Project 466593

Ovarian cancer is the most lethal gynecological cancer and has a 5-year survival rate of less than 45%. About 20% of patients with high-grade serous ovarian cancer have mutations in the genes. These genes code for the proteins in one of the main DNA repair pathways, known as homologous recombination. As such, the mutated cells become reliant on other DNA repair pathways, such as the poly-adenosine diphosphate-ribose polymerase (PARP) repair mechanisms. This causes these cells to become sensitive to a family of drugs known as PARP inhibitors (PARPi), which are now commonly used as maintenance therapy. Although PARPi have been very beneficial to patients, the PARPi induced response of the tissue surrounding the cancer cells, known as the tumour microenvironment (TME), remains unknown. Therefore, this project aims to study the changes in the ovarian TME following the administration of PARPi. To do this, we will induce the development of ovarian cancer in mice over 30 days and then administer PARPi for a total of 18 days. Thereafter, the tumours will be collected from the mice and analyzed for expression of markers of cell growth, inflammation, and cell death. Additionally, we will use flow cytometry, a technique that allows us to establish the immune cell composition of the TME. Because the TME is often highly immunosuppressive and is composed of anti-inflammatory cell types, we hypothesize that by learning the response of the TME to PARPi treatment, we can identify ways to manipulate the TME to boost the immune response. In the longer term, the outcomes of this study will be used to design more effective combination therapies to treat ovarian cancer and prolong patient survival.