Abstract 1588: Effects of the selective CYP17-lyase and androgen receptor (AR) inhibitor, seviteronel, and the cyclin-dependent kinase (CDK) 4/6 inhibitor, G1T38, on tumor growth in an AR-V7+ castration-resistant prostate cancer (CRPC) xenograft model
Authors: Wardell Suzanne E. , Yllanes Alexander P. , Norris John D. , Stice James P. , White Hannah , Fleming Ronald A. , Strum Jay C. , Moore William R. , McDonnell Donald P. 
Published: July 2017

Background: Castration-resistant prostate cancers that express the constitutively active androgen receptor (AR) variant AR-V7 exhibit significantly reduced progression-free and overall survival in response to the AR targeting agents, enzalutamide (ENZ) and abiraterone. Inhibition of Phosphoinositide-3-Kinase (PIK3CA) or CDK4/6 has been proposed as alternative therapies that directly target the cell cycle pathway in these tumors. However, the combined role of AR plus cell cycle inhibition in this treatment setting has not been established. G1T38 is a potent, selective clinical stage CDK 4/6 inhibitor. Seviteronel (SEVI) is a selective CYP17-lyase and AR inhibitor that blocks the growth of CRPC tumors with clinically relevant AR mutations, including T878A and AR-F876L. The activity of SEVI, ENZ and G1T38, alone or in combination, was evaluated using the 22Rv1 (AR-V7+) CRPC model in vitro and in vivo.

Methods: Cellular proliferation (7 days) of 22Rv1 prostate cancer cells treated with SEVI, ENZ, and G1T38 alone or in combination with SEVI or ENZA was assessed by measuring DNA content. Orchiectomized male nu/nu mice bearing 22Rv1 were randomized to receive vehicle, SEVI (150mg/kg/day p.o.), ENZ (30 mg/kg/day p.o.), G1T38 (25-100 mg/kg/day p.o.), or SEVI or ENZ in combination with G1T38. A docetaxel (20 mg/kg weekly i.p.) group was included as a standard of care comparison. Time to progression (X-fold increase in tumor volume) and tumor volume changes were assessed over a 3-7-week dosing period. Blood and tissues were collected for analysis of exposure and pharmacodynamics markers of response.

Results: SEVI and G1T38 alone or in combination, significantly reduced the proliferation of 22Rv1 cells in vitro (p&lt;0.05). Compared to vehicle, SEVI and G1T38 monotherapy significantly inhibited tumor growth and time to progression by 1.5 and 2.5 fold, respectively (p&lt;0.05); the combination of SEVI and G1T38 further decreased tumor growth and resulted in a 4-fold delay in progression (p&lt;0.001). In contrast, ENZ alone was without effect on tumor growth and did not increase response to G1T38 as compared to G1T38 alone.

Conclusions: SEVI and G1T38 mono- or combination therapy significantly decreased the growth of the AR-V7+ 22Rv1 CPRC model in vitro and in vivo, an activity that distinguishes SEVI from ENZ. Therefore, combining SEVI with a CDK4/6 inhibitor such as G1T38 may be an effective therapy for the treatment of CRPC that is resistant to current standards of care.

Citation Format: Suzanne E. Wardell, Alexander P. Yllanes, John D. Norris, James P. Stice, Hannah White, Ronald A. Fleming, Jay C. Strum, William R. Moore, Donald P. McDonnell. Effects of the selective CYP17-lyase and androgen receptor (AR) inhibitor, seviteronel, and the cyclin-dependent kinase (CDK) 4/6 inhibitor, G1T38, on tumor growth in an AR-V7+ castration-resistant prostate cancer (CRPC) xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1588. doi:10.1158/1538-7445.AM2017-1588