High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer-associated mortality. The high mortality of HGSOC is largely due to: 1) lack of novel therapeutic approaches and 2) incomplete understanding of molecular mechanisms underlying HGSOCs. For example, compared with our understanding of the genetic changes associated with HGSOC, how epigenetic drivers contribute to HGSOC and whether these reversible changes can be leveraged to develop urgently needed HGSOC therapies remain to be fully explored.
Epigenetic therapy represents a new frontier in the fight against cancer. For instance, several epigenetic inhibitors have recently entered into clinical trials. Relevant to this application, genes encoding epigenetic regulators are frequently altered in ovarian cancer. The current application focuses on several key epigenetic drivers in HGSOC such as BRD4, PRMT4, and Integrator complex.
The immunological microenvironment plays a key role in cancer. Indeed, a promising approach in ovarian cancer immunotherapy is the transferring of engineered tumor killing T cells. However, the approach is limited by suppressive factors in the tumor microenvironment which limit the effector function of the transferred tumor killing T cells. This application will also address whether targeting an epigenetic regulator FOXO1 can enhance the activity of the transferred T cells. Several epigenetic inhibitors investigated in the current proposal can boost either survival or tumor killing activity of transferred T cells. This raises the possibility of combining epigenetic therapy with engineered T cell based immunotherapy to eradicate ovarian cancer.
The overall goal of this application is to develop novel epigenetics-based approaches to combat ovarian cancer through better understanding how key epigenetic regulators contribute to the disease. To achieve this goal, we have assembled a group of outstanding investigators from The Wistar Institute with complimentary expertise in ovarian cancer, tumor immunology, and transcriptional regulation. The current application builds on the existing Ovarian Cancer Affinity Group at The Wistar Institute. The multi-disciplinary team has a strong track record in collaborative ovarian cancer research as evidenced by 15 co-authored ovarian cancer research articles.
In the immediate short-term, the proposed studies will provide fundamental mechanistic insights into the role of epigenetic drivers in ovarian cancer. In the long-term, they will lay the critical foundation for developing epigenetic-based intervention strategies for eradicating ovarian cancer. Notably, several of the epigenetic inhibitors examined here are ready for clinical trials. If successful, these newly developed approaches would be immediately translatable. A grant from the Ovarian Cancer Research Alliance will allow the team to strengthen the preliminary data and integration required to submit a competitive NIH/NCI program project grant.