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Discovery of new drugs for CRC prevention by targeting the BMP pathway


   Department of Oncology


About the Project

Colorectal carcinoma (CRC) is the most common cancer with no major avoidable risk factor in the UK, and is increasing in incidence. 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 new, improved CRC prevention strategies.

The aim of this project is to discover small molecules that will increase activity of the bone morphogenetic protein (BMP) pathway in the colon. In human genetic studies, we have found variation in this pathway to be central to the risk and pathogenesis of benign polyps and carcinoma of the colon. Our data from genetic mouse models show that increasing BMP activity can increase cellular differentiation and hence prevent colorectal tumours, with minimal toxicity. We have developed an organoid-based functional-screen to using pre-clinical models.

This project aims to identify known, repurposed drugs or new small molecules that safely activate the BMP pathway. The mechanisms of action of such molecules will be identified and potential side-effects analysed. We will refine the drugs identified to optimise delivery, specificity and toxicity, and test efficacy in pre-clinical models, with a view to trialling agents to prevent colorectal polyps and CRC in humans at high risk.

Training Opportunities:

  • 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

Funding Note

The deadline for applications for competition funded scholarships on the DPhil in Oncology at University of Oxford has now passed. Applications which were received before noon on Friday 9th December are currently being considered for places on the course (both funded and unfunded). Projects which are filled from this first round of applications will be removed from the website, this will happen in early February. The next application deadline will be at 12.00pm (noon) on Wednesday 1st March. This is for unfunded places only, meaning that, if accepted, you will need to provide your own funding to cover tuition fees and living expenses, either by self-funding or via an external scholarship. 


References

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.

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