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

研究表明，营养素，包括染料木素，一种异黄酮类，可以诱导细胞凋亡， 抑制前列腺癌(CAP)的形成和生长。因为这些异黄酮类在结构上和 在功能上类似于雌激素，它们被认为是植物雌激素。我们最近证明了雄激素 雌激素抑制了前列腺癌细胞中FOXO1的活性，这一过程不依赖于 PKB/AKT介导的FOXO1磷酸化。这种压制分别是AR和时代相关的，以及 通过受体-FOXO1蛋白复合体的形成而介导。我们的初步数据表明 FOXO1作为染料木素在帽子细胞中的新靶点。在最近完成的两项第二阶段试验中，我们观察到 治疗(40、60、80毫克)后血浆异黄酮量显著增加，且不产生毒性。意义重大 治疗后血清总雌二醇升高和前列腺癌细胞Ki-67表达降低 在40 mg治疗组中观察到。基于这些研究，我们假设提纯了40毫克 术前(从活检到前列腺切除术)给男性服用异黄酮类药物，为期4-6周 会显著提高血浆异黄酮值和血清雌二醇水平，导致前列腺癌标志物减少 通过验证的CAP进展标志物的变化来指示癌症进展，与接受 安慰剂，不产生毒性。我们认为异黄酮类化合物抑制的主要途径是 前列腺癌的发生是由ERF介导的，ERF可以被前列腺癌细胞中的ERA抑制，从而 事件相关电位降低。此外，染料木素通过下调AR来抑制通过FOXO1传递的雄激素信号 表达，导致细胞凋亡，从而抑制前列腺癌的发生。在此基础上 通过对作用机制的观察，我们推测异黄酮类化合物对前列腺的调节作用 与高加索男性相比，AA男性的致癌率明显更高。为了验证这一假设，我们的 具体目标将是将130名AA男性和130名高加索男性(n=260；65/ARM)随机分组并进行治疗 使用临床定位的CAP接受纯化的异黄酮类药物，每天40毫克或安慰剂，用于术前治疗 为期4-6周，评估依从性、症状、毒性和疾病进展的标志 治疗相关雄激素受体表达减少，FOXO1和FXO1表达增加 它在前列腺癌患者中的靶基因以及AR-FOXO轴的变化是否更深刻 与高加索男性相比，非裔美国人患者。

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 ERp 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.