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

• 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
• 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' -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

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驱病变子宫内膜增生的重要危险因素。二甲双胍是一种通用的口服降糖药，已被广泛用于治疗糖尿病和妇科疾病，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，二甲双胍通过激活AMP活化蛋白激酶（AMPK）和抑制mTOR通路，对子宫内膜增生和子宫内膜癌具有抗增殖作用。子宫内膜增生症的唯一治疗选择是子宫内膜异位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，这在容易患肥胖症和代谢综合征的人群中特别有害。我们假设二甲双胍可能为子宫内膜增生提供一种替代治疗，并可能带来次要益处，包括改善胰岛素抵抗、体重减轻和月经周期正常化。因此，我们有一个正在进行的试点临床试验，以评估二甲双胍在治疗子宫内膜增生症的疗效没有子宫内膜异位症。由于其理化性质，二甲双胍需要阳离子选择性转运蛋白穿过细胞膜。研究表明，某些乳腺癌细胞系中二甲双胍转运蛋白表达水平极低，可显著降低二甲双胍的细胞摄取。由于二甲双胍介导其抗增殖作用的靶点AMPK是细胞内的，因此预期在不存在二甲双胍转运蛋白或二甲双胍转运蛋白表达水平显著较低的情况下，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）确定二甲双胍转运蛋白在子宫内膜癌/增生细胞系和组织中的表达，以及（2）将二甲双胍转运蛋白表达与正在进行的二甲双胍治疗子宫内膜增生临床试验中二甲双胍治疗的反应相关联。还将探索治疗应答的其他潜在生物标志物，并将其与二甲双胍转运蛋白表达相关联，包括代谢综合征标志物和二甲双胍/mTOR信号通路下游靶点的分子标志物。我们假设二甲双胍转运蛋白的表达将预测哪些子宫内膜增生的妇女将从二甲双胍治疗中获得最大的益处，因此，二甲双胍治疗子宫内膜增生和子宫内膜癌的未来临床试验的关键组成部分。