data available for all patients) New 1000 stage I-III colorectal cancer patient tissue microarray with matched clinical data from Glasgow Royal Infirmary from New 190 T1-T2 screen detected colorectal cancer patient tissue microarray with matched clinical data from Greater Glasgow and Clyde Hospitals from State-of-the-art genomics suite with custom 150 and 250 cancer mutation panels Selected Papers Richards, C. H., Roxburgh, C. S.D., Powell, A. G., Foulis, A. K., Horgan, P. G. and McMillan, D. C. (2014) The clinical utility of the local inflammatory response in colorectal cancer. European Journal of Cancer, 50(2), pp Park, J.H., McMillan, D.C., Horgan, P.G. and Roxburgh, C.S.D. (2015) The clinical utility of a tumour microenvironment-based histopathological score in patients with primary operable colorectal cancer. Journal of Clinical Oncology, 33(3). Roseweir, A. K., McMillan, D. C., Horgan, P. G. and Edwards, J. (2017) Colorectal cancer subtypes: Translation to routine clinical pathology. Cancer Treatment Reviews, 57, pp Biankin, A.V. (2017) The road to precision oncology. Nature Genetics, 49(3), pp Bailey, P. et al. (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature, 531(7592), pp

7 CLINICAL RESEACH Research Interests Prognostic value and determinants of pre-operative cancer-associated systemic inflammation Worldwide comparisons of systemic inflammation in colorectal cancer The role of post-operative systemic inflammation in short and long-term outcomes Can immune cell responses and expression of MHC-1, PD-1 and PD-L1 be measured on sequential tumour biopsies to provide an assessment of patterns of immune priming in response to chemoradiotherapy? Are there gene signatures that can be applied to stratify a subset of patients by degree of immunogenicity present at baseline and during treatment? Assessment of different treatment regimens in colorectal cancer clinical trials Resources Population-level clinicopathological data for patients diagnosed with colorectal cancer in West of Scotland ( ) Clinicopathological data from first round of National Bowel Screening Programme NHS GG&C ( ) Prospectively maintained dataset of patients undergoing resection of colorectal cancer in Glasgow Royal Infirmary (1997-onwards, 1700 patients to date) SCOT trial tissue specimens, blood samples and patient data Selected Papers Canna, K., McArdle, C. and McMillan, D. (2003) Systemic inflammatory response predicts survival following curative resection of colorectal cancer. British Journal of Surgery, 90, pp Park, J. H. et al. (2017) Staging the tumor and staging the host: A two centre, two country comparison of systemic inflammatory responses of patients undergoing resection of primary operable colorectal cancer. American Journal of Surgery, doi: /j.amjsurg Watt, D., Mcsorley, S.T., Park, J.H., Horgan, P.G. and McMillan, D.C. (2017) A postoperative systemic inflammation score predicts short- and long-term outcomes in patients undergoing surgery for colorectal cancer. Annals of Surgical Oncology, 24(4), pp Andrea Cercek, Campbell SD Roxburgh, et. al. (2017) Total neoadjuvant chemotherapy to facilitate delivery and tolerance of systemic chemotherapy and response in locally advanced rectal cancer. Journal of Clinical Oncology. 35:15_suppl, C-Reactive Protein structure

8 College of Medical, Veterinary and Life Sciences GLASGOW COLLABORATIVE COLORECTAL INITIATIVE TEAM Senior Management Team J Edwards C Roxburgh A Biankin O Sansom D McMillan P Horgan S Coffelt J Graham Senior Lecturers and Lecturers A Roseweir J Park D Chang P Bailey C Steele S McSorley D Mansouri Liz Musgrove Researchers Research Associates/Post docs PhD students Clinical Research Fellows Bioinformaticians Technical Staff Scientific officers Technicians Data Managers Developers CONTACT US Discovery Research Translational Research Clinical Research o.sansom@beatson.ac.uk s.coffelt@beatson.ac.uk joanne.edwards@glasgow.ac.uk antonia.roseweir@glasgow.ac.uk campbell.roxburgh@glasgow.ac.uk james.park@glasgow.ac.uk janet.graham@ggc.scot.nhs.uk Wolfon Wohl Cancer Research Centre, Garscube Estate, Glasgow, Scotland, G61 1QH, UK