Abstract C16: Targeting AR in castration-resistant prostate cancer: Development of ARN-509 and second-generation antiandrogen resistance models
Authors: Joseph James D. , Aparicio Anna , Kaufman Josh , Julien Jackie , Bonnefous Celine , Smith Nicholas D. , Rix Peter , Jung Michael E. , Sawyers Charles L. , Heyman Richard A. , Hager Jeffrey H. , Clegg Nicola J. , Sensintaffar John , Lu Nhin , Grillot Kate , Bischoff Eric , Shao Gang , Qian Jing , Darimont Beatrice 
Published: May 2013

Abstract
The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Recent studies demonstrate that AR remains essential in the majority of castration resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed. The clinical efficacies of MDV3100 and abiraterone acetate, both of which target the AR pathway in the castrate resistant setting, support these findings. ARN-509 is a 2nd generation competitive AR antagonist that, unlike bicalutamide, maintains full antagonist activity in preclinical CRPC models. ARN-509 does not robustly induce AR nuclear localization or DNA binding. However, ARN-509 displays maximal efficacy in the LNCaP/AR xenograft model of CRPC at lower dose and steady state plasma concentrations compared to MDV3100, suggesting potential for higher therapeutic index and ability to deliver the maximally efficacious dose in man. To date, ARN-509 has shown promising antitumor activity in mCRPC patients enrolled in a Phase 1 study. Given that approximately 50% of CRPC patients have suboptimal response to MDV3100 and abiraterone acetate as well as the observation that resistance eventually develops in patients who initially respond to therapy, we sought to determine whether AR remains a viable therapeutic target in the MDV3100 and ARN-509 resistant setting. To this end, we generated several MDV3100 and ARN-509 resistant derivatives of the LNCaP and LNCaP/AR cell lines. While work is underway to determine the molecular mechanisms of resistance, a subset of cell lines does not require androgens for growth in vitro. These androgen independent derivatives express AR at levels comparable to LNCaP/AR (approximately 3X LNCaP) or 2-3 fold LNCaP-AR. When representative lines are injected into castrated mice, they demonstrate a decreased latency of tumor formation compared to the parental cell line both in the presence and absence of ARN-509. Importantly, in all lines tested, small interfering RNA mediated reduction in AR levels dramatically impaired the ability of the androgen independent resistant cell lines to proliferate in the absence of androgens. These data support the hypothesis that AR remains a viable therapeutic target for second generation anti-androgen resistant prostate cancer and is the first step toward establishing a platform to screen for next generation anti-androgens.
Citation Format: James D. Joseph, Anna Aparicio, Josh Kaufman, Jackie Julien, Celine Bonnefous, Nicholas D. Smith, Peter Rix, Michael E. Jung, Charles L. Sawyers, Richard A. Heyman, Jeffrey H. Hager, Nicola J. Clegg, John Sensintaffar, Nhin Lu, Kate Grillot, Eric Bischoff, Gang Shao, Jing Qian, Beatrice Darimont. Targeting AR in castration-resistant prostate cancer: Development of ARN-509 and second-generation antiandrogen resistance models [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C16.