Background: Prostate cancer (PCa) is the most prevalent cancer in men in the United States. Prostate cancer patients that progress to a lethal phenotype are currently treated with chemotherapy, second generation androgen therapies and immunotherapy. Unfortunately, patient response is not often durable; therefore novel treatments are urgently needed. Histone deacetylases (HDACs) have shown to be up-regulated in PCa. Preclinical data indicates that HDAC inhibitors induce apoptosis in androgen receptor (AR)-positive cells. Unfortunately, HDACi display minimal clinical benefit. From this, we propose that combination of HDACi with novel targeted therapies will result in greater therapeutic efficacy. Methods: PC3, PC3AR and PtenCaP8 PCa cell lines treated with panobinostat (HDACi) and BEZ235 (PI3K-mTORC1 inhibitor) as single treatment or in combination for 48 hours. Cell death/apoptosis was assessed by loss of cell membrane integrity, phosphotidylserine exposure, cell cycle and caspase activation by flow cytometry. Expression levels of activated AKT were assessed by immunoblot. Results: Panobinostat induces cell death/apoptosis greater in PC3AR than parental PC3 cells by increasing subG1 population (47.8±9.3 vs. 11.1±2.8,), phosphotidylserine exposeure (41.4±3.0 vs. 21±7.2,) and caspase activation (57.3±0.9 vs. 12.0 ±4.1,) respectively. Moreover, PC3AR cells treated with panobinostat results in loss of AKT activation, but not in PC3 cells. Further, combination of panobinostat with BEZ235 increases greater cell apoptosis in PC3AR cells compared to panobinostat single agent (30.6±1.9 vs. 19.9±1.4) and in PtenCaP8 cells (42.0±6.5 vs. 29.4±2.2). Western blotting also shows that combination treatment leads to loss of AKT activation compared to panobinostat and BEZ235 as a single agent. Conclusions: Overall, our results suggest that inhibition of HDACs induces greater cell death associated with loss of AKT activation in AR-positive cells, but not in AR-null cells. Also, combination of HDAC inhibitor and PI3K-mTORC1 inhibitor has more effective cell cytotoxicity compared to single agent, suggesting that inhibition of HDACs and PI3K-mTORC1 will exhibit greater therapeutic efficacy. In future work, combination of panobinostat with BEZ235 will be investigated in preclinical animal models to propose this therapy combination for clinical trials in patients with lethal PCa.

Citation Format: Sheng-Yu Ku, Roberto Pili, Leigh Ellis. Concomitant HDAC and PI3K-AKT pathway inhibition as a new therapeutic strategy for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1008. doi:10.1158/1538-7445.AM2013-1008