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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

基本信息

批准号：
8374882
负责人：
NAGI B. KUMAR
金额：
$ 32.07万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-12 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374882
关键词：
Address African American Aftercare 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 Epidemiologic Studies 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 Proto-Oncogene Proteins c-akt 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 Urologist Western Blotting angiogenesis arm base cancer cell cancer health disparity carcinogenesis 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

项目摘要

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.

研究表明，包括染料木黄酮（Genistein）在内的营养素可以诱导细胞凋亡，抑制前列腺癌（CaP）的形成和生长。由于这些雌激素在结构和功能上与雌激素相似，它们被认为是植物雌激素。我们最近证明，雄激素和雌激素抑制FOXO 1在前列腺癌细胞中的活性，这是一个独立于PKB/AKT介导的FOXO 1磷酸化的过程。该抑制分别是AR和ER α依赖性的，并且通过受体-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作为一个新的目标染料木素在CaP细胞。在最近完成的两项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。在40 mg治疗组中观察到治疗后血清总雌二醇显著增加和表达Ki-67的前列腺癌细胞百分比降低。我们假设在术前给予男性40毫克纯化的异黄酮（从活检到子宫切除术）4- 6周时间将显著增加血浆CaP水平和血清雌二醇，导致前列腺癌进展标志物减少，如经验证的CaP进展标志物的变化所示，与接受安慰剂的男性相比，没有产生毒性。我们认为，前列腺素酮抑制前列腺肿瘤发生的主要途径是由ERfS介导的，ERfS可以被前列腺癌细胞中的ER α抑制， ERB下降了。此外，染料木黄酮将通过下调AR表达来抑制雄激素通过FOXO 1的信号传导，导致细胞凋亡并导致前列腺癌发生的抑制。基于对作用机制的观察，我们假设，与白人男性相比，AA男性中的前列腺素酮调节前列腺癌发生的有效性将显著更高。为了验证这一假设，我们的具体目标将是随机分配和治疗130名AA男性和130名白人男性（n=260; 65/臂）诊断患有临床局部CaP，在手术前接受每天40毫克剂量的纯化异黄酮或安慰剂4- 6周，并评估依从性、症状、毒性，以及疾病进展和治疗相关的雄激素受体表达减少和FOXO 1表达增加的标志物，它在前列腺癌患者中的靶基因，以及与白人男性相比，非洲裔美国人患者中AR-FOXO轴的变化是否更深刻。