Grant: Doctoral Research Award: Canada Graduate Scholarships

BRCA1 and BRCA2 are known as tumour suppressor genes, both playing essential roles in the DNA repair pathway. Loss of function in either may lead to genetic instability of cells, ultimately leading to malignancy. Alterations (mutations) in either BRCA1 or BRCA2 pose the greatest risk factor for developing breast or ovarian cancer. With 1 in 300 to 500 people in the general population carrying mutations in either BRCA1 or BRCA2, the development of effective treatment for these cancers is an important topic in the field of cancer research. The treatment of BRCA1/2 mutated breast and ovarian cancers with certain specific DNA repair inhibitors (commonly known as PARPi) has initially led to promising outcomes. Oral PARPi treatment can selectively kill BRCA1/2 mutated cancer cells through a combination effect targeting the DNA repair pathway. Unfortunately, this treatment is not successful in all patients. Various mechanisms for PARPi resistance have been shown, including restoration of BRCA1/2 function due to differences in the genetic make-up of tumour cells or additional alternations in the BRCA1/2 genes. Oncolytic or "cancer-killing" viruses are an innovative approach to treating even the most complex cancers. Oncolytic viruses target and destroy cancer cells, leaving normal cells unharmed, all while activating a patient's own immune system to fight the cancer. The aim of this project is (1) to engineer cancer specific viruses targeting the BRCA1/2 genes, (2) evaluate the combination effect of these engineered BRCA1/2 targeting viruses with PARPi, and finally (3) complete a pre-clinical evaluation of BRCA1/2 targeting viruses with PARPi therapy including safety and efficacy by treating a panel of non-malignant cells, malignant cells and various mouse models. The overarching goal of this project is to develop a combination therapy using oncolytic viruses and PARPi that could overcome resistance and lead to curative treatment for patients with BRCA1/2 mutated cancers.