靶向MDM2/p53信号通路小分子抑制剂APG-115通过促进胃癌细胞自噬介导T细胞免疫激活的机制研究

MDM2/p53信号通路在肿瘤细胞的恶性转化过程中起关键的调控作用，是潜在的药物靶点。我们前期通过MDM2-p53蛋白-蛋白相互作用优化设计、筛选出了全新结构螺羟吲哚类小分子先导化合物APG-115靶向MDM2（抑癌分子p53的负调节因子）且激活p53基因表达，但其抗肿瘤作用的分子机制尚需进一步研究。我们发现70%的胃癌组织过表达MDM2，因而APG-115可通过促进野生型p53基因表达诱导胃癌细胞发生自噬，LC3-I向LC3-II转化，并可调控肿瘤抗原特异性T细胞频率及功能的改变。本项目拟通过体外细胞水平相关实验技术继续探讨APG-115诱导胃癌细胞自噬的分子机理，及其对肿瘤微环境T细胞功能的激活作用和调控机理，并在动物体内验证APG-115在胃癌中的抗癌作用及其作用机理。本研究结果将为APG-115在胃癌的临床应用及多药联用的治疗策略提供理论依据。

The MDM2/p53 signaling pathway is critical in tumorigenesis and development, which could be a potential antitumor drug target. In our previous study, a new structure spiro-oxindole small molecule compound APG-115 was developed through the optimization design of MDM2-p53 protein-protein interaction. APG-115 can target MDM2 (negative regulator of p53) and activate p53 gene expression, but its antitumor effect and molecular mechanism remain further investigation. Our previous work found that MDM2 is over-expressed in 70% of gastric cancer tissues, and APG-115 can promote autophagy in p53 wild-type gastric cancer cells by transforming LC3-I to LC3-II, which regulates the number and functions of tumor antigen specific T cell. Based on previous discoveries, this project intends to further explore the molecular mechanism of APG-115 inducing autophagy in gastric cancer cells, and its activation and regulation mechanism of T cell function in tumor microenvironment, and to verify the in vivo anti-cancer effect of APG-115. The results of this study provide experimental evidence for the clinical application of APG-115 in gastric cancer.