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

项目总结 肥胖、糖尿病和胰岛素抵抗与子宫内膜风险增加和预后恶化有关 癌症(EC)。二甲双胍是一种广泛用于治疗2型糖尿病的双胍类药物。流行病学和前病毒感染 临床数据表明，二甲双胍可能具有抗肿瘤活性，因为它在代谢中具有间接作用。 环境(↓胰岛素、↓葡萄糖)及其通过AMPK激活/mTOR抑制和抑制对肿瘤细胞的直接作用 脂肪酸/脂肪的生物合成。二甲双胍依赖于阳离子选择性转运体进入细胞，而 多种药物和毒素排出转运体MATE1和2在人EC细胞系和肿瘤中表达。因此， 二甲双胍可能会打破肥胖和EC之间的联系，成为这种疾病的新陈代谢靶向药物。 在癌症基因组图谱数据库中，肥胖女性与非肥胖女性相比，子宫内膜样内皮细胞 基因表达的不同模式，包括脂蛋白脂肪酶和脂蛋白脂酶调节因子的上调 胰岛素/胰岛素生长因子-1(IGF-1)途径。这些发现表明，在肥胖中产生的内皮细胞可能有明显的 可以作为治疗目标的新陈代谢弱点。在肥胖EC患者的0期临床试验中，短期 二甲双胍治疗减少IGF-1受体和mTOR靶点的增殖和表达 子宫内膜癌组织内的通路。二甲双胍的应答者在治疗前脂肪水平较高 血清中的酸/糖脂和内皮细胞中的Mate2，表明这些生物标志物可能预测二甲双胍 回应。最后，在LKB1fl/flp53fl/fl EC小鼠模型中，饮食诱导的肥胖导致肿瘤体积翻了一番， 伴随着能量代谢和脂质生物合成的增加。重要的是，二甲双胍提高了疗效。 对抗肥胖与瘦小鼠的EC，并通过分流逆转肥胖对ECs的有害代谢影响 脂肪酸转化为β-氧化，而不是脂肪的产生。 这项提案的总体目标是评估间接影响的贡献(通过下调 胰岛素/IGF-1信号)和直接效应(通过转运体依赖的细胞进入、激活AMPK/抑制mTOR 二甲双胍(+/-化疗)对其整体抗癌作用的信号转导、钝化作用 (I)临床相关的EC小鼠(肥胖/瘦)模型和(Ii)正在进行的随机2/3期临床试验评估 二甲双胍与安慰剂联合标准护理紫杉醇/卡铂治疗EC NRG肿瘤学小组]。我们的中心假设是二甲双胍疗效的预测因子(+/-化疗)将 包括分子和代谢生物标志物，特别是肥胖、胰岛素抵抗、胰岛素/胰岛素样生长因子上调- 1信号，脂肪酸/脂肪生物合成增加，Mate 1/2表达增加。拟议的研究将 在平行的临床前和临床研究中严格测试这一假设，并通过不同的测量来支持它 代谢和分子标记物与肥胖相关，并受二甲双胍治疗的调节。这一战略应该 阐明二甲双胍对肿瘤生长的间接和直接作用，确定代谢和分子水平 生物标志物预测对二甲双胍的反应，并定义该制剂在肥胖驱动的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.