Targets of Vitamin D Receptor Action in Prostate

描述(由申请人提供) 有证据表明，激活维生素D受体(VDR)有助于降低前列腺癌的风险，VDR激动剂是治疗前列腺癌的潜在治疗药物。虽然有许多研究表明VDR激动剂抑制前列腺癌细胞的生长，但产生这种反应的VDR靶点在很大程度上是未知的。在癌细胞系中观察到的变化是否也会发生在前列腺癌中，尚未得到解决。此外，除了有证据表明VDR激动剂也抑制正常原代前列腺上皮细胞的生长()外，关于VDR在正常前列腺中的作用还知之甚少。更好地了解VDR在正常和恶性前列腺细胞中的作用，对于评估VDR激动剂作为潜在的化学预防和化疗药物至关重要。因此，我们建议确定VDR激活在正常前列腺和肿瘤细胞中所引起的变化，并确定哪些变化对生长调节作用至关重要。为了实现这些目标，我们将：具体目标1：确定LNCaP和LAPC-4前列腺癌细胞中受VDR激动剂调控的基因，并确定这些基因是否也在肿瘤中受到调控。具体目的2：阐明VDR激动剂在正常前列腺上皮细胞和间质细胞中的作用。具体目标3：使用一种新的前列腺盘器官培养模型(PDOC)，以确定在细胞培养中发现的变化是否在人类组织中重现。将细胞培养和动物模型的研究成果转化为人体研究的主要限制之一是临床试验的复杂性和费用。我们提出了一种新的方法来测试人类前列腺癌以及正常前列腺组织对VDR激动剂的反应，如果成功，不仅将提供关于VDR激动剂的效用的信息，而且将在开始临床试验之前建立一个新的范式来测试小分子对人类肿瘤的影响。具体目标4：评估AIMS 1-3中确定的候选调控基因对VDR激动剂反应的贡献。成功完成这些目标不仅将使我们了解VDR激动剂如何有助于减少前列腺癌的发病率和帮助治疗，而且还可能使我们能够开发出预测哪些患者对治疗有反应的方法。

DESCRIPTION (provided by applicant) There is evidence both that activation of the vitamin D receptor (VDR) is beneficial in reducing the risk of prostate cancer and that VDR agonists are potential therapeutic agents in the treatment of prostate cancer. Although there are numerous studies showing that VDR agonists inhibit prostate cancer cell growth, the VDR targets that produce this response are, for the most part, unknown. Whether the changes observed in cancer cell lines will also occur in prostate tumors has not been addressed. Moreover, other than a demonstration that the growth of normal primary prostatic epithelial cells is also inhibited by VDR agonists (), little is known regarding the role of VDR in normal prostate. A better understanding of VDR action in normal and malignant prostate cells is critical to evaluating VDR agonists as potential chemopreventive and chemotherapeutic agents. Thus, we propose to identify the changes induced by activation of VDR in normal prostate and in tumor cells and to determine which of the changes are critical for the growth regulatory actions. To accomplish these goals, we will: Specific Aim 1: To identify genes regulated by VDR agonists in both LNCaP and LAPC-4 prostate cancer cells and to determine whether these genes are also regulated in tumors. Specific Aim 2: To elucidate the actions of VDR agonists in normal prostate epithelial and stromal cells. Specific Aim 3: Using a novel prostate disc organ culture model (PDOC), to determine whether the changes identified in cell culture are recapitulated in human tissues. One of the major limitations in translating findings from cell culture and animal models to human studies is the complexity and expense of a clinical trial. We propose a novel method to test the response of human prostate tumors as well as normal prostate tissue to VDR agonists that, if successful, will not only provide information regarding the utility of VDR agonists, but will establish a new paradigm for testing the effects of small molecules on human tumors prior to embarking on a clinical trial. Specific Aim 4: To assess the contribution of candidate regulated genes identified in aims 1-3, to the response to VDR agonist. Successful completion of these aims will not only lead to an understanding of how VDR agonists can contribute to reducing prostate incidence and aid in treatment, but may also allow us to develop methods to predict which patients will respond to treatment.