Abstract 4731: Targeted therapies for prostate cancer: Strategies for efficient combinatorial approaches

Abstract

Abstract Metastasis-associated protein 1(MTA1) is a cancer progression- related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). MTA1/HDAC unit is a part of the multi-protein nucleosome remodeling and deacetylation (NuRD) complex. In our previous studies we found that MTA1 expression is significantly increased in prostate-specific Pten-null model, and that potent natural analog of resveratrol, pterostilbene (PTER), exerts its anti-tumorigenic effects by blocking MTA1-associated inactivation (deacetylation) of tumor suppressors. SAHA (suberoylanilide hydroxamine, vorinostat) is a histone deacetylase (HDAC) inhibitor that has been shown to be an effective inhibitor of tumor cell growth. We hypothesize that targeting MTA1/HDAC unit of NuRD complex using PTER in combination with SAHA could act additively or synergistically to block prostate tumor progression in vivo with higher efficacy and lower toxicity. In the current study, we utilized the prostate-specific Pten-null mouse model to evaluate the MTA1/HDAC mediated anti-cancer efficacy of combinatorial approach for dietary PTER and clinically approved HDAC inhibitor, SAHA. After a series of carefully designed breeding strategies and genotyping, we collected 30 prostate-specific luciferase expressing Pten knockout (Pten f/f; Rosa26Luc/+; Pb-Cre4) male mice for our experiments. Prostate-specific luciferase expression allowed non-invasive monitoring of prostate tumor growth in these animals. Mice were randomized into four groups: Vehicle control (10% DMSO); PTER (10 mg/kg bw) alone, SAHA (50 mg/kg bw) alone, and PTER + SAHA. Compounds were injected daily, i.p., starting at 8 weeks of age. Mice were sacrificed at week 18. Histopathological (H&E, SMA, CK-8), immunohistochemical (Ki-67, cleaved caspase-3, CD31) and molecular evaluation (MTA1, pAkt, AR) of prostate tissues showed beneficial effects of treatments alone and more so in combination compared to the control group. Citation Format: Nasir A. Butt, Swati Dhar, Avinash Kumar, Agnes M. Rimando, Xu Zhang, Anait S. Levenson. Targeted therapies for prostate cancer: Strategies for efficient combinatorial approaches. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4731.