The Development of Vitamin D as a Therapy for Breast Cancer

维生素 D 治疗乳腺癌的进展

• 批准号: 7844552
• 负责人: David Feldman
• 金额: $ 0.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844552
• 关键词: Address; Adverse effects; Animal Model; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Attenuated; Biological; Blood Circulation; Breast; Breast Cancer Cell; Breast Cancer Treatment; Calcitriol; Cancer Cell Growth; Cancer Patient; Cancer cell line; Catabolism; Cells; Characteristics; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Complement; Data; Development; Disease; Dose; Down-Regulation; Effectiveness; Enzymes; Estrogen Receptors; Estrogen receptor positive; Estrogens; Exhibits; Feedback; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Grant; Growth; Hormonal; Human; Hydroxyprostaglandin Dehydrogenases; In Vitro; Inhibition of Cell Proliferation; Investigation; Knowledge; Light; Malignant Neoplasms; Measurement; Mediating; Mediator of activation protein; Molecular; Mus; Nude Mice; Osteoporosis; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Postmenopause; Production; Prostaglandin Receptor; Prostaglandins; Receptor Down-Regulation; Regulation; Repression; Research Design; Role; Stimulus; Stream; Therapeutic; Tissues; Treatment Protocols; Up-Regulation; Vitamin D; Xenograft procedure; angiogenesis; bone; bone cell; cancer cell; cost; cyclooxygenase 2; deprivation; in vivo; in vivo Model; malignant breast neoplasm; mouse model; novel; nuclear factor Y; prevent; progesterone 11-hemisuccinate-(2-iodohistamine); promoter; receptor expression; response

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.

描述（由申请人提供）： 钙三醇是维生素D的激素活性形式，具有众所周知的抗癌活性。我们最近确定了抑制乳腺癌（BCA）生长的额外骨化三醇作用的四个新途径。首先，钙三醇直接抑制BCA细胞中的芳香酶表达。通过减少局部雌激素合成，该作用降低了雌激素受体（ER）阳性BCA细胞的主要生长刺激剂。重要的是，钙三醇表现出组织特异性调节芳香酶，导致BCA下调和骨骼上调。由于芳香酶抑制剂（AI）治疗的患者常规观察到的雌激素剥夺，这种作用将保护骨头免受骨质疏松症的不耐副作用。其次，钙三醇通过多种作用（包括抑制COX-2表达）抑制前列腺素（PG）的合成。由于PG是BCA增长的主要刺激剂，因此它们的抑制作用增加了钙三醇疗法的有效性。第三，PG是BCA中芳香酶的主要刺激剂，而骨化三醇对PG的抑制也间接降低了芳香酶的表达。第四，钙三醇直接下调ER1表达。因此，钙三醇通过多种途径起作用来减弱BCA生长。我们假设，钙三醇与AI的联合疗法将使AIS更有效，并且在较低的剂量下，从而提高了疗效，从而潜在地减少骨质疏松症。目的：我们建议研究骨化三醇作用的这四个途径，并研究骨化三醇与AIS的联合疗法的价值，以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患者组合治疗的临床试验铺平道路。具体目的：目的我将检查芳香酶和PG途径基因的钙三醇调节以及对BCA细胞生长的影响。 AIM II将研究芳香酶差异调节的机制。 AIM III将检查钙三醇下调ER1的机制，AIM IV将在异种移植小鼠模型中研究骨化三醇，AIS及其在体内的组合。研究设计：将在培养物中评估既定的BCA细胞系和原代BCA细胞，以实现钙三醇对芳香酶和PG途径基因的影响。抑制这些途径的骨化三醇作用将包括临界基因和下游生物学反应的测量。机械研究将解决BCA和骨细胞中芳香酶启动子的差异调节。骨化三醇和AIS的影响将分别和组合评估。所有这些方面也将在裸鼠的BCA异种移植体的体内模型中进行检查。潜在的好处：拟议的研究将评估BCA患者治疗的骨化三醇，AIS和组合。骨化三醇和AI是经过批准的药物，口服活跃，安全且费用适中。将这些组合推向临床试验以治疗和/或预防BCA的进展可能会迅速。 我们假设钙三醇和AI将显示出增强的活性，以防止BCA的生长和发展。我们认为，这项研究产生的数据将为支持骨化三醇AI联合疗法快速发展为BCA治疗的临床试验的快速发展。该策略将为对BCA患者的常规治疗方案提供安全，经济的改进。项目叙述 我们假设钙三醇加AI将显示出增强的活动，以防止增长和 BCA的进展。我们认为，这项研究产生的数据将为支持的方式铺平道路 钙三醇-AI联合疗法迅速发展为临床试验的治疗 BCA。该策略将为通常的治疗提供安全，经济的改进 对BCA患者的治疗方案。