Abstract 4757: A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant breast cancer

Abstract

Abstract 80% of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can be activated in the absence of estrogens via point mutations in ERα or cellular signaling pathways supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling. We have identified two novel series of non-steroidal ERα antagonists, series I exemplified by ARN-810, now in clinical trials for treatment of endocrine resistant breast cancer, and series II, both of which induce degradation of ERα at picomolar concentrations resulting in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show that both series induce ERα conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. In vitro, both ligand series are active on wild-type and the constitutively active ERα mutants found in endocrine resistant breast cancer patients. Importantly, these compounds yield tumor regression in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Based on their unique in vitro profile, and good pharmacokinetics following oral dosing, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. Citation Format: James D. Joseph, Beatrice Darimont, Steven Govek, Dan Brigham, Jing Qian, John Sensintaffar, Gang Shao, Anna Aparicio, Mehmet Kahraman, Andiliy Lai, Kyoung-Jin Lee, Nhin Lu, Johnny Nagasawa, Michael Moon, Peter Rix, Nick Smith, Jeff Hager. A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-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 4757. doi:10.1158/1538-7445.AM2014-4757