Discovery of new drugs for CRC prevention by targeting the BMP pathway
Primary Supervisor: Dr Ian Tomlinson
Colorectal carcinoma (CRC) is the most common cancer, with no major avoidable risk factor in the UK, with an increasing frequency of diagnoses. Overall, current screening reduces CRC mortality only by <20%, endoscopy capacity is severely limited, and the financial burden on the NHS is very high. There is, therefore, much scope and need for improvement through new CRC prevention strategies.
The aim of this project is to discover small-molecules which will increase BMP activation and signalling in the colon, which we have found to be central to the risk and pathogenesis of benign polyps and carcinoma differentiation, and hence prevent polyps and CRC. Based on an existing discovery assay, we have developed an organoid-based functional-screen to a discovery-platform from pre-clinical models available in our group. Screens can identify small molecules as CRC-chemoprevention and/or therapeutic-agents that safely activate the BMP pathway. We plan to refine the drugs identified to optimise delivery, specificity and toxicity, and to test efficacy in pre-clinical models, with a view to trialling agents to prevent colorectal polyps and CRC.
• Develop skills in tissue culture and large screens of anti-cancer drugs and small molecules
• Develop skills in the analysis of large-scale data
• Work closely with experienced scientists to present data and contribute to publications
Jaeger, E., Leedham, S., Lewis, A., Segditsas, S., Becker, M., Cuadrado, P.R., Davis, H., Kaur, K., Heinimann, K., Howarth, K. and East, J., 2012. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nature genetics, 44(6), pp.699-703.
Tomlinson, I.P., Carvajal-Carmona, L.G., Dobbins, S.E., Tenesa, A., Jones, A.M., Howarth, K., Palles, C., Broderick, P., Jaeger, E.E., Farrington, S. and Lewis, A., 2011. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS genetics, 7(6), p.e1002105.
Davis, H., Irshad, S., Bansal, M., Rafferty, H., Boitsova, T., Bardella, C., Jaeger, E., Lewis, A., Freeman-Mills, L., Giner, F.C. and Rodenas-Cuadrado, P., 2015. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nature medicine, 21(1), pp.62-70.