Obesity-driven Metabolic and Molecular Biomarkers of Metformin Response in Endometrial Cancer

项目摘要 肥胖、糖尿病和胰岛素抵抗与子宫内膜异位症的风险增加和预后不良有关。 癌（EC）。二甲双胍是一种广泛用于治疗2型糖尿病的双胍。流行病学和预防 临床数据表明，二甲双胍可能具有抗肿瘤活性，这是由于其在代谢中的间接作用。 环境（↓胰岛素，↓葡萄糖）和通过AMPK激活/mTOR抑制和抑制对肿瘤细胞的直接作用 脂肪酸/脂质生物合成的过程。代谢依赖于阳离子选择性转运蛋白进入细胞， 多药物和毒素外排转运蛋白MATE 1和2在人EC细胞系和肿瘤中表达。因此，在本发明中， 二甲双胍可能会打破肥胖和EC之间的联系，成为这种疾病的代谢靶向药物。 在癌症基因组图谱数据库中，肥胖女性与非肥胖女性中出现的类胡萝卜素样内皮细胞， 基因表达的不同模式，包括脂蛋白脂酶和调节剂的上调， 胰岛素/胰岛素生长因子-1（IGF-1）途径。这些发现表明，肥胖引起的EC可能具有明显的 代谢脆弱性可以作为治疗的目标。在肥胖EC患者的0期临床试验中， 二甲双胍治疗可减少增殖并降低IGF-1受体和mTOR靶点的表达 子宫内膜肿瘤组织内的通路。二甲双胍的应答者治疗前的脂肪酸水平较高， 血清中的MATE 2和EC中的MATE 2，表明这些生物标志物可能预测二甲双胍 反应最后，在LKB 1 fl/flp 53 fl/fl EC小鼠模型中，饮食诱导的肥胖导致肿瘤大小加倍， 伴随着能量代谢和脂质生物合成的增加。重要的是，二甲双胍的疗效增加 在肥胖小鼠和瘦小鼠中对抗EC，并通过分流逆转肥胖在EC中的有害代谢作用。 脂肪酸的β-氧化，而不是脂质的生产。 该提案的总体目标是评估间接效应（通过下调 胰岛素/IGF-1信号传导）和直接作用（通过转运蛋白依赖性细胞进入、AMPK激活/mTOR抑制 信号传导、脂肪酸/脂质生物合成的钝化）与二甲双胍（+/-化疗）的总体抗癌功效之间的关系。 (i)临床相关EC小鼠（肥胖/消瘦）模型和（ii）正在进行的随机2/3期临床试验， 二甲双胍与安慰剂联合标准治疗紫杉醇/卡铂治疗EC [通过 NRG肿瘤组]。我们的中心假设是二甲双胍反应（+/-化疗）的预测因子将 包括分子和代谢生物标志物，特别是肥胖症、胰岛素抗性、胰岛素/IGF上调， 1信号传导，增强的脂肪酸/脂质生物合成和更高的MATE 1/2表达。拟议的研究将 在平行的临床前和临床研究中严格检验这一假设，并通过多种测量来支持这一假设。 与肥胖相关的代谢和分子标志物，并通过二甲双胍治疗进行调节。这一战略应 描述二甲双胍对肿瘤生长的间接和直接影响的相互作用， 预测二甲双胍应答的生物标志物，并确定该药物在肥胖驱动的EC治疗中的作用。

PROJECT SUMMARY Obesity, diabetes and insulin resistance are associated with increased risk and worse outcomes for endometrial cancer (EC). Metformin is a biguanide that is widely used in the treatment of type 2 diabetes. Epidemiological and pre- clinical data suggest that metformin may have anti-tumorigenic activity, due to its indirect effects within the metabolic milieu (↓insulin, ↓glucose) and direct effects on tumor cells through AMPK activation/mTOR inhibition and suppression of fatty acid/lipid biosynthesis. Metformin is dependent on cation-selective transporters for entry into cells, and the multi-drug and toxin extrusion transporters, MATE1 and 2, are expressed in human EC cell lines and tumors. Thus, metformin may break the link between obesity and EC, emerging as a metabolically targeted agent for this disease. Within The Cancer Genome Atlas database, endometrioid ECs arising in obese versus non-obese women have distinguishing patterns of gene expression, including upregulation of lipoprotein lipase and modulators of the insulin/insulin growth factor-1 (IGF-1) pathway. These findings suggest that ECs arising in obesity may have distinct metabolic vulnerabilities that could be targeted for treatment. In a phase 0 clinical trial of obese EC patients, short-term metformin treatment reduced proliferation and decreased expression of the IGF-1 receptor and targets of the mTOR pathway within the endometrial tumor tissues. Responders to metformin had higher pre-treatment levels of fatty acids/glycolipids in their serum and MATE2 in their ECs, suggesting that these biomarkers might predict metformin response. Lastly, in the LKB1fl/flp53fl/fl EC mouse model, diet-induced obesity led to a doubling of tumor size, accompanied by increases in energy metabolism and lipid biosynthesis. Importantly, metformin had increased efficacy against EC in obese versus lean mice and reversed the detrimental metabolic effects of obesity in the ECs, via shunting fatty acids to beta-oxidation as opposed to lipid production. The overall goal of this proposal is to assess the contribution of indirect effects (via downregulation of insulin/IGF-1 signaling) and direct effects (via transporter-dependent cell entry, activation of AMPK/inhibition of mTOR signaling, blunting of fatty acid/lipid biosynthesis) of metformin (+/- chemotherapy) to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC [through the NRG Oncology Group]. Our central hypothesis is that predictors of metformin response (+/- chemotherapy) will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/IGF- 1 signaling, heightened fatty acid/lipid biosynthesis and higher MATE 1/2 expression. The proposed research will rigorously test this hypothesis in parallel pre-clinical and clinical studies and support it with diverse measurements of metabolic and molecular markers associated with obesity and modulated by metformin treatment. This strategy should delineate the interplay of metformin’s indirect and direct effects on tumor growth, identify metabolic and molecular biomarkers predictive of response to metformin, and define the role of this agent in obesity-driven EC treatment.