TRANSPORTERS IN METFORMIN TREATMENT OF ENDOMETRIAL HYPERPLASIA

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，二甲双胍可以降低糖尿病患者的癌症风险和癌症死亡。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，对子宫内膜增生和癌症均有抗增殖作用。子宫内膜增生唯一可用的治疗选择是黄体酮治疗或子宫切除术。然而，黄体酮的副作用包括食欲增加和体重增加，这对易患肥胖症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一种替代治疗方法，并可能带来包括改善胰岛素抵抗、体重减轻和月经周期正常化在内的次要益处。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。由于其物理化学性质，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，在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是细胞内的，因此可以预期，在二甲双胍转运蛋白缺失或二甲双胍转运蛋白表达水平显著降低的情况下，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；(2)在正在进行的二甲双胍治疗子宫内膜增生的临床试验中，将二甲双胍转运蛋白表达与二甲双胍治疗反应联系起来。其他潜在的治疗反应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女性将从二甲双胍治疗中获益最大，因此，它将成为未来二甲双胍治疗子宫内膜增生和癌症的临床试验的关键组成部分。

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.