) Surrogate endpoints can be useful in phase I/II screening trials for identifying whether a new intervention is biologically active and for guiding decisions about whether the intervention is promising enough to justify a large definitive trial with clinically meaningful outcomes. Based on pre-clinical studies of biologic activity generated in the applicant's laboratory, sodium phenylbutyrate, an aromatic fatty acid, represents a potentially non-toxic, non-retinoid differentiating agent for use in the care of patients with prostate cancer and glioblastoma. To date, the role of differentiation therapy in the advanced, clinically progressing prostate cancer patient has not been defined or appropriately explored. Differentiation therapy lacks the allure of cytoreductive strategies and is likely to provide disease stabilization as a therapeutic endpoint. Given the projected, yet untested, endpoint of differentiation therapy using non-toxic agents, assessment of bioactivity is critical to the advancement and early clinical evaluation of agents such as phenylbutyrate. Two clinical trials evaluating continuous phenylbutyrate exposure, either through thrice daily oral administration (phase I), or by continuous intravenous infusion (phase II), provide the framework to develop, evaluate, and begin the process of validation of surrogate endpoints specific for prostate cancer in response to differentiation therapy. Specifically, the clinical trials will generate safety and toxicity data and efficacy data of phenylbutyrate in patients with prostate cancer. Using patient-derived samples, the laboratory aims to determine the patterns and the importance of cytokine alterations (IL-6, VEGF, ET-1), changes in prostate specific membrane antigen expression (PSMA, PSA), and the induction of cell cycle proteins associated with differentiation or growth arrest (p2lwaf1/cip, cyclin D1) in patients after phenylbutyrate treatment. Harvesting of large numbers of circulating, viable prostate cancer cells will provide the research material needed to assess in vivo inhibition of telomerase activity and effects of phenylbutyrate on cellular metabolism using NMR. These assays and quantitative bone scan imaging will be correlated with plasma phenylbutyrate levels, clinical response, and outcome in treated prostate cancer patients. This research application will provide new and clinically relevant information on differentiation therapy with phenylbutyrate and assessment of its bioactivity in patients with prostate cancer, as well as potentially identify useful surrogate endpoints of response and bioactivity.
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