P-4: Modulation of Prostate CA Cell Motility by Chemopreventive Agt Genistein

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细胞的脱离和侵袭，这是PCa细胞凋亡的初始步骤。 转移级联反应我们假设染料木黄酮也会通过抑制前列腺癌细胞的增殖来抑制前列腺癌的转移。 前列腺癌细胞从前列腺进入人体循环的运动。 在初步的体外研究中，我们证明了染料木黄酮抑制促细胞运动的激活， 信号传导p38-HSP 27（热休克蛋白27）通路，同时增强抗运动性ALK-2的激活 信号通路在小鼠中，我们已经证明染料木黄酮抑制人前列腺癌细胞脱离， 转移我们的第一个SPORE试验是一个I期临床试验，它定义了染料木黄酮在PCa中的药理学作用。 患者我们的第二项SPORE试验是2期前列腺切除术前设计。结果表明：（1） 染料木黄酮耐受性良好，（2）它抑制前列腺细胞脱落，（3）它选择性地 调节前列腺细胞运动的基因。 在这份提案中，我们提出了三个目标： 1)目的探讨染料木黄酮对人运动相关基因和调节蛋白的影响。 前列腺组织使用我们第二次SPORE试验的前列腺组织库，我们的研究将确定 染料木黄酮是否改变前列腺细胞中相关调节途径的功能。 2)在动物模型中评估促细胞运动性HSP 27的调节是否对染料木素的 抑制转移的能力。人类前列腺癌细胞工程化表达改变水平的热休克蛋白27将是 原位植入小鼠体内。我们将评估他们形成转移的能力，有和没有 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PCa细胞从 前列腺切除术前高危患者的前列腺进入循环。我们将实施第三个 SPORE试验来验证这一假设。患有临床局限性高风险PCa且可测量 循环前列腺细胞将累积到一个前瞻性的2期随机试验中， 安慰剂染料木黄酮对前列腺细胞循环水平的最终作用将通过以下方法评估： PSA的定量RT/PCR测定。

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.