Testing ER-beta Agonist Synergy with B7-H1 and mTOR Inhibitors as Novel and Effective Treatments for Ovarian Cancer
Abstract
Rationale and Objectives: Tumor suppressors are proteins that can reduce the growth of cancer cells. If they can be activated artificially in clinical cancer, that could be used as a treatment. Estrogen receptor-beta (ER-beta) is a tumor suppressor (a protein that prevents cancer growth or development) that is associated with improved survival in ovarian cancer. We found that drugs that activate ER-beta (ER-beta agonists) reduced the growth of ovarian cancer cells in the test tube (in vitro). We further found that B7-H1, a molecule expressed on the surface of most ovarian cancer cells, reduced ER-beta s ability to inhibit cancer cell growth. We thus predicted that if we could block B7-H1, the ER-beta agonists would work better, and then proved the concept in vitro. We further found that ER-beta activated a molecule called mTOR and this activation also reduced ER-beta agonist s ability to inhibit cancer cell growth in vitro. We predicted that an mTOR inhibitor drug would thus improve the ability of an ER-beta agonist to reduce tumor growth in vitro, and then proved the concept in vitro. Based on these in vitro findings, we now propose to give mice ovarian cancer cells to produce ovarian cancer in vivo and treat these cancer-bearing mice with combinations of ER-beta agonists, B7-H1 blockers, and mTOR inhibitors to determine if these combinations treat ovarian cancer effectively and if they can be translated into useful ovarian cancer treatments for humans. Our objectives are to use a well-established mouse model for ovarian cancer to (i) establish the treatment efficacy of ER-beta agonists in ovarian cancer and understand mechanisms, (ii) test efficacy of blocking B7-H1 or inhibiting mTOR on ER-beta agonist s efficacy and identify mechanisms, (iii) test mTOR inhibition to improve ER-beta agonist plus anti-B7-H1 strategies and understand mechanisms, and (iv) use human ovarian cancer cells to establish B7-H1/ER-beta/mTOR effects on tumor growth in vitro as a prelude for more advanced human studies in a follow-up proposal. Central Problem in Ovarian Cancer Addressed: We address two distinct, but related and important problems in ovarian cancer: (i) identification of novel and effective treatments and (ii) understanding disease pathogenesis. There are no agents available to cure ovarian cancer after failure of first-line therapy, and 70% of patients eventually fail first-line therapy. We thus fill an unmet medical need to identify additional drugs, drug combinations, or drug targets to improve treatment efficacy. We also help understand ovarian cancer pathogenesis by showing how ER-beta, B7-H1, and mTOR signals control tumor cell growth. Relevance to the Vision and Mission of the Ovarian Cancer Research Program (OCRP): We greatly assist the OCRP vision and mission of improving ovarian cancer treatments, lending insights into disease progression, improving therapy, and augmenting ovarian cancer researchers. Impact: In the short term, we will identify novel druggable targets and drug combinations. In the longer term, we will test concepts in clinical trials as all agents can be rapidly translated, with the ultimate goal of identifying more effective ovarian cancer treatment strategies. All drugs that we use here are either Food and Drug Administration-approved for another purpose or are in late clinical trials, meaning that all findings can be put into ovarian cancer clinical trials rapidly. We have extensive experience in taking ideas from the lab into human trials quickly, especially in ovarian cancer. There are no risks to human subjects in these studies, but there could be clinical benefits as we discover potential treatments. Military Impact: These findings help the military reduce the personnel, personal, and financial impact of ovarian cancer in active Service members, their families, and other military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510090
Entities
People
- Tyler J Curiel
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio