Grant: Doctoral Research Award: Canada Graduate Scholarships

When prostate cancer metastasizes beyond the prostate to bone and organs, it is invariably lethal and there is an urgent need for new therapeutic approaches. Immunotherapy has been a successful treatment avenue in other types of cancer, but similar success has not been replicated in prostate cancer. Genetically, prostate cancer is actually a collection of different diseases which are likely to require different treatments. One of these prostate cancer subtypes is referred to as "hyper-mutant", denoting the increased number of small genetic mutations distributed throughout the genome. These genomic scars occur as a result of the inactivation of one or more of a class of genes called mismatch repair genes, which in non-cancerous tissues act to correct errors that occur spontaneously during DNA replication. Importantly, in other cancers, high mutation rates and mutations in these genes indicate that the patients will respond to immunotherapy. Currently, there is no real-time method to identify (and therefore treat) these patients in a prospective fashion. This is especially true with metastatic prostate cancer, where the tumors that are actually killing the patients reside in the bone. I have developed techniques that analyze tumor DNA which is circulating in the blood. These "liquid biopsies" act as a real time indication of the genetics of metastatic tumors. My proposal is to use these methods to characterize the genomics of hyper-mutant prostate cancer. I will also develop methodology to detect currently used clinical biomarkers using blood instead of traditional biopsies. I will perform a retrospective analysis of collated clinical data to establish effects on response to conventional therapies. Finally, I will determine whether there is an association between somatic hyper-mutation and response to immunotherapy in two ongoing phase II clinical trials chaired by my co-supervisor Dr. Kim Chi.