Can colorectal cancer phenotypic subtypes predict response to therapy?

Supervisors: Owen Sansom (CRUK Beatson Institute), Joanne Edwards (University of Glasgow),

We recently proposed phenotypic subtypes for CRC as a novel histology based subtyping method to stratify patient outcome. The subtypes are based on phenotypic characteristics of the tumour microenvironment (immune and stromal infiltrate) and tumour growth. They are classified into four subgroups: immune, canonical, latent and stromal and are extrapolated from the consensus molecular subtypes (CMS) proposed by Guinney et al. in 2015. These phenotypic subtypes independently stratified cancer-specific survival in a cohort of 859 patients with CRC and could easily translate to the diagnostic setting as a prognostic tool to aid clinicians in their decision making.

The aim of the current project is to establish if these phenotypic subtypes can also be employed as predictive tools. This will be achieved by assessing the ability to predict response to adjuvant chemotherapy in 1500 patients from the SCOT trial which compared 12 to 24 weeks adjuvant chemotherapy. In parallel novel targets and therapeutic strategies will be examined in Genetically Engineered and organoid models of CRC.

This project will establish if phenotypic subtypes can be employed as predictive tools in the clinic and heighten awareness of the potential to develop a personalised medicine approach for treating CRC.

Keywords: Colorectal cancer; subtypes; mouse models; predictive biomarkers; patient tissue

Recent Publications:

RoseweirAK, BennettL, DicksonA, ChengK, QuintayoMA, BayaniJ, McMillan DC,Horgan PG, van de VeldeCJH, Seynaevee C HasenburgA, Kieback DJ, Markopoulos C, Dirix,LY, Rea DW, Mallon EA, BartlettJMS, Edwards J. Predictive biomarkers for endocrine therapy: retrospective study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Journal of the National Cancer Institute, (Accepted for Publication) 2017

Roseweir, A. K., McMillan, D. C., Horgan, P. G. and Edwards, J. Colorectal cancer subtypes: Translation to routine clinical pathology. Cancer Treatment Reviews, 57, pp. 1-7.(doi:10.1016/j.ctrv.2017.04.006) (PMID:28505475) 2017

Park, J.H. , van Wyk, H., Roxburgh, C.S.D., Horgan, P.G., Edwards, J.and McMillan, D.C. Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer. British Journal of Cancer, 116, pp. 1444-1450.(doi:10.1038/bjc.2017.108) 2017

Park, J. H. , Van Wyk, H. C., McMillan, D. C., Quinn, J. A., Clark, J., Roxburgh, C., Horgan, P. G. and Edwards, J. Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host. Clinical Cancer Research, 23(7), pp. 1698-1709. (doi:10.1158/1078-0432.CCR-16-1416) (PMID:27678454) 2017

Bennett, L., Quinn, J., McCall, P., Mallon, E. A., Horgan, P. G., McMillan, D. C., Paul, A. and Edwards, J. High IKKα expression is associated with reduced time to recurrence and cancer specific survival in oestrogen receptor (ER)-positive breast cancer. International Journal of Cancer, 140(7), pp. 1633-1644.(doi:10.1002/ijc.30578) (PMID:28006839) 2017

Myant KB, Cammareri P, Hodder MC, Wills J, Von Kriegsheim A, Győrffy 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. 2017 Feb;9(2):181-197

Steele CW, Karim SA, Leach JDG, Bailey P, Upstill-Goddard R, Rishi L, Foth M, Bryson S, McDaid K, Wilson Z, Eberlein C, Candido JB, Clarke M, Nixon C, Connelly J, Jamieson N, Carter CR, Balkwill F, Chang DK, Evans TRJ, Strathdee D, Biankin AV, Nibbs RJB, Barry ST, Sansom OJ, Morton JP. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2016 Jun 13;29(6):832-845.

Jackstadt R, Sansom OJ. Mouse models of intestinal cancer. J Pathol. 2016 Jan;238(2):141-51. doi: 10.1002/path.4645.

Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, Jones C, Radulescu S, Huels DJ, Myant KB, Dudek KM, Casey HA, Scopelliti A, Cordero JB, Vidal M, Pende M, Ryazanov AG, Sonenberg N, Meyuhas O, Hall MN, Bushell M, Willis AE, Sansom OJ. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature. 2015 Jan 22;517(7535):497-500

Cammareri P, Vincent DF, Hodder MC, Ridgway RA, Murgia C, Nobis M, Campbell AD, Varga J, Huels DJ, Subramani C, Prescott KLH, Nixon C, Hedley A, Barry ST, Greten FR, Inman GJ, Sansom OJ. TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis. Cell Death Differ. 2017 Oct;24(10):1681-169

 

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