The Development of Vitamin D as a Therapy for Breast Cancer

描述（由申请人提供）： 骨化三醇是维生素D的代谢活性形式，具有众所周知的抗癌活性。我们最近确定了四种新的途径，额外的骨化三醇行动，抑制乳腺癌（BCa）的生长。首先，骨化三醇直接抑制BCa细胞中芳香化酶的表达。通过减少局部雌激素合成，这种作用降低了雌激素受体（ER）阳性BCa细胞的主要生长刺激因子。重要的是，骨化三醇表现出芳香酶的组织特异性调节，导致BCa的下调和骨的上调。这种作用将保护骨免受骨质疏松症的不利副作用，骨质疏松症是由于芳香化酶抑制剂（AI）治疗患者中常见的雌激素缺乏引起的。其次，骨化三醇通过多种作用抑制前列腺素（PG）的合成，包括抑制考克斯-2的表达。由于PG是BCa生长的主要刺激物，它们的抑制增加了骨化三醇治疗的有效性。第三，PG是BCa中芳香化酶的主要刺激物，并且骨化三醇对PG的抑制也间接降低芳香化酶表达。第四，骨化三醇直接下调ER 1表达。因此，骨化三醇通过多种途径起作用以减弱BCa生长。我们假设骨化三醇与AI的联合治疗将使AI更有效且剂量更低，从而增加疗效，并具有减少骨质疏松症的潜在额外益处。目标：我们建议研究骨化三醇作用的这四种途径，并研究骨化三醇与AI联合治疗的价值，使药物比单独使用任何一种药物更有效。这些研究将迅速为BCa患者的联合治疗临床试验铺平道路。具体目的：目的我将检查骨化三醇调节芳香化酶和PG途径基因和对BCa细胞生长的影响。目的二研究芳香化酶的差异调节机制。目的III将研究骨化三醇下调ER 1的机制，目的IV将在异种移植小鼠模型中研究骨化三醇、AI及其组合。研究设计：将在培养物中评价建立的BCa细胞系和原代BCa细胞中骨化三醇对芳香酶和PG途径基因的影响。骨化三醇抑制这些途径的作用将包括测量关键基因和下游生物反应。机制研究将解决BCa和骨细胞中芳香化酶启动子的差异调节。将单独和联合评估骨化三醇和AI的作用。所有这些方面也将在裸鼠中BCa异种移植物的体内模型中进行检查。潜在获益：拟定研究将评价骨化三醇、AI和联合治疗BCa患者的效果。骨化三醇和AI是批准的药物，口服活性，安全和适度的成本。将这些组合推进临床试验以治疗和/或预防BCa的进展可能很快。 我们假设骨化三醇加AI将显示出增强的活性，以防止BCa的生长和进展。我们相信，这项研究产生的数据将为支持骨化三醇-AI联合治疗BCa的临床试验的快速发展铺平道路。该策略将为BCa患者的常规治疗方案提供安全且经济的改进。项目叙述 我们假设骨化三醇加AI将显示出增强的活性，以防止生长， BCa的进展我们相信这项研究产生的数据将为支持 骨化三醇-AI联合治疗在临床试验中的快速进展， BCa。这种策略将提供一种安全和经济的改进，以通常的治疗方法， 给BCa患者施用的方案。

DESCRIPTION (provided by applicant): Calcitriol, the hormonally active form of vitamin D, has well known anti-cancer activity. We have recently identified four novel pathways of additional calcitriol action that inhibit breast cancer (BCa) growth. First, calcitriol directly inhibits aromatase expression in BCa cells. By reducing local estrogen synthesis, this action decreases the major growth stimulator of estrogen receptor (ER) positive BCa cells. Importantly, calcitriol exhibits tissue specific regulation of aromatase resulting in down-regulation in BCa and up-regulation in bone. This action would protect bone from the untoward side effect of osteoporosis due to estrogen deprivation routinely seen in aromatase inhibitor (AI) treated patients. Second, calcitriol inhibits prostaglandin (PG) synthesis by multiple actions including suppression of COX-2 expression. Since PGs are major stimulators of BCa growth, their inhibition adds to the effectiveness of calcitriol therapy. Third, PGs are major stimulators of aromatase in BCa and calcitriol's inhibition of PGs also indirectly reduces aromatase expression. Fourth, calcitriol directly down-regulates ER1 expression. Thus calcitriol acts by multiple pathways to attenuate BCa growth. We postulate that combination therapy of calcitriol with an AI will make AIs more effective and at lower doses thus increasing efficacy with a potential additional benefit of reduced osteoporosis. Objective: We propose to study these four pathways of calcitriol action and investigate the value of combination therapy of calcitriol with AIs to render the drugs more effective than either drug alone. These studies will rapidly pave the way to clinical trials of combination therapy in BCa patients. Specific Aims: Aim I will examine calcitriol regulation of aromatase and PG pathway genes and the effect on BCa cell growth. Aim II will study the mechanism for the differential regulation of aromatase. Aim III will examine the mechanism by which calcitriol down-regulates ER1, Aim IV will study calcitriol, AIs and their combinations in vivo in a xenograft mouse model. Study Design: Established BCa cell lines and primary BCa cells will be evaluated in culture for effects of calcitriol on aromatase and PG pathway genes. Calcitriol actions to inhibit these pathways will include measurement of both critical genes and down-stream biological responses. Mechanistic studies will address differential regulation of aromatase promoters in BCa and bone cells. The effects of calcitriol, and AIs will be assessed individually and in combination. All of these aspects will also be examined in an in vivo model of BCa xenografts in nude mice. Potential Benefits: The proposed studies will evaluate calcitriol, AIs and combinations for therapy of BCa patients. Calcitriol and AIs are approved drugs, orally active, safe and of modest cost. Progress to advance these combinations to clinical trials to treat and/or prevent BCa can be swift. We postulate that calcitriol plus an AI will show enhanced activity to prevent the growth and progression of BCa. We believe the data generated by this study will pave the way to support the rapid advancement of calcitriol-AI combination therapy to clinical trials for the treatment of BCa. This strategy will provide a safe and economical improvement to the usual therapeutic regimen administered to BCa patients. PROJECT NARRATIVE We postulate that calcitriol plus an AI will show enhanced activity to prevent the growth and progression of BCa. We believe the data generated by this study will pave the way to support the rapid advancement of calcitriol-AI combination therapy to clinical trials for the treatment of BCa. This strategy will provide a safe and economical improvement to the usual therapeutic regimen administered to BCa patients.