Abstract B107: Characterization of a small molecule selective androgen receptor downregulator: A novel approach for the treatment of castration-resistant prostate cancer.

The androgen receptor (AR), an important molecular target in the aetiology and progression of prostate cancer, has been found recently to drive key signalling responses in castration resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed. Here we describe the biological characterisation of a novel and selective small molecule AR downregulator and propose this mechanism as a potential new approach for the treatment of CRPC. The compound is a derivative of a novel AR binding core with selectivity over other nuclear hormone receptors, and causes a reduction of AR protein in human LNCaP prostate cancer cells in vitro. The reduction in AR protein is observed in steroid depleted serum (CSS) conditions and demonstrates a differential mode of action from a classical AR antagonist (bicalutamide) which has no effect on AR protein expression. This AR downregulation translates into functional activity in vitro and in vivo. In cell viability assays in vitro the compound has activity in cells expressing wild-type (VCaP) and mutated (T877A) AR, but is inactive in AR-negative PC3 and DU145 prostate cancer cells, indicating a dependency on AR for efficacy. We have also observed a reduction in PSA synthesis in vitro, consistent with the inhibition of AR signalling. The compound also reduced AR protein expression, PSA synthesis and cell viability in LNCaP-Casodex™-Resistant and LNCaP-Androgen-Independent cells in vitro. We investigated in vivo activity using the Hershberger castrated rat assay where oral dosing (100mg/kg twice-daily for 7 days) resulted in a significant inhibition of testosterone-induced growth of sexual accessory organs. In summary we describe data supporting our hypothesis that a selective AR downregulator offers a novel approach for delivering therapeutic benefit in CRPC. 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 B107.