Grant: Doctoral: Vanier Canada Graduate Scholarships

In North America, ovarian cancer is the leading cause of death across all reproductive system cancers. The majority of women with this disease do not survive beyond five years. The high-grade serous subtype (HGSC) accounts for over 70% of ovarian cancers and the vast majority of lethalities. The current standard of treatment for HGSC-platinum-based chemotherapy-is initially effective at treating the disease. However, the majority of patients develop platinum resistant disease and eventually succumb to the cancer. My project will look at HGSC to understand the processes that give rise to platinum resistance. Previous research has shown that HGSC has a high mutation rate due to ineffective DNA repair. This fast rate of mutation is thought to lead to the acquisition of mutations that confer platinum resistance. Based on this idea, many research groups have tried to identify these mutations. Despite this effort, mutations involved in the vast majority of platinum resistant cases remain unknown. A major limitation in this search has been our longstanding inability to analyze mutations in 98% of our DNA-the part that does not code for genes (non-coding genome). Recently, I have developed a pioneering tool to analyze mutations in part of the non-coding genome. In this project, I will apply, refine, and extend this method to find previously undiscovered platinum resistance mutations in HGSC. Developing better treatment strategies for HGSC will also require knowledge of how HGSC tumours evolve to become treatment resistant. Our research has recently revealed that HGSC tumours are actually heterogeneous entities made up of "clones". Each clone is a group of tumour cells that share the same mutations. In order to study tumour evolution in HGSC, we will investigate the growth of these clones in mice transplanted with human HGSC tumours. Understanding tumour evolution in HGSC will open up exciting new avenues to explore individualized therapy for HGSC patients.