Vitamin D Analogs for Chemoprevention of Prostate CAncer

描述（由申请人提供）：由于维生素D具有多种抗癌活性，因此已将其作为前列腺癌（CaP）的潜在预防治疗进行了研究。我们在CaP的小鼠前列腺转基因腺癌（TRAMP）模型中证明，用1，25（OH）2D 3的早期治疗防止激素响应性CaP，并且与增殖降低和分化增加相关。TRAMP前列腺对1，25（OH）2D 3处理的体内反应表明调节G2/M转换的细胞周期调节剂减少，并且E-钙粘蛋白（分化标志物）增加。我们已经确定了一种新的相互作用的VDR与一种新的辅阻遏复合物。我们提出了一个模型，在该模型中，VDR辅阻遏物在前列腺癌进展和去势复发性疾病中增加，导致VDR介导的基因转录的抑制。这些变化的生物学后果是维生素D抗癌活性的丧失。因此，通过抑制辅阻遏物可以增强1，25（OH）2D 3的有效性。在目的I中，我们确定了体内1，25（OH）2D 3化学预防活性的分子介质。在目的II中，我们确定的分子机制的VDR介导的转录在CaP细胞逃避1，25（OH）2D 3的化学预防活性，通过检查一个新发现的VDR辅阻遏物的功能。该项目在使用转基因模型来确定维生素D在体内的化学预防作用的作用机制方面具有创新性。在这个提议中，我们详细研究了VDR与一个新发现的VDR辅阻遏复合物的相互作用，以及对维生素D生长抑制和基因转录的影响。我们测试是否抑制辅阻遏物的活性，提高化学预防活性的1，25（OH）2D 3在体内激素反应和去势复发性钙磷。因此，这些研究提供了有价值的临床前数据，使该项目在性质上具有转化性。这些研究的基本原理是，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治疗中获益的患者提供了基础。公共卫生相关性：前列腺癌自然史的渐进性与疾病的长潜伏期、迟发性和患病率相结合，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理解，确定改变细胞维生素D反应的VDR相互作用蛋白表达的变化，并测试旨在提高维生素D化学预防活性有效性的组合疗法。因此，鉴定VDR信号传导轴中的分子变化可用于鉴定将从维生素D治疗中获益最多或最少的男性，鉴定用于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.