Tamoxifen is the standard of care for many patients with estrogen receptor positive ER+ breast cancer, antagonizing the actions of endogenous estrogen at ER. Tamoxifen increases the risk of endometrial cancer and thrombotic events, and most significantly, half of women develop resistance or do not respond to tamoxifen therapy, underlining the need for an alternate therapeutic option. 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 transformational therapeutic strategy. Based on the benzothiophene scaffold, a chemical library consisting of 30 SEMs was synthesized in order to obtain an ideal SEM. The SEMs were assayed in tamoxifen-resistant cell lines, MCF-7:5C and T47D:PKCa, with the objective of developing partial agonists at ERa, which do not fuel growth of estrogen-dependent T47D xenografts and do not cause uterine growth; which we postulate as ideal characteristics for therapy of breast cancer beyond tamoxifen-resistance. Thrombosis risk is adversely increased in breast cancer and with chemotherapy, therefore, we sought in parallel to address this cause of increased mortality. A prodrug strategy was developed for SEMs to add ancillary anticoagulant activity, whilst maintaining the anti-cancer activity towards breast tumors. This research paves the way for use of SEMs with partial agonist activity at ER, for use in breast cancer, with enhanced safety profiles through reduced risk of endometrial cancer and thrombotic events.

Lead based development and evaluation of selecitve estrogen mimics in tamoxifen resistant breast cancer

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.