Abstract 940: Inhibition of androgen receptor activity in refractory prostate cancer cells by the novel Millennium-Takeda compound T-1759243

Abstract

Abstract Purpose. Prostate cancer (PCa) continues to be a leading cause of cancer death in males worldwide. In the prostate, androgens play a crucial role in both normal and cancerous growth by acting through the androgen receptor (AR), a member of the nuclear receptor super-family; hence, the AR has become a target of therapeutic intervention. The standard treatment for advanced PCa is androgen ablation therapy, initially leading to tumor regression through inhibition of AR activity. However, the success of androgen ablation therapy is often terminated by the emergence of castration- recurrent PCa (CRPC), for which there is still no cure. CRPC remains dependent on a functional AR-axis for proliferation and drugs targeting this network are continually being developed. We have examined the effects of Millennium-Takeda investigational compound T-1759243 on both androgen-responsive and androgen-refractory PCa cells in order to assess its therapeutic potential. Methods. We used PCa cell lines LNCaP, LNCaP-C42 and 22RV1 and assessed effects on cell viability and proliferation using MTS and BrdU assays. AR activity was measured using PSA-luciferase reporter constructs and protein levels by western blot. Microarray analysis with the Illumina HT-12 platform was used to identify genes affected by treatment with T-1759243, followed by real-time PCR confirmation. Pathway analysis was performed using MetaCoreTM software. Results. Our studies have revealed that T-1759243 reduces viability in all cell lines examined, regardless of androgen responsiveness. Treatment resulted in decreased proliferation in androgen-responsive cells and increased apoptosis in refractory cells. AR activity, as measured by PSA-luciferase assay, was greatly decreased in all cell lines by 10uM T-1759243 and T-1759243 abrogated the ability of synthetic androgen R1881 to increase AR activity by inhibiting nuclear translocation of the AR in refractory cells. Pathway analysis revealed changes in genes involved in cell-cycle, cell adhesion and cytoskeletal remodeling in addition to genes in androgen target pathways. Conclusions. T-1759243 is a novel AR antagonist that inhibits AR activity in both androgen-dependent and androgen-refractory prostate cancer cells. Additionally, it inhibits the ability of androgen to promote nuclear translocation of the AR and thus stimulate AR activity in castrate-resistant prostate cancer cells. Pathways affected by treatment with T-1759243 are cell-specific and dependent on AR status and may reveal novel gene targets in PCa treatment. This work was supported in part by Grant #35 from Millennium Pharmaceuticals, Inc the Takeda Oncology Company. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 940. doi:1538-7445.AM2012-940