Abstract C89: Galeterone suppresses castration-resistant and enzalutamide-resistant prostate cancer growth in vitro.

Background: Despite the progress and innovation in chemo- and immunotherapies, androgen deprivation therapy remains the standard treatment of metastatic prostate cancer. However, progression to castrate resistance disease (CRPC) occurs in the majority of patients and intriguingly, over 80% of CRPC specimens continue to express androgen receptor (AR) and androgen-responsive genes, indicating that the AR axis remains paradoxically activated despite castration. Hence, several new classes of AR-targeting agents have been recently introduced into clinic, including more potent AR antagonists (enzalutamide). Despite the substantial clinical efficacy reported with Enzalutamide, resistance to this therapy has already been observed and reactivation of AR signaling following treatment occurs. Thus, the next major clinical challenge that we will face is identifying new therapies that prevent or treat anti-androgen resistance. Galeterone is a novel drug that exhibits three mechanisms of action to inhibit AR activity, via inhibition of de novo androgen synthesis, blocking the ligand binding domain to prevent androgen binding, and inducing AR degradation. Thus, in this study we evaluated the efficacy of this multi-potent drug to inhibit AR activity in enzalutamide resistant cells. Results: As a pre-clinical model of enzalutamide resistance, drug resistant and CRPC cell lines were derived from three generations of serially passaged enzalutamide resistant, or vehicle control treated, LNCaP xenografts. Resistant cells were maintained in vitro under constant exposure to 10 μM of enzalutamide and were used to study the anti-cancer and AR targeting effects of galeterone in the enzalutamide resistant setting. Using crystal violet and MTT assays, we found that galeterone had anti-proliferative effects in LNCaP cells, in CRPC cells, and most importantly, in those resistant to enzalutamide. Compared to enzalutamide treatment, galeterone induced a drastic decrease in Probasin luciferase reporter (AR) activity, a greater reduction in AR and prostate-specific antigen (PSA) protein expression, and the inhibition of AR nuclear translocation in all cell lines. Strikingly, these effects were still observed in resistant cells, which show no decrease in AR expression or nuclear translocation upon enzalutmide treatment. Together, our data show that galeterone strongly inhibits AR activity and suppresses castration-resistant LNCaP growth as well as enzalutamide -resistant cell growth in vitro. Conclusion: In this study, we provide a preclinical proof-of-principle that Galeterone is a potent inhibitor of the AR pathway and may represent the next generation of hormone therapy for patients with not only CRPC but also Enzalutamide resistant disease. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C89. Citation Format: Nader Al Nakouzi, Chris Wang, Douglas Jacoby, Martin E. Gleave, Amina Zoubeidi. Galeterone suppresses castration-resistant and enzalutamide-resistant prostate cancer growth in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C89.