Abstract 611: Co-targeting the PI3K and androgen receptor signal pathways in castration resistant prostate cancer

Abstract

Abstract PTEN-deficient castration-naïve prostate tumors respond well to PI3K pathway inhibition, however, treatment response is largely ineffective in castration-resistant prostate cancer (CRPC). Reciprocal feedback regulation between the PI3K and androgen receptor (AR) signaling pathways helps maintain survival. We hypothesized that combined PI3K and AR pathway inhibition would improve the therapeutic outcome. Using an in vivo model of prostate cancer, we assessed the rational therapeutic combination of the mTOR inhibitor, everolimus, and the anti-androgen, chlormadinone acetate (CA), in PTEN deficient tumors. Treatment efficacy was examined in conditional PTEN-mutant mice that developed CRPC after surgical castration. Drug efficacy was evaluated by comparing differences in tumor burden, inhibition of tumor cell proliferation and induction of apoptosis. Treatment-specific responses were measured by downstream PI3K signal molecules, nuclear translocation of AR and activation of compensatory signaling pathways. Mice treated with everolimus or CA alone did not show a significant reduction in tumor burden compared to controls, however, the combination of everolimus and CA significantly inhibited tumor burden. Combination therapy also significantly inhibited cellular proliferation and increased apoptosis. PI3K pathway activation was effectively suppressed by everolimus as measured the levels of phosphorylated S6. No significant differences were noted in the nuclear translocation of the AR between control and treatment groups. Mice treated with the combination therapy demonstrated suppression of MAPK pathway activation. Interestingly, all treatments resulted in an increase of STAT3 activation. In summary, our findings show that AR re-challenge can sensitize CRPC to PI3K inhibition. This study provides a rationale for the developing combination therapies for CRPC by co-targeting the AR and PI3K signal transduction pathways. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Co-targeting the PI3K and androgen receptor signal pathways in castration resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 611. doi:10.1158/1538-7445.AM2014-611