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Metformin for the Chemoprevention of Endometrial Cancer In Obese, Insulin-Resista

二甲双胍用于肥胖、胰岛素抵抗者子宫内膜癌的化学预防

基本信息

批准号：
7961962
负责人：
Karen Hsieh Lu
金额：
$ 97.29万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7961962
关键词：
Accounting Adipose tissue Aftercare American Animal Model Biological Markers Biopsy Body mass index Cancer cell line Carcinoma Chemoprevention Chemopreventive Agent Clinical Data Diabetes Mellitus Disease Resistance Drug usage Endometrial Endometrial Carcinoma Endometrial Hyperplasia Endometrium Epidemiologic Studies Estrogens Estrone Funding Gene Expression Goals Histologic Incidence Institutes Insulin Insulin Resistance Ligands Malignant Neoplasms Metformin Modeling Molecular Obesity Pathway interactions Pharmaceutical Preparations Phase II Clinical Trials Prevention Production Proteomics Receptor Signaling Risk Rodent Model Role Serum Signal Pathway Testing Weight Woman adipokines adiponectin anticancer research arm cohort diabetic diet and cancer disorder risk endometrial cancer prevention high risk human FRAP1 protein human data lifetime risk novel novel strategies obesity prevention pre-clinical prevent randomized placebo controlled trial receptor response

项目摘要

Obese women clearly are at increased risk for developing endometrial cancer. Numerous epidemiologic studies have demonstrated that obesity is strongly associated with an increased risk of endometrial cancer. While an average woman has a 3% lifetime risk of endometrial cancer, obese women have a 9-10% lifetime risk of endometrial cancer. In a review of diet and cancer by the American Institute for Cancer Research and World Cancer Research Fund (WCRF), authors stated that the evidence relating body mass index and cancer is strongest for endometrial cancer. While excessive production of extragonadal estrogens (estrone) in the adipose tissue of obese women is presumed to be the major contributor to the risk of endometrial cancer, increased serum estrogen levels alone are unlikely to fully account for this effect. Studies by our group and others suggest that insulin resistance associated with obesity contributes to the increased risk of endometrial cancer. In addition, data from our previous funding period suggest that other mechanisms are involved in activating pro-proliferative signaling pathways in the obese endometrium. For the current proposal, our central hypothesis is that metformin can decrease endometrial hyperproliferation and can act as a chemopreventive agent in insulin-resistant obese women. Our three specific aims are 1) to test the hypothesis that metformin can reverse the estrogen-dependent hyperproliferation in the endometrium in an animal model of obesity- induced insulin-resistance, 2) to study novel mechanisms related to the use of metformin for the prevention of endometrial cancer. More specifically, we will examine the hypothesis that adipokines expressed in adipose tissue regulate endometrial proliferation via adipokine receptors, and metformin treatment can prevent this proliferation, and 3) to assess the ability of metformin to modulate surrogate endometrial biomarkers in a cohort of obese, insulin resistant women. It is the goal of this Project to develop novel strategies for the chemoprevention of endometrial cancer in obese, insulin resistant women, a high risk cohort.

肥胖妇女患子宫内膜癌的风险明显增加。许多流行病学研究表明，肥胖与子宫内膜癌风险增加密切相关。虽然平均女性一生中患子宫内膜癌的风险为3%，但肥胖女性一生中患子宫内膜癌的风险为9- 10 子宫内膜癌的风险。在美国癌症研究所的一篇关于饮食与癌症的综述中，世界癌症研究基金会（WCRF），作者指出，有关体重指数和子宫内膜癌的发病率最高。同时产生过多的性腺外雌激素（雌酮）据推测，肥胖妇女脂肪组织中的蛋白质是子宫内膜异位症风险的主要因素。癌症，血清雌激素水平的增加本身不太可能完全解释这种影响。我们的研究研究小组和其他研究人员认为，与肥胖相关的胰岛素抵抗导致肥胖风险增加，子宫内膜癌此外，我们上一个供资期的数据表明，参与激活肥胖子宫内膜的促增殖信号通路。为当前我们的中心假设是二甲双胍可以减少子宫内膜过度增殖，可以作为抗胰岛素肥胖妇女的化学预防剂。我们的三个具体目标是：验证二甲双胍可以逆转雌激素依赖性过度增殖的假设，肥胖诱导的胰岛素抵抗动物模型中的子宫内膜，2）研究新的机制与使用二甲双胍预防子宫内膜癌有关。更具体地说，我们将研究脂肪组织中表达的脂肪因子通过脂肪因子调节子宫内膜增殖的假说受体，二甲双胍治疗可以防止这种增殖，和3）评估二甲双胍的能力，在肥胖、胰岛素抵抗妇女队列中调节替代子宫内膜生物标志物。它的目标是该项目旨在开发肥胖、胰岛素和胰岛素治疗子宫内膜癌的化学预防新策略。耐药女性是高危人群