靶向干预糖代谢信号通路联合化疗提高肥胖型子宫内膜癌治疗疗效及其机制研究

Endometrial cancer has becomes one of the most malignant cancer. Obesity is its most common complication. Our preliminary studies of the current project have shown that all endometrial cancer patients that are obese have dysregulated glucose metabolism at certain degrees, as well as poor response after treatments. Modulators of signaling pathway, such as Metformin, could activate AMPK pathway, which in turn inhibits mTOR pathway, resulting in the growth arrest or endometrial cancer cells. These modulators have shown synergistic effects with Paclitaxel。The current projects aim to study endometrial cancer cell lines in vitro, animal models that recapitulate obese patients with endometrial cancer, and primary cell culture from human patients. We will further investigate the underlying mechanisms of impaired glucose metabolism-exacerbated development of endometrial cancer, using gene array analysis, MS analysis and cellular biologic techniques. We aim to determine the dysregulated glucose metabolism, the abnormal gene expression, and the changes of key signaling pathways in obese endometrial cancer patients, as well as how these changes affect the patients’ response to therapies. We will evaluate the therapeutic effects using targeted mTOR Everolimus, and AMPK agonist Metformin,in vitro and in vivo. Meanwhile, we will study the potential synergistic effects by combined therapies. Therefore, the goal of the current project is to elucidate the role of obese in the chemo-therapeutic effects in endometrial cancer, and the mechanisms of synergistic effects by using targeted agents and chemo-therapies, in order to find a novel target for the treatment of endometrial cancer.

子宫内膜癌是女性常见恶性肿瘤，肥胖为其最常见合并症。课题组初期研究结果显示，肥胖型子宫内膜癌患者均有不同程度的糖代谢异常，化疗疗效差。高糖状态可抑制细胞凋亡，通过调节AMPK/mTOR和Akt/mTOR/S6信号通路提高葡萄糖摄取和酵解率，促进子宫内膜癌细胞生长。利用子宫内膜癌细胞株、肥胖型子宫内膜癌动物模型及人子宫内膜癌原代培养三种平台，运用基因芯片检测、质谱分析和多种分子生物学技术，观察肥胖型子宫内膜癌糖代谢改变、异常基因表达及主要信号通路的变化，探讨肥胖患者糖代谢异常促进子宫内膜癌发生发展的机制。应用mTOR抑制剂依维莫司、AMPK激动剂二甲双胍靶向作用关键信号分子，观察高血糖环境下两者对子宫内膜癌生长代谢的干预效果，深入研究靶向干预和化疗药物联合的协同作用及机制。分析肥胖和非肥胖患者肿瘤组织和血清标本基因组学和代谢组学，验证上述结果，以期找到肥胖型子宫内膜癌患者新的治疗突破点。

项目背景：子宫内膜癌是女性常见恶性肿瘤，肥胖为其最常见合并症。糖代谢异常促进肥胖型子宫内膜癌发生的作用机制尚未明了。子宫内膜癌细胞的高糖摄取和酵解速率保证了子宫内膜癌的快速生长，而糖代谢异常通过调控信号通路促进肥胖型子宫内膜癌的发生发展，干预糖代谢及其主要信号通路可以为肥胖型子宫内膜癌个体化治疗提供新的思路。.主要研究内容：利用子宫内膜癌细胞株与肥胖型子宫内膜癌动物模型，通过运用基因芯片检测、质谱分析和多种分子生物学技术，探讨肥胖患者糖代谢异常促进子宫内膜癌发生发展的机制。应用二甲双胍与雷帕霉素靶向作用关键信号分子，观察高血糖环境下两者对子宫内膜癌生长代谢的干预效果，深入研究靶向干预和化疗药物联合的协同作用及机制。分析肥胖和非肥胖小鼠肿瘤代谢组学改变以及靶向药干预后的代谢改变，以期找到肥胖型子宫内膜癌患者新的治疗突破点。.重要结果：体外模拟高血糖环境下，二甲双胍以及雷帕霉素单药抑制子宫内膜癌细胞生长的作用减弱，二者与化疗药联合增强对肿瘤生长和糖代谢的抑制作用，AMPK/mTOR和Akt/mTOR/S6信号通路在联合用药的作用下抑制更明显，mTOR基因敲除后，单药及联合用药抑制糖代谢关键酶LDHA的作用增强。在高血糖状态下，建立转基因子宫内膜癌小鼠模型，分别通过高脂和低脂饮食诱导肥胖和非肥胖状态，二甲双胍干预后，肥胖和非肥胖子宫内膜癌小鼠肿瘤生长均被抑制，而肥胖小鼠肿瘤抑制更明显。非靶向代谢组学结果显示肥胖小鼠糖酵解和氧化磷酸化能力均增强，脂质合成能力增强，应用二甲双胍明显逆转了肥胖小鼠的脂肪合成。模拟小鼠体内高血糖状态，皮下种植子宫内膜癌细胞，通过二甲双胍、雷帕霉素单药以及联合化疗药物干预后，小鼠移植瘤生长受到抑制，高血糖状态减弱了药物的抑制作用。.关键数据：高血糖状态影响二甲双胍、雷帕霉素以及与化疗药联合的抗癌作用，降低mTOR表达后，药物抑制作用增强。肥胖促进子宫内膜癌小鼠肿瘤的生长，并且增加能量代谢和脂肪合成。二甲双胍提高肥胖子宫内膜癌小鼠的疗效，逆转肥胖对子宫内膜肿瘤的有害代谢改变。.科学意义：二甲双胍提高肥胖子宫内膜癌小鼠的疗效，降低小鼠体内葡萄糖及脂肪代谢，为肥胖型子宫内膜癌患者的治疗提供新的选择。二甲双胍、雷帕霉素与化疗药联合增强肥胖患者子宫内膜癌的治疗效果。