Abstract 2710: Lead based development and evaluation of selective estrogen mimics in tamoxifen resistant breast cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Tamoxifen is the standard of care for many patients with ER+ breast cancer and works by antagonizing the actions of estrogen at ER. However it poses an increased risk of endometrial cancer and thrombotic events, and most significantly, 30-50% women develop resistance to tamoxifen therapy, underlining the need for superior therapeutic options. Paradoxically, prior to tamoxifen therapy, estradiol (E2) and the ER agonist, diethylstilbestrol, had been used in breast cancer therapy, though with serious side effects. Development of Selective Estrogen Mimics (SEMs) that cause regression of tamoxifen-resistant breast cancer, but without the side effects of E2, represents a rational therapeutic strategy. Novel SEMs were developed, which in vitro in 3D cultures and in vivo caused complete regression of tamoxifen-resistant xenografts, with characteristics similar to those of E2. These SEMs did not fuel growth of estrogen-dependent T47D xenografts and did not cause uterine growth. SEM mediation of classical ER-signaling was profiled in MCF7 and MDA-MB231:β41 cells. A tamoxifen-resistant cell line, MCF-7: 5C, was used to assay induction of cell death by both E2 and the SEMs and to probe the mechanism of action. Several SEMs were observed to act as partial agonists at ERα , suggesting ideal characteristics as therapeutics. Structure-activity relationships were explored, suggesting that partial ERα agonist have the capacity to cause regression of tamoxifen-resistant tumors, without adverse effects associated with estrogenic actions in normal gynecological tissues of the breast and uterus, which might contribute to carcinogenesis. The ER-mediated agonist/antagonist activity, regression efficacy, and pharmacokinetic profiles of these SEMs were examined to obtain lead compounds that are effective with minimal estrogenic side effects. In MCF-7:5C cells, SEM-induced cell death was mediated by activation of classical nuclear ERα signaling, via induction of apoptosis. This research paves the way for use of SEMs with partial agonist activity at ER for use in tamoxifen-resistant breast cancer with enhanced safety profiles. Citation Format: Hitisha Patel, Rui Xiong, Jiong Zhao, Mary Ellen Molloy, Debra Tonetti, Gregory R.J Thatcher. Lead based development and evaluation of selective estrogen mimics in tamoxifen resistant breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2710. doi:10.1158/1538-7445.AM2014-2710