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

纯化异黄酮治疗前列腺癌的 II 期临床试验：比较 Safet

• 批准号: 7686500
• 负责人: NAGI B. KUMAR
• 金额: $ 26.67万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686500
• 关键词: Address; African American; Aftercare; American; Androgen Receptor; Androgens; Antioxidants; Apoptosis; Apoptotic; Biochemical; Biological; Biological Markers; Biopsy; Blood; Cancer Patient; Caucasians; Caucasoid Race; Cell Cycle Regulation; Cell Death; Cell Proliferation; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Communities; Control Groups; Data; Death Rate; Densitometry; Detection; Diagnosis; Diet Records; Disease; Disease Progression; Dose; Down-Regulation; Effectiveness; Ensure; Epidemiology; Estradiol; Estrogen Receptors; Estrogens; Evaluation; Family history of; Future; Gene Targeting; Genetic; Genetic Markers; Genistein; Genomics; Gleason Grade for Prostate Cancer; Goals; Growth; Human; In Vitro; Incidence; Inherited; Intervention; Isoflavones; Knowledge; Laboratory Study; Length; Liver Function Tests; Long-Term Effects; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Modeling; Molecular; Molecular Target; Monitor; Morbidity - disease rate; N-terminal; Neoplasm Metastasis; Nutrient; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Phosphorylation; Phytoestrogens; Pilot Projects; Placebos; Plasma; Population; Positioning Attribute; Prevention; Preventive; Process; Prostate; Prostate-Specific Antigen; Prostatectomy; Public Health; Questionnaires; Race; Radical Prostatectomy; Randomized; Randomized Controlled Trials; Recruitment Activity; Reporting; Repression; Research; Research Infrastructure; Research Personnel; Risk; Role; Safety; Sampling; Screening procedure; Serum; Signal Transduction; Staging; Supplementation; Surgical Models; Surrogate Markers; Symptoms; Target Populations; Testing; Testosterone; Time; Tissues; Toxic effect; Trust; Tumor Cell Invasion; Tumor Volume; Upper arm; Urologist; Western Blotting; angiogenesis; base; cancer cell; cancer health disparity; carcinogenesis; caucasian American; cohort; compare effectiveness; experience; health disparity; high risk; high risk men; indexing; innovation; lower urinary tract symptoms; men; mortality; non-genomic; novel; pharmacokinetic characteristic; pill; polyglutamine; prevent; progression marker; prostate cancer prevention; prostate carcinogenesis; protein complex; receptor; receptor expression; research clinical testing; research study; safety study; soy; steroid hormone; treatment effect; tumor; tumor progression; tumorigenesis

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.

研究表明，营养素，包括染料木黄酮，一种黄酮类化合物，可以诱导细胞凋亡， 抑制前列腺癌（CaP）的形成和生长。由于这些化合物在结构上和 它们的功能与雌激素相似，被认为是植物雌激素。我们最近证明了雄激素 和雌激素抑制前列腺癌细胞中的FOXO 1活性，这一过程独立于 PKB/AKT介导的FOXO 1磷酸化。抑制分别是AR和ER α依赖性的， 通过受体-FOXO 1蛋白复合物的形成介导。因此，我们的初步数据表明 FOXO 1是CaP细胞中染料木素的新靶点。在最近完成的两个II期试验中，我们观察到， 治疗（40、60、80 mg）显著增加血浆中的孕酮，而不产生毒性。显著 治疗后血清总雌二醇增加，表达Ki-67的前列腺癌细胞百分比降低 基于这些研究，我们假设40 mg纯化的 在术前阶段（从活检到乳房切除术），对男性给予4-6周的异黄酮 将显著增加血浆雌二醇水平和血清雌二醇，导致前列腺标志物减少 癌症进展，如通过验证的CaP进展标志物的变化所指示的，与接受 安慰剂，不产生毒性。我们认为，主要途径，通过它的干扰素将抑制 前列腺肿瘤发生由ERfS介导，ERfS可被前列腺癌细胞中的ER α抑制， ERp下降。此外，染料木黄酮通过下调雄激素受体（AR），抑制雄激素通过FOXO 1的信号传导。 表达，导致细胞凋亡并导致前列腺癌发生的抑制。基于此 通过观察其作用机制，我们推测，前列腺素酮调节前列腺增生的有效性， AA男性的致癌性显著高于高加索男性。为了验证这一假设，我们 具体目标是随机分配和治疗130名AA男性和130名白人男性（n=260; 65/组）， 在术前接受每天40毫克剂量的纯化的马诺酮或安慰剂， 为期4- 6周，并评估依从性、症状、毒性和疾病进展标志物 治疗相关的雄激素受体表达减少和FOXO 1表达增加， 它在前列腺癌患者中的靶基因，以及AR-FOXO轴的变化是否在前列腺癌患者中更深刻， 非裔美国人与白人男性相比。