Grant: Doctoral Research Award: Canada Graduate Scholarships

Despite decades of clinical study, advanced prostate cancer remains a lethal disease. Research has shown that some prostate tumours are unable to properly repair changes (mutations) to their DNA; these cases are often particularly aggressive, and can rapidly develop resistance to most treatments. However, the inability to repair DNA also creates vulnerabilities to specific therapies, as seen by the dramatic response these tumours can have to platinum chemotherapy. Moreover, recent findings have shown the efficacy of a new therapy, poly ADP ribose polymerase (PARP) inhibitors, in treating tumours that have non-functional DNA repair. Unfortunately, the disruption of DNA repair in prostate cancer is poorly understood, and patients that could benefit from specific anticancer medications are often missed, and instead managed with conventional, but ultimately ineffective, therapy. My project aims to better characterize DNA repair-deficient prostate tumours, in order to help guide rational therapy selection. My preliminary research has identified three genes (BRCA2, ATM, and CDK12) that contribute to DNA repair, but are non-functional in ~15% of advanced prostate cancer cases. Initial findings suggest that tumours with a loss of one of these genes are unique, possessing specific mutations that set them apart from other prostate tumours. In this project, I will use DNA sequencing to determine the frequency of BRCA2, ATM, and CDK12 disruption in ~1800 prostate cancer samples. I will then employ computational tools to identify specific combinations of mutations unique to DNA repair-deficient prostate tumours. Given the poor response of these tumours to most standard therapies, there is an unmet need to determine which patients might benefit from anticancer treatments that exploit non-functional DNA repair. Findings from my research will readily translate to the clinic, facilitating a more personalized approach for the treatment of men with advanced prostate cancer.