Abstract P5-05-05: Targeting the androgen receptor with seviteronel, a CYP17 lyase and AR inhibitor, in triple negative breast cancer

Abstract

Abstract Background: Androgen receptor (AR) protein is expressed across breast cancer (BC) subtypes, including up to 50% of triple negative breast cancers (TNBC) and it is often maintained in metastases. Our research demonstrated that TNBC cell lines rely on increased AR for anchorage independent survival, mammosphere formation, tumor initiation, and other stem-cell like properties. Further, AR mRNA levels increased in circulating tumor cells in the blood as compared to levels in the primary tumors of mice harboring human patient derived xenografts (PDX). Seviteronel (SEVI), a CYP17 lyase and AR inhibitor that blocks androgen and estrogen biosynthesis and AR activation, is in phase 2 clinical development for men and women with AR+ solid tumors, including advanced BC and has clinical activity in both basal and LAR subtypes (Innocrin data on file). Hypothesis: We hypothesized that targeting both androgen biosynthesis and AR activation with an agent such as SEVI would decrease tumor growth in preclinical models of AR+ TNBC. Methods: Genes regulated by AR under anchorage independent conditions with and without 10 nM dihydrotestosterone (DHT) were identified by AR chromatin immunoprecipitation (ChIP)-seq, RNA-seq, and Ingenuity Pathway Analysis. In vitro activity of SEVI was assayed in AR+ TNBC cell lines (MDA-MB-453 and SUM159). The IC50 of SEVI was determined via crystal violet. Soft agar colony formation assays and growth on poly-HEMA coated plates measured anchorage independent growth. In vivo, an AR+ TNBC patient derived xenograft (HCI-009, generated by Dr. Alana Welm) was grown in NSG mice given either DHT vs. vehicle control or, in a separate experiment, SEVI (150 mg/kg/day PO) vs. vehicle control. Results: ChIP-seq and RNA-seq in MDA-MB-453 demonstrated that AR chromatin binding and gene regulation increased under anchorage independent conditions in a ligand dependent manner and showed an increase in mTOR signaling, aryl hydrocarbon receptor signaling and metabolism. SEVI inhibited proliferation of AR+ TNBC in a dose-dependent manner and growth on soft agar. In vivo, the AR+ TNBC HCI-009 PDX exhibited a significant increase in tumor volume with DHT indicating AR dependence. SEVI treatment also decreased HCI-009 tumor volume (p=0.0054) and rate of growth (p=0.0146). Nuclear AR protein and classical AR-regulated genes such as KLK3 and FKBP5 were increased with DHT in the HCI-009 xenograft tumors and decreased in mice treated with SEVI and were confirmed at the protein level. Conclusion: These results further demonstrate the activity of SEVI, a CYP17 lyase and AR inhibitor, in preclinical models of AR+ TNBC. Use of AR targeting agents may be a rational treatment approach for a subset of patients with AR+ TNBC since such tumors may respond less well to chemotherapy than other TNBC molecular subtypes. We continue to identify markers of AR dependence/responsiveness to AR-targeted therapy. Citation Format: Reese JM, Babbs BL, Christenson JL, Spoelstra NS, Elias A, Eisner JR, Baskin-Bey ES, Gertz J, Richer JK. Targeting the androgen receptor with seviteronel, a CYP17 lyase and AR inhibitor, in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-05.