Modulation of Prostate Cancer Cell Motility by Chemopreventive Agent Genistein

化学预防剂金雀异黄素对前列腺癌细胞运动的调节

• 批准号: 7587126
• 负责人: Raymond C. Bergan
• 金额: $ 21.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587126
• 关键词: Affect; Animal Model; Animals; Biological Assay; Biological Markers; Blood; Blood Circulation; Cancer Patient; Cells; Cessation of life; Chemopreventive Agent; Clinical; Clinical Research; Consumption; Data; Development; Diet; Distant; Dose; Event; Face; Funding; Future; Gelatinase A; Gene Expression; Genes; Genistein; Goals; Heat Shock Protein 27; Human; Implant; In Vitro; Invaded; Investigation; Lead; Link; MAPK14 gene; Malignant neoplasm of prostate; Matrix Metalloproteinases; Measurable; Measures; Modeling; Molecular; Movement; Mus; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Phosphorylation; Placebo Control; Placebos; Process; Proliferating; Prostate; Prostate specific antigen measurement; Prostatectomy; Randomized; Randomized Controlled Clinical Trials; Regulatory Pathway; Reproduction spores; Research Personnel; Sampling; Signal Pathway; Signal Transduction; Site; Specimen; Testing; Tissue Sample; Tissues; cancer cell; cell motility; cellular engineering; design; genetic regulatory protein; high risk; inhibitor/antagonist; man; men; mortality; pre-clinical; prevent; programs; prospective; translational study; tumor progression; tumorigenesis

Genistein is a NCI high priority putative prostate cancer (PCa) chemopreventive agent. Our preliminary studies demonstrate that genistein inhibits PCa cell detachment and invasion, which are initial steps in the metastatic cascade. We hypothesize that genistein will also inhibit PCa metastasis by inhibiting the movement of prostate cancer cells from the prostate gland into the circulation in man. In preliminary in vitro studies, we demonstrated that genistein inhibits activation of the pro-cell-motility signaling p38-HSP27 (heat shock protein 27) pathway, while enhancing activation of the anti-motility ALK-2 signaling pathway. In mice, we have shown that genistein inhibits human PCa cell detachment and metastasis. Our first SPORE trial was a phase I clinical trial, and it defined genistein's pharmacology in PCa patients. Our second SPORE trial was a phase 2 pre-prostatectomy design. It demonstrated that (1) genistein was well tolerated, (2) that it inhibited prostate cell detachment, and (3) that it selectively modulated genes that regulate prostate cell motility. In this proposal, we propose three Aims: 1) To determine whether genistein affects motility associated genes and regulatory proteins in human prostate tissue. Using banked prostate tissue from our second SPORE trial, our studies will determine whether genistein alters the function of relevant regulatory pathways in prostate cells. 2) Evaluate in an animal model whether modulation of pro-cell-motility HSP27 has an impact on genistein's ability to inhibit metastases. Human PCa cells engineered to express altered levels of HSP27 will be orthotopically implanted into mice. We will evaluate their ability to form metastasis, with and without genistein treatment. 3) To conduct a Phase II clinical trial to determine whether genistein inhibits movement of PCa cells from the prostate gland into the circulation in high risk pre-prostatectomy patients. We will implement a third SPORE trial to test this hypothesis. Subjects with clinically-localized, high-risk PCa with measurable circulating prostate cells will be accrued on to a prospective phase 2, randomized trial of genistein versus placebo. The resultant effects of genistein on circulating levels of prostate cells will be assessed by a quantitative RT/PCR assay for PSA.

染料木黄酮是NCI高优先级推定的前列腺癌（PCA）化学预防剂。我们的初步 研究表明，染料木黄酮抑制PCA细胞脱离和侵袭，这是 转移性级联。我们假设染料木黄酮还将通过抑制PCA转移来抑制PCA转移 前列腺癌细胞从前列腺的运动进入人的循环。 在初步的体外研究中，我们证明染料木黄酮抑制了促细胞动力的激活 信号P38-HSP27（热激蛋白27）途径，同时增强了抗动力ALK-2的激活 信号通路。在小鼠中，我们表明染料木黄酮抑制了人类PCA细胞脱离，并且 转移。我们的第一个孢子试验是I期临床试验，它定义 患者。我们的第二次孢子试验是第二阶段前切除术设计。它证明了（1） 染料木黄酮的耐受性良好，（2）它抑制了前列腺细胞脱离，并且（3）有选择地 调节调节前列腺细胞运动的基因。 在此提案中，我们提出了三个目标： 1）确定染料木黄酮是否会影响人类与运动相关的基因和调节蛋白 前列腺组织。使用第二个孢子试验中的排列前列腺组织，我们的研究将确定 染料木黄酮是否会改变前列腺细胞中相关调节途径的功能。 2）在动物模型中评估pro细胞动力HSP27的调节是否对Genastein的影响有影响 抑制转移酶的能力。设计以表达改变HSP27水平的人PCA细胞将是 原位植入小鼠。我们将评估他们在有或没有的情况下形成转移的能力 染料木黄酮治疗。 3）进行II期临床试验，以确定染料木黄酮是否抑制了PCA细胞的运动 前列腺进入高风险前切除术患者的循环腺。我们将实施第三个 孢子试验以检验该假设。具有可测量的临床定位，高风险PCA的受试者 循环前列腺细胞将被纳入前瞻性2期，染料木黄酮与 安慰剂。染料木黄酮对前列腺细胞循环水平的产生影响将通过a评估 PSA的定量RT/PCR分析。