Abstract 4557: A novel approach of disrupting androgen-receptor signaling for prostate cancer intervention
Authors: Liu Shuang , Cao Bo , Liu Xichun , Qi Yanfeng , Xiong Zhenggang , Sartor Oliver , Zhang Haitao , Dong Yan 
Published: June 2012

The development of castration-resistant prostate cancer after androgen deprivation therapy remains the major challenge in the treatment of advanced prostate cancer. Current androgen deprivation therapy targets the action of androgen receptor by reducing circulating androgen level through castration or by disrupting the binding of androgens to the receptor with anti-androgen. Despite the initial efficacy of androgen deprivation therapy, relapse with incurable castration-resistant prostate cancer invariably occurs, constituting the major cause of prostate cancer mortality. Although castration-resistant prostate cancer is no longer responsive to androgen deprivation, the expression and signaling of androgen receptor are maintained. Agents such as abiraterone are effective in prolonging survival in patients with castration-resistant prostate cancer, but even this potent and irreversible CYP17 inhibitor has a relatively short time to disease progression in these patients. One potential mechanism is the prevalent upregulation of the constitutively-active, ligand-binding-domain-truncated androgen receptor splice variants, which have been shown to contribute to castration-resistant tumor growth. Thus, developing effective strategies attacking the androgen receptor itself to reduce its availability is urgently needed in the battle against prostate cancer recurrence during androgen deprivation therapy. Our data show that two potent second-generation selenium-containing drugs, methylseleninic acid (MSA) and methylselenocysteine (MSC), are very effective in decreasing the abundance of both the full-length and the truncated androgen receptor. They not only enhance the efficacy of anti-androgen in both androgen-dependent and castration-resistant prostate cancer cells, but also inhibit prostate tumor relapse after castration in a xenograft model. Our results also show that combination of these agents with anti-androgen produces a robust downregulation of an androgen receptor target, telomerase and its catalytic subunit, telomere reverse transcriptase (hTERT). The combination efficacy is significantly mitigated when hTERT/telomerase expression is restored. In addition, their inhibition of prostate tumor relapse after castration is also accompanied by a pronounced decrease of hTERT. The importance of the findings on hTERT/telomerase lies not only in its key role in regulating cell growth and survival, but also in the association of high hTERT expression with biochemical recurrence in prostate cancer patients undergoing radical prostatectomy and neoadjuvant androgen deprivation therapy. Taken together, our findings provide strong justification and lay the groundwork for an effective therapeutic modality that capitalizes on a new approach of disrupting androgen-receptor-mediated growth response important for the development of castration resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4557. doi:10.1158/1538-7445.AM2011-4557