1214

Androgen suppression has been the central theme in the treatment of recurrent prostate cancer for many decades, yet virtually no patients are cured by this means. Prostate cancer progresses from androgen-dependent tumors that respond favorably to androgen ablation to androgen-independent metastatic tumors that are invariablyfatal. Recent data indicate that androgen receptor signaling is active in androgen independent prostate cancer which indicates that the means currently used to achieve androgen ablation are insufficient to suppress all androgen receptor-mediated signaling. The factors that facilitate growth of androgen independent prostate cancer are many, one of which may be the presence of adrenal androgens following classical androgen ablation. The objective of this study was to determine if a compound capable of inhibiting prostate cancer cell growth could be identified from a proprietary steroid library developed around the structure of the adrenal hormone 5-androstenediol (AED). Using an in vitro proliferation assay, HE3235, a chemically-modified androstane that exhibits potent inhibition of LNCaP cell growth was identified. Our results showed that HE3235 inhibits growth of LNCaP cells in the presence and absence of DHT and/or AED. Flow cytometry results indicate that treatment with HE3235 stimulates apoptosis and alters cell cycle as demonstrated by increases in number of PI positive cells and cells in G1 phase respectively. Interestingly, HE3235 stimulated androgen receptor-mediated transcriptional activity as determined by a reporter assay and increased levels of PSA in conditioned media of treated LNCaP cells. The in vivo activity of HE3235 was also investigated using LNCaP and LuCaP 35V prostate cancer xenografts. HE3235 inhibited initiation of LNCaP tumor growth in a dose dependent fashion and the growth of existing LNCaP tumors in castrated SCID mice supplemented with AED. Growth of androgen independent LuCaP 35V in castrated male SCID mice was also significantly inhibited by administration of HE3235. In conclusion, our results demonstrate that HE3235 significantly inhibits growth of androgen-independent prostate cancer. Additional experiments are ongoing to investigate the mechanisms of action of this compound.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA