Grant: CIHR Fellowship

Ovarian cancer is the most common gynecologic cancer and the fifth leading cause of cancer death in women. Although patients with high grade ovarian cancer often responds to chemotherapy initially, most eventually develop and succumb to recurrent disease. Through the ovarian cancer sequencing effort, redundant copies of genes in the pro-survival PI3-kinase pathway were identified in 25% of the patients. It is thought that PI3-kinase may contribute to chemotherapy resistance by activating pro-survival signals in tumor cells during treatment. Interestingly, recent research showed that PI3-kinase may also help tumor cells repair damaged DNA, rendering DNA-damaging chemotherapy less effective. Because of its vital functions in tumor cells, targeting the PI3-kinase pathway presents as an appealing strategy, especially in combination with chemotherapy. While this combinatorial strategy is being explored in clinical trials, it remains to be determined what tumor characteristics would best respond to this treatment regimen. Our proposal aims to study the molecular features of ovarian tumor cells that confer sensitivity or resistance to the combination of PI3-kinase inhibitor and chemotherapy. We will test the hypothesis that tumor cells with higher level of PI3-kinase activity will be most responsive to the combined treatment of PI3-kinase inhibitor and chemotherapy. Understanding how PI3-kinase promotes chemotherapy resistance will help toward discovery of predictive resistance biomarkers, and provide insights for optimizing treatment of resistant tumors. We will use both cell culture and animal models to study treatment effects on tumor cells, in order to identify molecular changes paramount to the survival of resistant tumor cells. In summary, by studying how tumor cells co-opt pro-survival strategies such as the PI3-kinase pathway to counter chemotherapy, we hope to improve combination therapy to treat ovarian cancer.