Abstract P6-12-06: Nonsteroidal, tissue selective androgen receptor modulator (SARM), enobosarm, reduces growth of androgen receptor-positive breast cancer in patient-derived preclinical models
Authors: Narayanan R , Ponnusamy S , Fan M , Yang CH , Grimes BL , Fleming MD , Pritchard EF , Berry MP , Oswaks RM , Fine RE , Loiseau J-C , Schwartzberg LS , Pfeffer LM 
Published: March 2017

Introduction: In breast cancer the androgen receptor (AR) is the most abundantly expressed steroid receptor with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing the AR. Historically, advanced breast cancer has been treated with androgens, resulting in significant clinical response. However, the use of steroidal androgens fell from favor as a result of their virilizing side effects. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) will provide a novel targeted approach to exploit the therapeutic benefits of androgens in breast cancer.

Aims: To test the effects of enobosarm (a first-in-class SARM) and enzalutamide (AR antagonist) on the growth of patient-derived breast cancer xenografts (PDX) and to discern the mechanism of action of AR-targeted therapies in AR-positive breast cancer.

Materials and Methods: AR-positive PDXs with varying receptor expression (ER, progesterone receptor (PR), and HER2) were implanted in immunecompromised mice. Mice carrying PDXs were treated with vehicle, 10 mg/kg/day (mpk) enobosarm (GTx, Inc., Memphis, TN), or 20 mpk enzalutamide (Medivation Inc.), orally. Tumor volume was measured twice or thrice weekly. Tumors that received enobosarm were further analyzed to determine the mechanism of action.

Results: Enobosarm significantly (p&lt;0.01) inhibited the growth of ER-, PR-, and HER2- positive HCI-7 and ER- and PR- negative and HER2-positive HCI-12 PDX. While enobosarm inhibited the growth of HCI-12 by ~80% and HCI-7 by ~60%, enzalutamide failed to inhibit the growth of the HCI-7 PDX. In contrast, neither enobosarm nor enzalutamide inhibited the growth of ER- and PR-negative and HER2-positive HCI-9 PDX, consistent with the heterogeneity of AR-positive breast cancers. Growth of two triple-negative breast cancer (TNBC) PDXs were inhibited by 30-40% by enobosarm, but not by enzalutamide. These results were reproduced in xenografts developed with breast cancer cell lines, MCF-7 and MDA-MB-231 expressing the AR. Gene expression studies conducted with the HCI-12 tumors indicated that enobosarm inhibited the expression of various proliferative genes (MUC2, IL10RA, IGSF1, SLC6A4, and others) and increased the expression of growth inhibitory genes (CYP4F8, MYBPC1, and others). Ingenuity pathway analysis demonstrated that enobosarm inhibited genes that are downstream of HER2 signaling. Interestingly, miR-21-3p, which has been implicated in chemo-resistance, was consistently expressed at approximately 10-50-fold higher than miR-21-5p in PDXs. This imbalance was partially reversed by enobosarm.

Conclusion: These results indicate that AR-positive breast cancers are highly heterogeneous and that enobosarm has promise as novel targeted therapy to treat AR-positive breast cancer. Enobosarm is currently in phase II clinical trial in both ER-positive breast cancer and in TNBC patients.

Citation Format: Narayanan R, Ponnusamy S, Fan M, Yang CH, Grimes BL, Fleming MD, Pritchard EF, Berry MP, Oswaks RM, Fine RE, Loiseau J-C, Schwartzberg LS, Pfeffer LM. Nonsteroidal, tissue selective androgen receptor modulator (SARM), enobosarm, reduces growth of androgen receptor-positive breast cancer in patient-derived preclinical models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-06.