Targets of Vitamin D Receptor Action in Prostate

描述（由申请人提供） 有证据表明，维生素D受体（VDR）的激活有利于降低前列腺癌的风险，并且VDR激动剂是治疗前列腺癌的潜在治疗剂。 尽管有许多研究表明VDR激动剂抑制前列腺癌细胞生长，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肿瘤中尚未解决。此外，除了证明正常原代前列腺上皮细胞的生长也受到VDR激动剂的抑制（）外，关于VDR在正常前列腺中的作用知之甚少。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学治疗剂至关重要。因此，我们建议确定在正常前列腺和肿瘤细胞中VDR激活引起的变化，并确定哪些变化是生长调节作用的关键。具体目标1：鉴定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。具体目标2：阐明VDR激动剂在正常前列腺上皮细胞和基质细胞中的作用。具体目标3：使用一种新的前列腺椎间盘器官培养模型（PDOC），以确定在细胞培养中发现的变化是否在人体组织中重现。将细胞培养和动物模型的发现转化为人类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肿瘤以及正常前列腺组织对VDR激动剂的反应，如果成功的话，不仅将提供关于VDR激动剂效用的信息，而且将建立一个新的范例，用于在开始临床试验之前测试小分子对人类肿瘤的影响。具体目标4：评估目标1-3中鉴定的候选调控基因对VDR激动剂应答的贡献。这些目标的成功完成不仅将使我们了解VDR激动剂如何有助于降低前列腺发病率和帮助治疗，而且还可能使我们能够开发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.