Abstract IA30: Targeting hormone receptors for degradation: Nuclear receptor downregulation as a therapeutic approach in cancer

Durable clinical responses to endocrine therapies in breast cancer are limited by the development of resistance that can occur as a consequence of estrogen receptor–alpha (ERα) mutations, the production of non-canonical ER ligands, or to the reprogramming of ER signaling pathways. This contemporary view of resistance has driven the search for Selective Estrogen Receptor Degraders (SERDs), compounds that target the receptor for proteasomal degradation. The clinical activity of fulvestrant, the first drug in this class, confirmed the utility of SERDs in late stage disease; however the poor pharmaceutical properties of this drug have limited its use. Previously, we reported the discovery and early clinical development of the first orally bioavailable SERD (GW5638) and although its development was discontinued, the early positive signals from clinical studies of this drug provided others with the impetus to develop additional molecules that function using the same mechanism of action (GDC810 and AZ9694). These latter drugs, if approved, will be significant additions to the breast cancer armamentarium. Anticipating that acquired resistance is likely to be a response to SERD treatment, we have recently embarked on an effort to identify targets/pathways that are required for the maintenance of the receptor expression. It is anticipated that combined treatment with SERDs and agents that inhibit ERα expression would result in more durable clinical responses. These efforts have led to the discovery that the AGR2/LYPD3 signaling axis within cancer cells is required for ERα expression and that its inhibition achieves a quantitative downregulation of this receptor in tumor models. The impact of targeting ERα expression, directly (SERDs) and/or indirectly (AGR2 blocking antibodies) in breast cancer will be the focus of this presentation. Citation Format: Donald McDonnell, Kimberly Cocce, Suzanne Wardell, John Norris. Targeting hormone receptors for degradation: Nuclear receptor downregulation as a therapeutic approach in cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA30.