Accelerating progress from pre-clinical modelling to novel therapeutics: a stratified medicine approach to colorectal cancer

Supervisors: Richard Wilson (University of Glasgow/Beatson West of Scotland Cancer Centre), Owen Sansom (CRUK Beatson Institute)

Outcomes in advanced colorectal cancer (CRC) are poor and we urgently need innovative approaches to increase cure rates, prolong disease control and enhance quality of life. The ACRCelerate colorectal cancer stratified medicine network will provide the ecosystem in which this fellowship will be undertaken. As well as working in the ACRCelerate team in the Sansom lab in the CRUK Beatson Institute, the student will work in the Glasgow Experimental Cancer Medicine Centre and the Lower GI Cancer team in the Beatson West of Scotland Cancer Centre in translational research and innovative trials in CRC under the supervision of Wilson.

The underlying hypothesis for this project is that improved outcomes in CRC will come from an increased understanding of signalling between the tumour microenvironment and malignant epithelium based on sophisticated pre-clinical model systems and their exploitation through rational use of targeted therapeutics.

The aims of this research fellowship are to define the impact of standard of care therapeutics, repurposed and novel agents as monotherapies and in combination in our pre-clinical CRC models, to investigate the use of innovative therapies in a stratified medicine approach in patients with advanced CRC in clinical trials and to undertake translational research to understand their pharmacodynamic effects on surrogate normal and tumour tissues and to try to develop prognostic and predictive biomarkers for these therapies.

Keywords: colorectal cancer, stratified medicine, preclinical models, therapeutics, tumour microenvironment

Background
Outcomes in advanced colorectal cancer (CRC) have gradually improved over the last few decades, but progress has lagged behind that seen in many other common solid tumours, and it remains the second most common cause of cancer death. Many targeted agents have failed in the clinic despite encouraging preclinical research. We now realise that the biological complexities revealed through molecular subtyping; the deeply immunosuppressive tumour microenvironment; the inadequacies of investigations focusing solely on the proliferating tumour epithelium but ignoring the role of the stroma and tumour microenvironment in driving progression and modulating response to therapy; and the inappropriate nature of 'one size fits all' approaches through empirical therapies have all greatly hampered our ability to improve outcomes to date. The Cancer Research UK award to our consortium (led by Sansom) allows us to learn from past mistakes through the work of the ACRCelerate colorectal cancer stratified medicine network. The tumour stroma is an important and complex tissue compartment consisting of cancer-associated fibroblasts, endothelium and a constellation of innate and adaptive immune cells. Therapeutically exploiting inter-compartmental signalling from the stroma in the tumour microenvironment to the malignant epithelium could represent an important new paradigm for therapeutic innovation in CRC, as demonstrated by the effect of immune checkpoint inhibition in microsatellite unstable CRC. This approach, which currently benefits under 5% of patients with advanced CRC, is an exemplar of what we wish to achieve in this fellowship. In this, we will embed an oncology trainee in the Sansom lab in the CRUK Beatson Institute where they will work as part of the ACRCelerate team, and in the Glasgow Experimental Cancer Medicine Centre and the Lower GI Cancer team in the Beatson West of Scotland Cancer Centre where they will work in linked translational and clinical research including innovative trials in CRC under the supervision of Wilson.

Hypothesis
Improved outcomes in the treatment of advanced CRC will come from an increased understanding of CRC biology and of signalling between the tumour microenvironment and malignant epithelium based on sophisticated pre-clinical model systems and their exploitation through rational use of targeted therapeutics including combinations with standard of care chemotherapies, novel and repurposed agents.

Aims
(i) to define the impact of the full range of standard of care therapeutic regimens (cytotoxics, ionising radiation, EGFR inhibitors, anti-angiogenics, PD-1 and CTLA4 inhibitors) used routinely in CRC as monotherapies and in combination on our wide variety of pre-clinical CRC models, particularly on the stroma and signalling between this and malignant epithelial cells.
(ii) to define the impact of novel and repurposed agents alone and in combination with standard of care therapies in relevant CRC model systems
(iii) to investigate the use of innovative therapies in a stratified medicine approach in patients with advanced CRC in clinical trials
(iv) to undertake translational research to understand the pharmacodynamic effects of investigational therapeutic regimens on surrogate normal and tumour tissues from patients in the above trials and to develop associated prognostic and predictive biomarkers for these therapies.

Methodology
The trainee will work alongside ACRCelerate team members who are developing a suite of pre-clinical CRC model systems, which faithfully recapitulate the human disease, and integrating these new model systems with patient-derived xenografts (PDX), patient and PDX derived cell-lines (PDCL and PDXCL) and organoid models already used within the laboratories of our consortium members. These will provide tools to underpin precise CRC stratification approaches using standard, repurposed and novel therapies. They will use both the Consensus Molecular Subtype (CMS) and Colorectal Cancer Intrinsic Subtype (CRIS) classifications to focus on specific and potentially targetable inter-compartmental signalling pathways that are consistently disrupted through multiple mechanisms in poor prognostic tumours. Investigation of single agent and combination use of standard of care licensed therapeutics, ionising radiation and repurposed and novel agents will be undertaken to assess their effects on both stromal and epithelial compartments in our model systems and their interplay through signalling pathways.

Genetically engineered mouse models (GEMMs) of CRC that metastasise to liver routinely, have a high penetrance, a relative short latency and which strongly overlap with the CMS signatures will be used. These models have a complex stroma and disrupt many of the same signalling pathways seen in human tumours while retaining an intact immune system and are amenable for testing immunotherapy combinations. Oganoid models developed from both man and mouse with recapitulation of the commonly mutated oncogene and tumour suppressors will be used. These models will be interrogated based both on their epithelial contribution in vitro (e.g. in organoid culture) and on their in vivo profile post-transplantation as the organoid educates the surrounding stroma. Murine organoids will be implanted into syngeneic mice. Organoids will be transplanted orthtopically into the colon, rectum, caecum or directly into the liver, modelling all sites of human primary and metastatic CRC. Patient-derived xenografts will be used to assess subclonal evolution, mesenchymal-epithelial crosstalk and therapeutic efficacy. The consortium PDX bank recapitulates the genetic and functional heterogeneity of CRC at a population level, and provides a unique resource for proof-of-concept "xenotrials" as well as an invaluable validation cohort for human tissue efficacy studies. Our consortium patient derived isogenic CRC cell line bank includes CRC cell lines including drug-resistant cells and tumour (patient or PDX-derived) derived cells which will support the stratification of therapies that target cell intrinsic tumour mechanisms. Full training in both clinical and translational aspects of early and late phase stratified trials in advanced CRC will be provided.

Publications
Kaplan R, Maughan T, Crook A, Fisher D, Wilson RH, Brown L, Parmar M. Evaluating many treatments and biomarkers in oncology: a new design. Journal of Clinical Oncology. December 2013: 31 (36): 4562-4568.

Alvi MA, Loughrey MB, Dunne P, McQuaid S, Turkington R, Fuchs M-A, McGready C, Bingham V, Pang B, Moore W, Maxwell P, Lawler M, James J, Murray G, Wilson R, Salto-Tellez M. Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies. British Journal of Cancer. July 2017; 117 (2): 203-209.

Schrock AB, Devoe CE, McWilliams R, Sun J, Aparicio T, Stephens PJ, Ross JS, Wilson R, Miller VA, Ali SM, Overman M. Genomic Profiling of Small Bowel Adenocarcinoma: Insights from a Comparative Analysis with Gastric and Colorectal Cancer. JAMA Oncology. November 2017; 3 (11): 1546-1553.

Adams R, Brown E, Brown L, Butler R, Falk S, Fisher D, Kaplan R, Quirke P, Richman S, Samuel L, Seligmann J, Seymour M, Shiu KK, Wasan H, Wilson RH, Maughan T on behalf of the FOCUS4 Trial Investigators. HER1-3 inhibition in patients with colorectal cancer that is wild-type for BRAF, PIK3CA, KRAS, and NRAS mutations (FOCUS-4D): first results from the multi-arm multi-stage phase II/III FOCUS-4 randomised trial. Lancet Gastroenterology and Hepatology. March 2018; 3: 162–71.

Allen WL, Dunne PD, McDade S, Scanlon E, Loughrey M, Coleman H, McCann C, McLaughlin K, Nemeth Z, Syed N, Jithesh P, Arthur K, Wilson R, Coyle V, McArt D, Murray GI, Samuel L, Nuciforo P, Jimenez J, Argiles G, Dienstmann R, Tabernero T, Messerini L, Nobili S, Mini E, Sheahan K, Ryan E, Johnston PG, Van Schaeybroeck S, Lawler M, Longley DB. Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III CRC patients who benefit from adjuvant chemotherapy. JCO Precision Oncology. June 2018; 10.1200/PO.17.00241.

Gay DM, Ridgway RA, Müller M, Hodder MC, Hedley A, Clark W, Leach JD, Jackstadt R, Nixon C, Huels DJ, Campbell AD, Bird TG, Sansom OJ. Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nat Commun. 2019 Feb 13;10(1):723.

Morris HT, Fort L, Spence HJ, Patel R, Vincent DF, Park JH, Snapper SB, Carey FA, Sansom OJ, Machesky LM. Loss of N-WASP drives early progression in an Apc model of intestinal tumourigenesis. J Pathol. 2018 Jul;245(3):337-348.

Fumagalli A, Drost J, Suijkerbuijk SJ, van Boxtel R, de Ligt J, Offerhaus GJ, Begthel H, Beerling E, Tan EH, Sansom OJ, Cuppen E, Clevers H, van Rheenen J. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):E2357-E2364.

Gonzalez PS, O'Prey J, Cardaci S, Barthet VJA, Sakamaki JI, Beaumatin F, Roseweir A, Gay DM, Mackay G, Malviya G, Kania E, Ritchie S, Baudot AD, Zunino B, Mrowinska A, Nixon C, Ennis D, Hoyle A, Millan D, McNeish IA, Sansom OJ, Edwards J, Ryan KM. Mannose impairs tumour growth and enhances chemotherapy. Nature. 2018 Nov;563(7733):719-723.

Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernández-Mateos J, Khan K, Lampis A, Eason K, Huntingford I, Burke R, Rata M, Koh DM, Tunariu N, Collins D, Hulkki-Wilson S, Ragulan C, Spiteri I, Moorcraft SY, Chau I, Rao S, Watkins D, Fotiadis N, Bali M, Darvish-Damavandi M, Lote H, Eltahir Z, Smyth EC, Begum R, Clarke PA, Hahne JC, Dowsett M, de Bono J, Workman P, Sadanandam A, Fassan M, Sansom OJ, Eccles S, Starling N, Braconi C, Sottoriva A, Robinson SP, Cunningham D, Valeri N. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018 Feb 23;359(6378):920-926.

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