Abstract 319: Expanding the experimental potential of a novelex vivomodel for primary human prostate cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC A major impediment to the discovery of clinically effective prostate cancer therapies is the lack of pre-clinical models that accurately depict human prostate cancer. While studies with cell lines and mouse models have been extremely valuable, the resulting strategies for adjuvant and neoadjuvant interventions have not significantly extended overall survival in the past 50 years, and prostate cancer remains the second deadliest cancer in American men. Progress in testing new therapeutics is limited by cost and toxicity profiles in humans, and current pre-clinical models are limited by inherent cellular, genetic, and physiological deficiencies. To address this problem, we are optimizing, characterizing, and evaluating a novel ex vivo model for primary human prostate cancer called “tissue slice culture” (TSC) that overcomes the deficiencies of current pre-clinical models. Tissue is procured from fresh prostatectomy specimens and 300-μm slices are precision-cut using the Krumdieck microtome. The slices are cultured in a defined system that allows for diffusion of oxygen and nutrients throughout the tissue that, in addition to an optimized medium containing synthetic androgen, is critical for survival in vitro. Our optimized system overcame setbacks common to culture of primary prostate tissue including luminal cell degeneration and basal hyperplasia, and we successfully maintained viability of both normal and cancer tissue up to 5 days in vitro. We verified that TSCs exhibit cellular, genetic, and structural fidelity to the native normal and cancer tissue specimens across different Gleason Grades, supporting its relevance as a realistic model system. Furthermore, TSCs respond to androgen-ablation with reduced proliferation, ductal degeneration, and reduced PSA expression. Regulation of androgen signaling is implicit in prostate pathogenesis, so androgen-dependence is necessary in a model system. Others have suggested that prostate tissue slices accurately predict drug responses in humans, and we purport TSC to be a feasible model for validating findings from cell lines. For example, the natural alkaloid piperlongumine has recently been reported to reduce AR expression and activity specifically in prostate cancer cell lines. TSCs with mixed populations of normal and cancer regions are well suited for evaluating drug specificity, as they provide internal controls. Piperlongumine-treated TSCs showed reduced AR expression and increased cell death specifically in cancer cells, validating the results found in cell lines and encouraging further pre-clinical studies. While various forms of prostate TSC have already been in use, the optimization and characterization described here are necessary steps in maximizing its experimental potential. Citation Format: Sophia L. Maund, Rosalie Nolley, Donna M. Peehl. Expanding the experimental potential of a novel ex vivo model for primary human 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 319. doi:10.1158/1538-7445.AM2013-319