Testing ER-Beta Agonist Synergy with B7-H1 and mTOR Inhibitors as Novel and Effective Treatments for Ovarian Cancer

Factors driving growth of epithelial ovarian cancer cells are poorly understood. Estrogen receptor- ER is a tumor suppressor gene that reduces growth of ovarian cancer cells and to correlate with survival in ovarian cancer patients. We found that the immune co-signaling molecule B7-H1 regulates ER signals in cells. Using available agents to manipulate B7-H1, which is highly expressed in most ovarian cancers, we found that ER signals can be altered through mTOR signals to reduce tumor growth. We will test if manipulating ER signals through B7-H1 can treat ovarian cancer effectively in the well-established ID8 ovarian cancer model, test improvements through simultaneous mTOR inhibition, and assess effects in human ovarian cancer cells. Innovation B7-H1 is an immune modulator, but we found that it modulates estrogen signals through ER, which is an unknown function for B7-H1 or any immune co-signaling molecule. We found that ER-mediated tumor growth inhibition can potentially be improved using anti-B7-H1 antibodies for direct effects on tumor cells and that mTOR inhibitors can augment this effect. This mTOR inhibitor effect is also novel as mTOR inhibitors are primarily used as direct modulators of tumor mTOR. Impact Novel uses for drugs in clinical trials to treat ovarian cancer effectively would be a great benefit to patients.