Identifying opportunities for repurposing of approved drugs to new cancer indications using genetic and observational approaches

Background: Genetic approaches play an important role in prioritising therapeutic targets for disease treatment. Mendelian randomization (MR) is an epidemiological technique that exploits the random distribution and fixed nature of germline genotypes to identify causal relationships between intervention targets and disease. An exciting area of application is "drug repurposing Mendelian randomization" - where new indications are found for existing drugs using only the results from genome-wide association studies (GWAS) of disease. In the context of cancer, this could be applied to existing oncological medications (i.e. drugs approved to treat one type of cancer that are repurposed for the treatment of a different cancer) or non-oncological medications (e.g. drugs approved to treat cardiovascular disease that are repurposed for treatment of cancer). Along with MR, observational studies can be used to estimate the effects of medication use on cancer survival by employing a "target trial" framework. This approach involves applying design principles from randomised trials to observational research to minimise key sources of bias and confounding. Replication of findings from MR in target trial analyses can provide further support for the repurposing of existing drugs for cancer treatment. In this project, the student will apply MR and "target trial" approaches to investigate opportunities for repurposing of drugs to new cancer indications.

Methods: Using regions of the genome that influence proteins as drug proxies, the student will test if selected drugs are associated with cancer survival (a Mendelian randomization approach). Findings from the latter analyses will be replicated in a "target trial" observational study of the Clinical Practice Research Datalink, a primary care database of anonymised records in up to 16 million patients. Overall findings will be used to prioritise treatments for cancer.