Abstract A7: A novel class of selective estrogen receptors degraders regresses tumors in pre-clinical models of endocrine-resistant breast cancer

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Abstract Eighty percent of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with antihormonal therapies that directly block ERα 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 signal in the absence of estrogens 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 novel, nonsteroidal ERα antagonists that 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 these ligands induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. 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.