TRANSPORTERS IN METFORMIN TREATMENT OF ENDOMETRIAL HYPERPLASIA

二甲双胍治疗子宫内膜增生症中的转运蛋白

基本信息

批准号：
8513580
负责人：
Victoria Lin Bae-Jump
金额：
$ 7.6万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2013-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513580
关键词：
5&apos -AMP-activated protein kinase Adverse effects Antidiabetic Drugs Biological Markers Body Weight decreased Breast Cancer Cell Cancer cell line Carrier Proteins Cations Cell Line Cell membrane Cells Cessation of life Charge Chemicals Clinical Trials Complement Data Development Diabetes Mellitus Disease Dose Endometrial Carcinoma Endometrial Hyperplasia Endometrial Hyperplasia without Atypia Endometrium Epidemiology Future Generic Drugs Genetic Polymorphism Glucose Goals Gynecologic Human Hyperglycemia Hyperplasia Hysterectomy Immunohistochemistry In Vitro Infertility Insulin Resistance Intestines Kidney Laboratories Lesion Liver Malignant Neoplasms Mediating Menstrual cycle Metabolic Metabolic syndrome Metformin Molecular Obesity Oral Organic Cation Transporter Organic Cation Transporter 1 Outcome Ovarian PTEN gene Pathway interactions Patients Pharmaceutical Preparations Physiological Population Prevention Progestin Therapy Progestins Property Proto-Oncogene Proteins c-akt Resolution Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Role STK11 gene Serum Specimen Syndrome Therapeutic Time Tissues Toxin Urine Waist-Hip Ratio Weight Gain Woman alternative treatment base cancer cell cancer risk diabetic diabetic patient human disease in vivo increased appetite inhibitor/antagonist innovation mTOR Signaling Pathway mTOR inhibition metabolomics molecular marker monoamine multi drug transporter novel pre-clinical precursor cell public health relevance response treatment response treatment strategy tumorigenic uptake

项目摘要

DESCRIPTION (provided by applicant): Obesity and diabetes are strong risk factors for endometrial cancer and its precursor lesion, endometrial hyperplasia. Metformin, a generic oral anti-hyperglycemic, has been widely used to treat diabetes and gynecologic problems including anovulatory-related infertility and polycystic ovarian syndrome. Mounting epidemiological evidence suggests that metformin reduces cancer risk and cancer deaths among diabetic patients. Based on preclinical in vitro and in vivo studies, metformin demonstrates anti-proliferative effects for both endometrial hyperplasia and cancer through AMP-activated protein kinase (AMPK) activation and inhibition of the mTOR pathway. The only available treatment options for endometrial hyperplasia are progestin therapy or hysterectomy. However, side effects of progestins include increased appetite and weight gain which are particularly detrimental in a population prone to obesity and the metabolic syndrome. We hypothesize that metformin may offer an alternative treatment for endometrial hyperplasia and possibly confer secondary benefits including improvements in insulin resistance, weight loss, and normalization of menstrual cycles. Thus, we have an ongoing pilot clinical trial to assess the efficacy of metformin in the treatment of endometrial hyperplasia without atypia. Due to its physicochemical properties, metformin requires cation-selective transport proteins to traverse cell membranes. Studies show that very low levels of metformin transporter expression in some breast cancer cell lines significantly reduces cellular uptake of metformin. Since AMPK, the target of metformin that mediates its anti-proliferative effects is intracellular, it is expected that in the absence o metformin transporters or significantly low levels of metformin transporter expression, metformin would be ineffective as a treatment for endometrial hyperplasia/cancer. Thus, the aim of this study is (1) to determine metformin transporter expression in endometrial cancer/hyperplasia cell lines and tissue, and (2) to correlate metformin transporter expression with response to metformin treatment in an ongoing clinical trial of this agent for the treatment of endometrial hyperplasia. Other potential biomarkers of treatment response will also be explored and correlated with metformin transporter expression, including markers of metabolic syndrome and molecular markers of downstream targets of the metformin/mTOR signaling pathway. We hypothesize that expression of the metformin transporters will predict which women with endometrial hyperplasia will derive the greatest benefit from metformin treatment, and thus, be a critical component of future clinical trials of metformin for both endometrial hyperplasia and cancer.

描述（由申请人提供）：肥胖和糖尿病是子宫内膜癌及其前兆病变子宫内膜增生的强烈危险因素。二甲双胍是一种通用口服抗高血糖药，已广泛用于治疗糖尿病和妇科问题，包括无排卵相关的不孕症和多囊卵巢综合征。越来越多的流行病学证据表明，二甲双胍可降低糖尿病患者的癌症风险和癌症死亡率。基于临床前体外和体内研究，二甲双胍通过 AMP 激活蛋白激酶 (AMPK) 激活和抑制 mTOR 通路，显示出对子宫内膜增生和癌症的抗增殖作用。子宫内膜增生唯一可用的治疗选择是孕激素治疗或子宫切除术。然而，孕激素的副作用包括食欲增加和体重增加，这对于易患肥胖和代谢综合征的人群尤其有害。我们假设二甲双胍可能为子宫内膜增生提供替代治疗，并可能带来次要益处，包括改善胰岛素抵抗、减肥和月经周期正常化。因此，我们正在进行一项试点临床试验，以评估二甲双胍治疗无异型性子宫内膜增生的疗效。由于其物理化学特性，二甲双胍需要阳离子选择性转运蛋白才能穿过细胞膜。研究表明，一些乳腺癌细胞系中二甲双胍转运蛋白表达水平非常低，显着降低了细胞对二甲双胍的摄取。由于二甲双胍介导其抗增殖作用的靶点 AMPK 位于细胞内，因此预计在缺乏二甲双胍转运蛋白或二甲双胍转运蛋白表达水平显着低的情况下，二甲双胍作为子宫内膜增生/癌症的治疗无效。因此，本研究的目的是（1）确定子宫内膜癌/增生细胞系和组织中二甲双胍转运蛋白的表达，以及（2）在正在进行的该药物临床试验中将二甲双胍转运蛋白表达与对二甲双胍治疗的反应相关联。治疗子宫内膜增生。治疗反应的其他潜在生物标志物也将被探索并与二甲双胍转运蛋白表达相关，包括代谢综合征标志物和二甲双胍/mTOR信号通路下游靶标的分子标志物。我们假设二甲双胍转运蛋白的表达将预测哪些患有子宫内膜增生的女性将从二甲双胍治疗中获得最大益处，因此成为未来二甲双胍治疗子宫内膜增生和癌症临床试验的关键组成部分。