继发胶质母细胞瘤中2型PTPRZ1-MET融合的生物学功能及小分子药物靶向治疗的研究

Glioma is the most frequency brain tumor in adults. It is difficult to cure secondary GBM, which is termed as glioma progressed from low grade to high grade. Few further researches focous on the marker identification and targeted therapy of sGBM samples. The research group has performed RNA sequencing and validation on 272 whole-grade glioma samples and found PTPRZ1-MET fusion gene in secondary gliomas. Based on the previous work and the Chinese Glioma Genome Atlas (CGGA) database, we intend to expand the sample bank and to validate clinical characteristics of type II PTPRZ1-MET fusion. To predict the biological behavious of type II PTPRZ1-MET fusion, bioinformatic analysis will be performed, followed by detection for mechanism of type II PTPRZ1-MET fusion activation dependent with HGF ligand. In addition, fusion protein expression as well as changes of cell proliferation , invasion and cell cycle regulation will be detected by experiments in vitro and in vivo. Using drug X, the possibility of type II PTPRZ1-MET fusion as a molecular therapeutic target will be accessed in vivo. In summary, the present study aims to investigate the role of type II PTPRZ1-MET fusion gene and evaluate the possibility of type II PTPRZ1-MET fusion as a potential target for gene therapy in secondary GBM patients.

脑胶质瘤是临床最为常见的原发性颅内肿瘤，继发性脑胶质瘤（sGBM）是由低恶性阶段逐渐演化为高恶性的肿瘤，治疗非常困难。对其临床标记物和靶向治疗药物的研究尚未深入。申请人所在课题组首次发现国人sGBM功能性融合基因PTPRZ1-MET（ZM），其2型融合形式与肿瘤侵袭高度相关。本研究拟在前期工作基础上，扩大样本量，在不同恶性等级脑胶质瘤中重点验证2型ZM融合基因的临床特征，通过生物信息学分析，预测2型ZM融合基因的生物学行为。在细胞系和动物体内，证实2型ZM融合蛋白水平的表达，探讨2型ZM融合蛋白依赖肝细胞生长因子HGF的激活机制，证实其影响胶质瘤细胞功能的作用。在体内外应用drugX药物实现2型ZM融合基因的表达沉默，探讨2型ZM融合基因作为分子治疗靶点的临床意义。最终为继发胶质母细胞瘤的诊断标记物的确立、靶向治疗靶点的发现以及个体化靶向治疗的选择提供理论依据。

脑胶质瘤是临床最为常见的原发性颅内肿瘤,继发性脑胶质瘤(sGBM)是由低恶性阶段逐渐演化为高恶性的肿瘤,治疗非常困难。对其临床标记物和靶向治疗药物的研究尚未深入。项目负责人所在课题组首次发现国人sGBM功能性融合基因PTPRZ1-MET(ZM),其2型融合形式与肿瘤 侵袭高度相关。本研究在前期工作基础上,扩大样本量,在不同恶性等级脑胶质瘤中重点验证2型ZM融合基因的临床特征,通过生物信息学分析,预测2型ZM融合基因的生物学行为。在细胞系和动物体内,证实2型ZM融合蛋白水平的表达,探讨2型ZM融合蛋白促进肿瘤微环境激活肿瘤生长机制,证实其影响胶质瘤细胞功能的作用。在体内外应用PLB-1001药物实现2型ZM融合基因的表达沉默,探讨2型ZM融合基因作为分子治疗靶点的临床意义。最终为继发胶质母细胞瘤的诊断标记物的确立、靶向治疗靶点的发现以及个体化靶向治疗的选择提供理论依据。