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的激素活性形式，具有众所周知的抗癌活性。我们最近发现了四种新的骨化三醇抑制乳腺癌(BCA)生长的作用途径。首先，骨化三醇直接抑制BCA细胞芳香化酶的表达。通过减少局部雌激素的合成，这种作用减少了雌激素受体(ER)阳性的BCA细胞的主要生长刺激因子。重要的是，骨化三醇表现出组织特异性的芳香化酶调节，导致BCA下调，骨骼上调。这一作用将保护骨骼免受由于雌激素缺乏而导致的骨质疏松症的不良副作用，这种副作用通常出现在芳香酶抑制剂(AI)治疗的患者中。第二，骨化三醇通过抑制COX-2表达等多种作用抑制前列腺素(PG)的合成。由于PG是BCA生长的主要刺激因子，它们的抑制增加了骨化三醇治疗的有效性。第三，PGs是BCA中芳香酶的主要刺激物，骨化三醇对PGs的抑制也间接降低了芳香酶的表达。第四，骨化三醇直接下调ER1的表达。因此，骨化三醇通过多种途径抑制BCA的生长。我们推测，骨化三醇与人工智能的联合治疗将使人工智能更有效，剂量更低，从而增加疗效，潜在的额外好处是减少骨质疏松症。目的：我们建议研究骨化三醇的四种作用途径，并探讨骨化三醇与人工血管紧张素转换酶(AIS)联合治疗的价值，使这些药物比单独使用任何一种药物都更有效。这些研究将迅速为联合治疗BCA患者的临床试验铺平道路。目的：研究骨化三醇对芳香酶和PG途径基因的调控及其对BCA细胞生长的影响。目的II研究芳香酶的差异调节机制。目的III将研究骨化三醇下调ER1的机制，目的IV将在异种移植小鼠模型中研究骨化三醇、AIS及其组合。研究设计：将在培养中评估已建立的BCA细胞系和原代BCA细胞对骨化三醇对芳香化酶和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。机制研究将解决芳香酶启动子在BCA和骨细胞中的不同调节。骨化三醇和人工授精的效果将单独和联合进行评估。所有这些方面也将在BCA裸鼠异种移植的活体模型中进行检查。潜在的好处：拟议的研究将评估骨化三醇、人工授精及其联合治疗BCA患者的效果。骨化三醇和人工智能是经批准的药物，口服有效，安全，价格适中。将这些组合推进到临床试验以治疗和/或预防BCA的进展可能会很快。 我们推测，骨化三醇加人工智能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联合疗法迅速进入治疗BCA的临床试验铺平道路。这一策略将对BCA患者的常规治疗方案提供安全和经济的改进。项目叙事 我们推测，骨化三醇加人工智能将显示出增强的活性，以防止生长和 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联合治疗慢性粒细胞白血病的临床研究进展 BCA。这一策略将为通常的治疗提供安全和经济的改进。 对BCA患者实施治疗方案。

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.