Vitamin D Analogs for Chemoprevention of Prostate CAncer

描述(申请人提供)：维生素D已被研究为前列腺癌(CAP)的潜在预防疗法，因为它具有许多抗癌活性。我们在转基因小鼠前列腺癌(TRAMP)的CAP模型中证明，早期用1，25(OH)2D3治疗可以阻止激素反应性CAP，并与减少增殖和增加分化有关。前列腺细胞对1，25(OH)2D3处理的体内反应表明，调节G2/M转变的细胞周期调节器减少，而分化标志物E-钙粘附素的表达增加。我们发现了一种新的VDR与一种新的辅阻遏子复合体的相互作用。我们提出了一个模型，在该模型中，VDR辅阻遏子在前列腺癌进展和去势复发疾病中增加，导致VDR介导的基因转录受到抑制。这些变化的生物学后果是维生素D的抗癌活性丧失。因此，1，25(OH)2D3的作用可以通过抑制辅阻遏子来增强。在目的I中，我们确定了体内1，25(OH)2D3化学预防活性的分子介体。在AIM II中，我们通过检测一个新发现的VdR辅阻遏子的功能，确定了CAP细胞中VdR介导的转录失控逃脱1，25(OH)2D3‘S化学预防作用的分子机制。该项目的创新之处在于使用转基因模型来确定维生素D在体内的化学预防作用机制。在这项建议中，我们详细研究了VDR与新发现的VDR辅阻遏子复合体的相互作用，以及对维生素D生长抑制和基因转录的影响。我们测试抑制辅抑制子活性是否改善了1，25(OH)2D3在体内对激素反应和去势复发CAP的化学预防活性。因此，这些研究提供了有价值的临床前数据，使该项目具有转化性。这些研究的理论基础是，在分子水平上了解维生素D化学预防活性的作用机制，为开发改进的治疗方法和确定最有可能/最不可能从维生素D治疗中受益的患者提供基础。公共卫生相关性：前列腺癌自然病史的渐进性，再加上疾病潜伏期长、发病晚和流行的特点，使前列腺癌成为预防策略的主要目标。这些研究的结果将增加我们对维生素D对分化和增殖的化学预防作用的了解，识别VDR相互作用蛋白表达的变化，改变细胞对维生素D的反应，并测试旨在提高维生素D化学预防活性有效性的联合疗法。因此，确定VDR信号轴的分子变化可用于确定谁将从维生素D治疗中受益最多或最少，确定预防和治疗前列腺癌的新治疗靶点，并最终影响前列腺癌的诊断、治疗和管理。

DESCRIPTION (provided by applicant): Vitamin D has been investigated as a potential preventive therapy for prostate cancer (CaP) because of its many anti-cancer activities. We demonstrate in the transgenic adenocarcinoma of mouse prostate (TRAMP) model of CaP that early treatment with 1,25(OH)2D3 prevents hormone responsive CaP and is associated with decreased proliferation and increased differentiation. The in vivo response of TRAMP prostate to 1,25(OH)2D3 treatment indicates a decrease in cell cycle modulators that regulate G2/M transition and n increase in E- Cadherin, a marker of differentiation. We have identified a novel interaction of VDR with a novel corepressor complex. We propose a model in which VDR corepressor increases during prostate cancer progression and in castration recurrent disease, resulting in repression of VDR mediated gene transcription. The biological consequence of these changes is a loss of vitamin D's anti-cancer activity. Therefore, the effectiveness of 1,25(OH)2D3 can be enhanced by inhibiting the corepressor. In Aim I we determine the molecular mediators of 1,25(OH)2D3 chemopreventive activity in vivo. In Aim II we determine the molecular mechanism of deregulated VDR-mediated transcription in CaP cells that escape 1,25(OH)2D3's chemopreventive activity by examine the function of a newly identified VDR corepressor. This project is innovative in the use of a transgenic model to define the mechanism of action of vitamin D's chemopreventive action in vivo. In this proposal we examine in detail VDR interaction with a newly identified VDR corepressor complex and the impact on vitamin D growth inhibition and gene transcription. We test whether inhibition of the corepressor activity improves the chemopreventive activity of 1,25(OH)2D3 in vivo for hormone responsive and castration recurrent CaP. Thus, these studies provide valuable preclinical data making this project translational in nature. The rationale for these studies is that an understanding of the mechanism of action of vitamin D chemopreventive activity at the molecular level provides the basis for developing improved therapeutics and identifying patients most/least likely to benefit from vitamin D therapy. PUBLIC HEALTH RELEVANCE: The progressive nature of the natural history of prostate cancer in combination with the long latency period, late onset and prevalence of the disease make prostate cancer a prime target for preventive strategies. The results from these studies will increase our understanding of the chemopreventive effects of vitamin D on differentiation and proliferation, identify changes in the expression of VDR interacting proteins that alters vitamin D response of the cell, and test a combinational therapy designed to improve the effectiveness of vitamin D's chemopreventive activity. Thereby, identifying molecular changes in the VDR signaling axis that may be used to identify men who would benefit the most or least from vitamin D therapy, identify new therapeutic targets for prevention and treatment of prostate cancer and ultimately impacting diagnosis, treatment and management prostate cancer.