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：
8620630
负责人：
Victoria Lin Bae-Jump
金额：
$ 7.37万
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 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8620630
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体病变，子宫内膜增生的强大风险因素。二甲双胍是一种通用的口服抗血糖，已被广泛用于治疗糖尿病和妇科问题，包括发音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。基于临床前的体外和体内研究，二甲双胍通过AMP激活的蛋白激酶（AMPK）激活和MTOR途径抑制子宫内膜增生和癌症的抗增殖作用。子宫内膜增生的唯一可用治疗选择是孕激素治疗或子宫切除术。但是，孕激素的副作用包括食欲增加和体重增加，这在容易肥胖和代谢综合征的人群中尤其有害。我们假设二甲双胍可以为子宫内膜增生提供另一种治疗方法，并可能赋予次要益处，包括改善胰岛素抵抗，体重减轻和月经周期的归一化。因此，我们进行了一项持续的试验临床试验，以评估二甲双胍在不受欢迎的子宫内膜增生方面的疗效。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，某些乳腺癌细胞系中二甲双胍转运蛋白的表达非常低可显着降低二甲双胍的细胞摄取。由于AMPK，介导其抗增殖作用的二甲双胍的靶标是细胞内的，因此预计在不存在O二甲双胍转运蛋白或明显较低水平的二甲双胍转运蛋白表达的情况下，二甲双胍作为内膜增生/癌症的治疗方法将无效。因此，这项研究的目的是（1）在子宫内膜癌/增生细胞系和组织中确定二甲双胍转运蛋白的表达，以及（2）在该药物的持续临床试验中，将二甲双胍转运蛋白的表达与对二甲双胍治疗的响应相吻合，以治疗子宫内膜增生。还将探索其他潜在的治疗反应生物标志物，并与二甲双胍转运蛋白的表达，包括代谢综合征的标记和二甲双胍/MTOR信号通路的下游靶标的分子标记。我们假设二甲双胍转运蛋白的表达将预测哪些子宫内膜增生的女性将从二甲双胍治疗中获得最大的好处，因此，这是子宫内膜增生和癌症的二甲双胍未来临床试验的关键组成部分。