Phase II Clincal Trial of Purified Isofavones in Prostate Cancer: Comparing Safet

University Of South Florida, Tampa FL

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Abstract

Research studies have demonstrated that nutrients, including genistein, an isoflavones, could induce apoptosis, suppress the formation and growth of prostate cancer (CaP). As these isoflavones are structurally and funcrtionally similar to estrogen, they are considered phytoestrogens. We recently demonstrated that androgens and estrogens repressed the FOXO1 activity in prostate cancer cells, a process that is independent of the PKB/AKT-mediated FOXO1 phosphorylation. The repression is AR and ERa-dependent, respectively, and mediated through the formation of receptor-FOXOl protein complex. Our preliminary data thus demonstrates that FOXO1 as a novel target for genistein in CaP cells. In two recently completed phase II trials, we observed significant increases in plasma isoflavones with treatment (40,60, 80 mgs) without producing toxicity. Significant increases in serum total estradiol and lower percentage of prostate cancer cells expressing Ki-67, post treatment were observed in the 40 mgs treatment arm. Based on these studies, we hypothesize that 40 mgs purified isoflavones administered to men in the presurgical period (from biopsy to prostatectomy) for a 4-6 week period will significantly increase plasma isoflavone levels and serum estradiol resulting in decrease in markers of prostate cancer progression as indicated by changes in validated CaP progression markers, compared with men receiving a placebo, without producing toxicity. We propose that the primary pathway by which isoflavones will suppress prostate tumorigenesis is mediated by the ERfS, which can be suppressed by ERa in prostate cancer cells such that ERB is decreased. In addition, genistein will inhibit androgen signaling through FOXO1 by down regulating AR expression, resulting in apoptosis and leading to the suppression of prostate carcinogenesis. Based on this observation of mechanism of action, we hypothesize that the effectiveness of isoflavones to modulate prostate carcinogenesis will be significantly higher in AA men compared to Caucasian men. To test this hypothesis, our specific aims will be to randomize and treat 130 AA men and 130 Caucasian men (n=260;65/arm) diagnosed with clinically localized CaP to receive purified isoflavones at a dose of 40 mgs per day or placebo in the presurgical period for 4-6weeks and evaluate compliance, symptoms, toxicity, and markers of disease progression and treatment-related decrease in expression of the androgen receptor and increased expression of FOXO1 and its target genes in prostate cancer patients and whether the changes in the AR-FOXO axis is more profound in African American patients as compared to Caucasian men.