Long-term clinical outcomes for women diagnosed with advanced epithelial ovarian cancer (EOC) have not significantly improved in the last 20 years. More than 70% of women will relapse after initial treatment with surgery and traditional chemotherapy and most women will ultimately die of their disease. As the disease progresses, the tumors become resistant to multiple types of chemotherapy resulting in devastating symptoms, decreased quality of life, and poor survival. There is an urgent need to develop novel treatment strategies by identifying and targeting the cellular pathways the tumor uses to survive and/or develop resistance to chemotherapy (termed chemoresistance).
Recent studies have shown that alterations in cellular metabolism can initiate and promote tumor growth and contribute to the development of chemoresistance. In particular, aberrations in mitochondria, the energy powerhouse of the cell, are linked to tumor growth and resistance through changes in energy usage and the formation of reactive oxygen species. Mitochondrial function is regulated by numerous cellular proteins. However, the estrogen-receptor related receptor alpha (ERRalpha), a protein similar to the estrogen receptor, has been identified as a master regulator of mitochondrial metabolism. Increased levels of ERRalpha in breast, colon, and ovarian tumors appear to associate with more aggressive tumor characteristics and poorer clinical outcome. In cell and animal models of breast cancer, drugs that inactivate ERRalpha have shown promise in causing tumor regression. In a lung cancer model, a drug that inactivated ERRalpha reversed the tumor’s resistance to paclitaxel, a chemotherapy commonly used in ovarian cancer. In our own preliminary studies, we found that tumors from patients whose tumors expressed a higher level of ERRalpha did not survive as long as patients with lower levels of ERRalpha. In addition, cells treated with XCT790, a drug that inactivates ERRalpha, did not as readily form tumors. We hypothesize that ovarian tumors with elevated levels of ERRalpha have metabolic alterations that promote cancer formation and chemoresistance and that inactivating this receptor will reverse these effects.
In this project, we will determine 1. Whether ERRalpha and the metabolic pathways it regulates are associated with tumor aggressiveness and clinical outcome in EOC, 2. Whether the metabolic pathways it regulates are associated with tumor growth and chemoresistance in culture and animal models of EOC, and 3. Whether drugs targeting ERRalpha can be used to treat EOC. Our long term objective is to translate these findings into novel therapeutic strategies to be tested in early phase clinical trials for women with advanced, recurrent EOC.