Recent advances in immunotherapy hold the promise to one day permit a cure for ovarian cancer. Nonetheless, in clinical trials, ovarian cancer has so far been nonresponsive to immunotherapy approaches, suggesting that the relatively “direct” approach of using a single immune checkpoint blocker is insufficient in ovarian cancer.
My studies have focused on a gene that is gained in more than 70% of women with high grade serous ovarian cancer. The gene codes for the focal adhesion kinase (FAK) protein, and most studies to date have focused on its ability to help tumor growth or drug resistance. Using a new preclinical model I codeveloped, which mimics the human disease in many aspects of gene gain, loss and overall aggression, I found that FAK expression in the tumors shapes their interaction with the local microenvironment. Importantly , the presence of FAK led to signaling that caused factors to be secreted which are known to suppress the immune system. When I knocked out the gene encoding FAK, mutated it, or used newly developed drugs that target it, we found that the levels of these immune suppressing factors dropped dramatically, tumors were much smaller, and I could detect active immune cells. In the studies proposed here, I am seeking to better characterize the factors which FAK elevates to block the immune system, and to compare my results to other preclinical models, which I will treat with the FAK inhibitor. I believe these studies will allow me to identify a panel of key factors that block the immune response, many of which may be targetable alone or in conjunction with drugs that target FAK.
This grant was made possible by generous donations from Gary Ockey, in memory of Ann Virginia Zeidman, and Ovarian Cycle Tampa.