Ovarian cancer was the leading cause of gynecologic cancer-related deaths in the US in 2016. Despite high initial response rates to platinum-based chemotherapy, the majority of patients develop resistance and relapse, leaving few options for further treatment and a dismal prognosis. The underlying genetics of ovarian cancer vary widely across different subtypes and between patients. Thus, to improve treatment outcomes, the future lies in applying a precision medicine approach to match effective drugs to tumor-specific genetic features.
The MYC family of proteins are master regulators of cell proliferation and are central drivers in many human cancers. We have identified that over 90% of ovarian cancers display mutations in the MYC pathway network, highlighting MYC as a promising target in ovarian cancer. Moreover, ovarian cancer patients with high MYC levels have been associated with chemotherapy resistance and decreased overall survival. As it is difficult to directly drug MYC, we have identified indirect strategies to target MYC through its dependencies on other genes through a high-throughput functional genomics screen.
In preliminary studies, we have prioritized and validated nine gene targets for MYC-driven ovarian cancers. In this proposal, we will focus on further developing two of these promising gene targets for clinical translation. Using both genetic and chemical approaches, we will validate these genes as effective targets in a broader set of patient-derived ovarian tumor cultures, identify the molecular mechanisms by which targeting these genes leads to cell death, and propose candidate drugs for clinical testing.
In summary, this research proposal will facilitate the development and rapid clinical translation of novel, less toxic, and more effective targeted therapies for ovarian cancer.
This grant was made possible in part by a generous donation from The Teal Foundation.