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New Strategy for Prostate Cancer Prevention Based on Selenium Suppression of Androgen Receptor Signaling

Abstract : Androgen plays an important role in prostate carcinogenesis. Testosterone is the major androgen in circulation; it is converted to the more potent dihydrotestosterone in the prostate by the enzyme 5 -reductase. The Prostate Cancer Prevention Trial (PCPT) demonstrated that treatment with finasteride, an inhibitor of 5 -reductase, reduced prostate cancer incidence by 25%. Selenium, on the other hand, is shown to reduce prostate cancer risk by 50% by the Nutrition Prevention of Cancer (NPC) trial. In vitro studies have shown that selenium suppresses androgen signaling by downregulating expression of the androgen receptor (AR). This project is consists of two specific aims: 1). To evaluate the combined use of selenium and a 5 -reductase inhibitor in preventing prostate cancer; 2). To investigate the role of FOXO1A in mediating the anticancer effect of selenium. For Aim 1, we originally proposed to use dutasteride, a proprietary drug of GlaxoSmithKlein (GSK), as the 5 -reductase inhibitor. We submitted a research proposal to GSK to request the compound (not funding) after the grant was recommended for funding. However, after much delay, no agreement was reached between Roswell Park and GSK because the company insisted on full ownership of all intellectual properties and research products, even though the study was designed solely by investigators at Roswell Park with no input from GSK. Our Technology Transfer Office felt that we could not possibly accede to this demand. Finasteride, despite being an older drug, has several advantages over dutasteride. First, its efficacy has been proven by a phase III trial, whereas dutasteride is being tested and the result will not be available for a few years. Second, there are minimal side effects with long-term finasteride treatment. No such information is available with dutasteride. Third, finasteride is available commercially from Steraloids (Newport, RI).