EGFR/β-catenin联合靶向抑制高表达GOLPH3胶质母细胞瘤增殖的作用与机制研究

脑胶质母细胞瘤占颅内原发恶性肿瘤47.1%,由于其发生发展涉及多种分子通路异常调控及脑肿瘤微环境的异质性的存在，单一靶点治疗往往无法取得较好效果，如何开展多靶点联合治疗是目前研究的瓶颈。申请人前期已经发现胶质母细胞瘤中高表达GOLPH3可抑制EGFR的内吞降解并持续激活PI3K-AKT促进其恶性增殖，高表达GOLPH3可增敏EGFR抑制剂的疗效。申请人在前期实验中进一步发现EGFR抑制剂AZD9291处理胶质母细胞瘤细胞后可上调β-catenin表达和活性，同时下调 β-catenin可提高 AZD9291 的治疗效果。因此，本项目拟从分子、细胞与整体水平阐明在高表达GOLPH3的胶质母细胞瘤中使用AZD9291激活β-catenin的分子机制，并合成制备纳米脂质体联合靶向递送EGFR和β-catenin抑制剂协同抑制高表达GOLPH3的胶质母细胞瘤增殖能力从而提高多靶点联合治疗的效果。

Glioblastoma accounts for 47.1% of primary intracranial malignant tumors. Due to the abnormal regulation of various molecular pathways and the heterogeneity of brain tumor microenvironment, single target therapy often fails to achieve effective results. Therefore, how to carry out multi-target combination therapy is the bottleneck of research. The applicant has previously found that high expression of GOLPH3 in glioblastoma could inhibit the endocytic degradation of EGFR and continuously activate PI3K-Akt to promote its malignant proliferation. High expression of GOLPH3 could sensitize the efficacy of EGFR inhibitor. In previous experiments, the applicant further found that the EGFR inhibitor AZD9291 could up-regulate the expression and activity of β-catenin, while down-regulating β-catenin could improve the therapeutic effect of AZD9291.Therefore, this project aims to elucidate the molecular mechanism of AZD9291 activation of β-catenin in glioblastoma with high expression of GOLPH3 from the molecular, cellular and overall levels, and synthesize and prepare nano-liposomes to deliver EGFR and β-catenin inhibitors to synergistically inhibit the proliferation of glioblastoma with high expression of GOLPH3, so as to improve the effect of multi-target combination therapy.