Abstract CN08-05: A combinatorial approach to targeting androgen receptor signaling in prostate cancer.

Abstract

Abstract When androgen deprivation therapy (ADT) for prostate cancer fails and the disease progresses to a castrate-resistant state (castrate-resistant prostate cancer; CRPC), therapeutic options for patients are limited. It is now recognized that the majority of CRPC still express the androgen receptor (AR) and remain dependent on AR signaling for growth and survival. To limit growth or evolution of AR-dependent disease and thereby improve patient survival, we propose that a treatment strategy that simultaneously targets multiple features of the AR signaling axis will more effectively eliminate AR-dependent prostate cancer cells than single agent treatment strategies. We have shown that pharmacologically low doses of an AR antagonist (bicalutamide) in combination with either a heat shock protein 90 inhibitor (Hsp90i; 17-AAG) or a histone deacetylase inhibitor (vorinostat), results in synergistic growth suppression and induction of caspase-dependent death in AR-dependent prostate cancer cells. These drug combinations did not alter steady state protein levels of the AR, but suppressed AR activity, as evidenced by reduced prostate specific antigen levels. As expected, the drug combinations were not effective in androgen-independent, AR negative prostate cancer cells. To elucidate the mechanisms of drug synergy, we performed microarray studies to identify genetic programs modulated by each combination therapy or bicalutamide alone. Resultant data suggest that the combination treatments did not markedly enhance abrogation of androgen signaling compared with bicalutamide alone. Rather, the combination treatments regulated the expression of unique gene sets that were enriched for cell cycle, apoptosis, MAPK and insulin signaling compared to individual agents. To assess the potential efficacy of the combinatorial approach in human disease, we have developed a unique approach to study human prostate cancer where tumor specimens collected from men undergoing radical prostatectomy are cultured as explants for up to 7 days with maintenance of tissue integrity, cell proliferation and androgen signaling. Using this ex vivo strategy, we demonstrated that human prostate tumor tissue responds to the novel synthetic Hsp90 inhibitors (HSP990 and AUY922) with a marked reduction in proliferation and AR levels. Importantly, these studies have revealed a dissociation between client protein modulation (i.e. the established clinical biomarker of Hsp90 inhibition, HSP70) and proliferative response to Hsp90 inhibition, which was not seen in prostate cancer cell lines in vitro. Collectively, these findings suggest that the ex vivo methodology may better predict individual patient response to Hsp90 inhibitors and could be useful as a pre-clinical model of drug development, including identification of robust biomarkers of response. Currently we are using human tumor explants to identify optimal combinations of AR-targeting agents and potential markers of response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN08-05.