The Development of Vitamin D as a Therapy for Breast Cancer

维生素 D 治疗乳腺癌的进展

基本信息

批准号：
8014932
负责人：
David Feldman
金额：
$ 28.62万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8014932
关键词：
Address Adipose tissue 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 Cell Culture Techniques Cells Characteristics Cholecalciferol Clinical Treatment Clinical Trials Combined Modality Therapy Complement Data Development Disease Down-Regulation Effectiveness Enzymes Estrogen Receptors Estrogen receptor positive Estrogens Exhibits Feedback Gene Expression Genes Genetic Transcription Genomics Goals Grant Growth Growth and Development function Hormonal Human Hydroxyprostaglandin Dehydrogenases In Vitro Individual Inhibition of Cell Proliferation Investigation Knowledge Ligands Light Malignant Neoplasms Mediating Mediator of activation protein Molecular Mus Nude Mice Osteoporosis Ovarian Ovary Pathway interactions Patients Pharmaceutical Preparations Postmenopause Production Prostaglandin Receptor Prostaglandins Regimen Regulation Repression Research Design Resistance Risk Role Safety Specimen Stimulus Stream Therapeutic Tissue Banking Tissue Banks Tissues Up-Regulation Vitamin D Woman Xenograft procedure angiogenesis bone bone cell cancer cell cost cyclooxygenase 2 deprivation improved in vivo malignant breast neoplasm mouse model novel nuclear factor Y prevent promoter response tumor growth

项目摘要

DESCRIPTION (provided by applicant): Calcitriol, the hormonally active form of vitamin D3, has well known anti-cancer activity. We have recently identified four novel pathways of additional calcitriol actions that inhibit breast cancer (BCa) growth. (1) Calcitriol directly inhibits aromatase expression in BCa cells and adipose tissue thereby reducing local estrogen synthesis and the major growth stimulus to estrogen receptor (ER) positive BCa cells. Importantly, calcitriol exhibits tissue specific regulation of aromatase causing down-regulation in BCa and adipose tissue and up-regulation in bone. The latter action would protect bone from the side effect of osteoporosis due to estrogen deprivation routinely seen in aromatase inhibitor (AI)-treated patients. (2) Calcitriol inhibits the synthesis of prostaglandins (PG), major stimulators of BCa growth, by multiple actions including suppression of COX-2 expression. (3) PGs are potent inducers of aromatase transcription in BCa and calcitriol's inhibition of PGs also indirectly reduces aromatase expression. (4) Calcitriol directly down-regulates ER1 expression. Thus calcitriol acts by multiple pathways to reduce the levels of both the ligand (estrogens) and the receptor (ER) and thereby suppress BCa growth. We postulate that calcitriol and AI combination therapy will improve AI efficacy, potency and safety, reduce osteoporosis risk and delay the development of AI-resistance. Objective: We will study these four pathways of calcitriol action and evaluate the effectiveness of the combination of calcitriol with AIs compared to individual drugs. These studies will rapidly pave the way to clinical trials of calcitriol-AI combination therapy in BCa patients. Specific Aims: Aim I examines calcitriol regulation of aromatase and PG pathway genes in BCa, adipose, ovary and bone cells and the effect of the calcitriol-AI combination to inhibit BCa cell growth. Aim II studies the mechanism for the differential regulation of aromatase. Aim III determines the mechanism by which calcitriol down-regulates ER1. In vivo studies in Aim IV assess the effects of calcitriol, AIs and their combinations in xenograft mouse models on tumor growth and the development of AI-resistance. Regulation of aromatase expression will be examined in tissue-banked human BCa specimens from women treated with vitamin D3. Study Design: Calcitriol effects on aromatase and PG pathway genes and down-stream biological responses will be studied in BCa cell lines, primary normal breast and BCa cells and BCa xenografts in nude mice. Mechanistic studies will address differential regulation of aromatase promoters in BCa, adipose, ovary and bone cells and ER1 in BCa cells. The effects of calcitriol, AIs and combinations on BCa growth will be assessed in cell culture and animal models of BCa. 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 are of modest cost. We expect these findings to swiftly advance calcitriol-AI combinations to clinical trials to treat and/or prevent BCa. PUBLICHEALTH RELEVANCE 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D3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）生长的其他骨化三醇作用的四个新途径。（1）钙三醇直接抑制BCA细胞和脂肪组织中的芳香酶表达，从而将局部雌激素合成和主要生长刺激降低为雌激素受体（ER）阳性BCA细胞。重要的是，钙三醇表现出组织特异性调节芳香酶，导致BCA和脂肪组织中的下调以及骨骼上的上调。后一种作用将保护骨头免受骨质疏松症的副作用，这是由于芳香酶抑制剂（AI）治疗的患者常规上造成的雌激素缺乏。（2）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，BCA生长的主要刺激剂。（3）PG是BCA中芳香酶转录的有效诱导剂，而Clacitriol的PG抑制也间接降低了芳香酶的表达。（4）钙三醇直接下调ER1表达。因此，钙三醇通过多种途径起作用，以降低配体（雌激素）和受体（ER）的水平，从而抑制BCA的生长。我们假设钙三醇和AI组合疗法将提高AI功效，效力和安全性，降低骨质疏松症的风险并延迟AI抗性的发展。目的：我们将研究骨化三醇作用的这四个途径，并评估与单个药物相比，与AIS与AIS组合的有效性。这些研究将迅速为BCA患者的骨化三醇-AI联合疗法的临床试验铺平道路。具体目的：目标I检查了BCA，脂肪，卵巢和骨细胞中芳香酶和PG途径基因的钙三醇调节，以及钙三醇-AI组合对抑制BCA细胞生长的影响。 AIM II研究芳香酶差异调节的机制。 AIM III确定钙三醇对ER1进行调节的机制。 AIM IV中的体内研究评估了异种移植小鼠模型中钙化，AIS及其组合对肿瘤生长和AI抗性发展的影响。芳香酶表达的调节将在接受维生素D3治疗的妇女的组织储备的人BCA标本中检查。研究设计：将在BCA细胞系，原发性正常乳腺和BCA细胞以及裸鼠的BCA异种移植物中研究对芳香酶和PG途径基因以及下游生物学反应的钙化作用。机械研究将解决BCA，脂肪，卵巢和骨细胞以及BCA细胞中芳香化酶启动子的差异调节。在BCA的细胞培养和动物模型中，将评估钙三醇，AI和组合对BCA生长的影响。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，安全并且成本适中。我们希望这些发现将迅速将骨化三醇-AI组合推向临床试验，以治疗和/或预防BCA。 Publichealth相关性我们假设Calcitriol加AI将显示出增强的活动，以防止BCA的增长和发展。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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: importance of mammary CYP27B1 for treatment and prevention.

DOI：
10.1016/j.jsbmb.2012.08.005
发表时间：
2013-07
期刊：
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
影响因子：
4.1
作者：
Krishnan, Aruna V.;Swami, Srilatha;Feldman, David
通讯作者：
Feldman, David

The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer.

DOI：
10.1016/j.steroids.2012.06.005
发表时间：
2012-09
期刊：
Steroids
影响因子：
2.7
作者：
Krishnan AV;Swami S;Feldman D
通讯作者：
Feldman D

Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo.

DOI：
10.1007/s12672-011-0073-7
发表时间：
2011-06
期刊：
HORMONES & CANCER
影响因子：
3
作者：
Swami, Srilatha;Krishnan, Aruna V;Wang, Jennifer Y;Jensen, Kristin;Peng, Lihong;Albertelli, Megan A;Feldman, David
通讯作者：
Feldman, David

Combination of calcitriol and dietary soy exhibits enhanced anticancer activity and increased hypercalcemic toxicity in a mouse xenograft model of prostate cancer.