Abstract A262: Antiandrogen modulation of prostate-specific membrane antigen (PSMA): Dynamics and synergy with PSMA-targeted therapy.

Abstract

Abstract Introduction: Recent approvals of new prostate cancer (PCa) drugs and a growing number of pipeline agents have created opportunities for designing rational drug combinations. Potent antiandrogens such as enzalutamide and abiraterone affect expression of numerous androgen-regulated molecules, including PSMA, a well-characterized cell-surface target for PCa therapy. Methods: Cytotoxicity and the kinetics of antigen expression were evaluated in PCa cell lines (LNCaP, C4-2 and 22Rv1) that vary according to androgen dependence and level of PSMA expression. Expression of PSMA and prostate-specific antigen (PSA) was evaluated over time in cells cultured in enzalutamide or abiraterone. Reversibility was examined following drug washout. Cells were tested for susceptibility to antiandrogens used alone and in combination with PSMA ADC, which is a fully human PSMA monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE). Potential drug synergy or antagonism was evaluated using the Combination Index and Bliss independence methods. Results: In androgen-dependent LNCaP cells, enzalutamide and abiraterone exerted antiproliferative effects that were accompanied by a 2- to 3-fold increase in PSMA expression and a decrease in PSA expression. PSMA expression reached maximum levels after four weeks’ culture in enzalutamide and returned to baseline levels within days following enzalutamide removal. In androgen-independent C4-2 cells, enzalutamide and abiraterone increased PSMA expression in the absence of any significant anti-proliferative effect. PSMA ADC exhibited synergistic antitumor activity with both enzalutamide and abiraterone in LNCaP and C4-2 cells. Lesser effects were observed using 22Rv1 cells, an androgen-independent cell line with low basal expression of PSMA. Conclusions: Enzalutamide and abiraterone significantly and reversibly augmented PSMA expression and potentiated the activity of PSMA ADC in androgen-dependent and -independent PCa cell lines in vitro. In androgen-independent cells, the effects on PSMA expression and PSMA ADC activity were uncoupled from any anti-proliferative effect of the antiandrogens. The findings support clinical exploration of regimens that combine potent antiandrogens and PSMA-targeted therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A262. Citation Format: Jose D. Murga, Wells W. Magargal, Sameer M. Moorji, Vincent A. DiPippo, William C. Olson. Antiandrogen modulation of prostate-specific membrane antigen (PSMA): Dynamics and synergy with PSMA-targeted therapy. [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 A262.