TRANSPORTERS IN METFORMIN TREATMENT OF ENDOMETRIAL HYPERPLASIA

描述(申请人提供)：肥胖和糖尿病是子宫内膜癌及其前驱病变--子宫内膜增生症的强烈危险因素。二甲双胍是一种非专利口服降血糖药物，已被广泛用于治疗糖尿病和妇科疾病，包括无排卵性不孕症和多囊卵巢综合征。越来越多的流行病学证据表明，二甲双胍降低了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，二甲双胍通过激活AMP激活的蛋白激酶(AMPK)和抑制mTOR途径，显示出对子宫内膜增生症和癌症的抗增殖作用。对于子宫内膜增生症，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增加食欲和体重增加，这在容易肥胖和代谢综合征的人群中尤其有害。我们推测，二甲双胍可能为子宫内膜增生症提供一种替代治疗方法，并可能提供辅助益处，包括改善胰岛素抵抗、体重减轻和月经周期正常化。因此，我们正在进行一项试验性临床试验，以评估二甲双胍治疗无异型性子宫内膜增生症的疗效。由于二甲双胍的物理化学性质，它需要阳离子选择性转运蛋白来穿越细胞膜。研究表明，在一些乳腺癌细胞系中，二甲双胍转运体的表达水平非常低，显著降低了细胞对二甲双胍的摄取。由于介导其抗增殖作用的二甲双胍的靶点是细胞内的AMPK，预计在缺乏二甲双胍转运体或二甲双胍转运体表达水平显著降低的情况下，二甲双胍作为治疗子宫内膜增生症/癌症的药物将无效。因此，这项研究的目的是(1)确定二甲双胍转运体在子宫内膜癌/增生性细胞系和组织中的表达，以及(2)在正在进行的该药物治疗子宫内膜增生症的临床试验中，将二甲双胍转运体的表达与二甲双胍治疗的反应联系起来。治疗反应的其他潜在生物标记物也将被探索并与二甲双胍转运体的表达相关，包括代谢综合征的标记物和二甲双胍/mTOR信号通路下游靶标的分子标记物。我们假设，二甲双胍转运体的表达将预测哪些患有子宫内膜增生症的妇女将从二甲双胍治疗中获得最大好处，从而成为未来二甲双胍治疗子宫内膜增生症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.