Metformin for Reduction of Obesity Associated Breast Cancer Risk

二甲双胍可降低肥胖相关乳腺癌风险

基本信息

批准号：
9108151
负责人：
H-H. Sherry CHOW
金额：
$ 62.86万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-11 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108151
关键词：
5&apos -AMP-activated protein kinase Adult Adverse effects Animals Antidiabetic Drugs Biochemical Blood Glucose Body Weight Breast Breast Cancer Patient Breast Cancer Prevention Breast Cancer Risk Factor Breast Cancer Treatment Case-Control Studies Cell Proliferation Chemopreventive Agent Clinical Clinical Research Clinical Trials Cohort Studies Detection Development Diabetes Mellitus Disease Evaluation Fatty acid glycerol esters General Population Gonadal Steroid Hormones Health High Prevalence Hormones Incidence Induction of Apoptosis Insulin Insulin Resistance Intervention Lead Life Style Magnetic Resonance Imaging Malignant Neoplasms Mammary gland Measures Mediating Menopause Metabolic Metabolic Diseases Metabolic syndrome Metformin Obesity Overweight Pharmaceutical Preparations Phase Placebo Control Placebos Plasma Populations at Risk Postmenopause Premenopause Prevention Preventive Public Health Randomized Research Risk Risk Factors Risk Reduction Signal Pathway Somatomedins Systems Biology Tissues Water Weight Weight Gain Woman Work adipokines breast density cancer risk cancer therapy cytokine diabetic double-blind placebo controlled trial experience high risk malignant breast neoplasm metabolic phenotype metabolome metabolomics nipple aspirate fluid novel prospective research clinical testing study population treatment group tumor uptake

项目摘要

DESCRIPTION (provided by applicant): High adiposity is a major risk factor for a number of diseases, including postmenopausal breast cancer. It has been suggested that adulthood weight gain is more strongly associated with postmenopausal breast cancer than current weight. Prospective cohort studies suggested that approximately 20% of the postmenopausal breast cancer cases are attributable to adulthood weight gain. The increased postmenopausal breast cancer risk in women with high adiposity is likely to be attributed to multiple metabolic disturbances. Metformin, a widely used antidiabetic drug, exerts favorable effects on multiple metabolic disturbances which may lead to reduction of breast cancer risk in women with high adiposity. In addition, metformin may work directly in mammary tissue through the activation of the AMP- activated protein kinase (AMPK) signaling pathway, leading to an antiprolierative effect and induction of apoptosis. Recent case control and cohort studies found that treatment with metformin appears to substantially reduce the risk for development of cancer in diabetics, including breast cancer. There are a large number of ongoing clinical trials of metformin in breast cancer patients. However, the concurrent or prior breast cancer treatments in these studies hinder the evaluation of metformin as a single agent for breast cancer prevention in at risk healthy women. We propose to conduct a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have experienced moderate to significant adulthood weight gain, have high breast density and are insulin resistant. This study population is at increased risk for postmenopausal breast cancer and has a high prevalence of metabolic disturbances associated with breast cancer risk. The overall hypothesis is that metformin intervention can modulate risk features of the breast and metabolic disturbances associated with breast cancer risk in women with high adiposity. The specific aims for this project are 1) to determine the effect of metformin intervention on breast density, 2) to determine the effect of metformin intervention on metabolic disturbances and body weight/composition, and 3) to explore the application of metabolomics as a systems biology approach to assess the chemopreventive mechanisms of metformin. Our proposed study represents the initial steps in clinical evaluation of metformin for modulation of breast cancer rik in a population at risk for multiple diseases. Findings from this study will have wide public healt impact because of the growing overweight and obese populations. With its demonstrated effect in reducing the incidence of diabetes in high risk adults, metformin would have a high level of acceptance and uptake in at risk women with high adiposity if it has also been shown to exert favorable activities in breast cancer risk reduction. Considering the challenges in maintaining a healthy life style by the majority of general public and the pleiotropic activities of metformin fo multiple metabolic disorders, metformin could be developed as an integrated pharmacological approach for at risk women with high adiposity for prevention of multiple diseases.

描述（由申请人提供）：高肥胖是许多疾病的主要危险因素，包括绝经后乳腺癌。有人认为，成年期体重增加与绝经后乳腺癌的相关性比目前的体重更为密切。前瞻性队列研究表明，大约 20% 的绝经后乳腺癌病例可归因于成年期体重增加。高肥胖女性绝经后乳腺癌风险增加可能归因于多种代谢紊乱。二甲双胍是一种广泛使用的抗糖尿病药物，对多种代谢紊乱具有良好的作用，可能会降低高肥胖女性患乳腺癌的风险。此外，二甲双胍可能通过激活 AMP 激活蛋白激酶 (AMPK) 信号通路直接作用于乳腺组织，从而产生抗增殖作用并诱导细胞凋亡。最近的病例对照和队列研究发现，二甲双胍治疗似乎可以大大降低糖尿病患者患癌症（包括乳腺癌）的风险。目前有大量二甲双胍在乳腺癌患者中正在进行的临床试验。然而，这些研究中同时或之前的乳腺癌治疗阻碍了对二甲双胍作为单一药物预防高危健康女性乳腺癌的评估。我们建议对成年后体重中度至显着增加、乳腺密度高且具有胰岛素抵抗的超重/肥胖绝经前女性进行二甲双胍的 II 期随机、双盲、安慰剂对照试验。该研究人群患绝经后乳腺癌的风险增加，并且与乳腺癌风险相关的代谢紊乱的患病率很高。总体假设是，二甲双胍干预可以调节高肥胖女性的乳房风险特征以及与乳腺癌风险相关的代谢紊乱。该项目的具体目标是 1) 确定二甲双胍干预对乳腺密度的影响，2) 确定二甲双胍干预对代谢紊乱和体重/成分的影响，3) 探索代谢组学作为系统的应用生物学方法评估二甲双胍的化学预防机制。我们提出的研究代表了二甲双胍在多种疾病风险人群中调节乳腺癌 rik 的临床评估的初步步骤。由于超重和肥胖人口不断增长，这项研究的结果将对公众健康产生广泛的影响。二甲双胍在降低高危成人糖尿病发病率方面已得到证实，如果它也被证明在降低乳腺癌风险方面发挥了有利作用，那么二甲双胍将在高肥胖风险女性中获得较高的接受度和吸收率。考虑到大多数公众在维持健康生活方式方面面临的挑战以及二甲双胍对多种代谢紊乱的多效活性，二甲双胍可以开发为一种综合药理学方法，用于高肥胖风险女性预防多种疾病。