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PTPRZ1-METFUsion GENe(ZM-FUGEN)trial:study protocol for a multicentric,randomized,open-label phase II/III trial

Chinese Neurosurgical Journal 2023年第4期9卷 315-319页

作者： zhaoshi bao Shouwei Li Liang Wang Bisi Zhang Peilong Zhang Hepeng Shi Xiaoguang Qiu Tao Jiang Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Chinese Glioma Genome Atlas Network(CGGA)and Asian Glioma Genome Atlas Network(AGGA) BeijingChina Department of Neurosurgery Sanbo Brain HospitalCapital Medical UniversityBeijing 100093China Department of Neurosurgery Tangdu HospitalFourth Military Medical UniversityXi’anChina Beijing Pearl Biotechnology Limited Liability Company BeijingChina Department of Radio‑Therapy Beijing Tiantan HospitalCapital Medical UniversityBeijing 100050China Beijing Neurosurgical Institute Capital Medical UniversityBeijing 100070China Center of Brain Tumor Beijing Institute for Brain DisordersBeijing 100069China China National Clinical Research Center for Neurological Diseases Beijing 100050China

Background PTPRZ1-MET fusion was reported to associate with glioma progression from low-grade to high-grade glioma,which was a target by a MET inhibitor vebreltinib.However,little is known about the further efficacy of vebreltinib among more glioma patients.This trial aims to evaluate the safety and efficacy of vebreltinib enteric-coated capsules in the treatment of sGBM/IDH mutant glioblastoma patients with the ZM fusion gene.Methods This multicentric,randomized,open-label,controlled trial plans to include 19 neurosurgical centers and recruit 84 sGBM or IDH mutant glioblastoma patients with the ZM fusion gene.This trial enrolls sGBM or IDH mutant glioblastoma patients with the inclusion criteria and without the exclusion criteria.It was registered with ***(CTR20181664).The primary efficacy endpoint is overall survival(OS).The secondary endpoints are progression-free survival(PFS)and objective response rate(ORR).Discussion If proven effective,this targeted multifaceted intervention protocol will be extended for more glioma patients as a protocol to evaluate the safety and efficacy of MET inhibitors.Trial registration It was registered with ***(CTR20181664).

关键词： Glioblastoma IDH mutation PTPRZ1-MET Vebreltinib Phase II/III Clinical trial

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Progress on molecular biomarkers and classification of malignant gliomas

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Frontiers of Medicine 2013年第2期7卷 150-156页

作者： Chuanbao Zhang zhaoshi bao Wei Zhang Tao Jiang Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100050China Beijing Neurosurgical Institute Beijing 100050China

Gliomas are the most common primary intracranial tumors in adults.Anaplastic gliomas(WHO gradeⅢ)and glioblastomas(WHO gradeⅣ)represent the major groups of malignant gliomas in the brain.Several diagnostic,predictive,and prognostic biomarkers for malignant gliomas have been reported over the last few decades,and these markers have made great contributions to the accuracy of diagnosis,therapeutic decision making,and prognosis of patients.However,heterogeneity in patient outcomes may still be observed,which highlights the insufficiency of a classification system based purely on histopathology.Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment.In this review,we summarize three distinctive biomarkers,three most commonly altered pathways,and three classifications based on microarray data in malignant gliomas.

关键词： malignant glioma molecular biomarker IDH1 MGMT molecular classification

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Intratumor heterogeneity,microenvironment,and mechanisms of drug resistance in glioma recurrence and evolution

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Frontiers of Medicine 2021年第4期15卷 551-561页

作者： zhaoshi bao Yongzhi Wang Qiangwei Wang Shengyu Fang Xia Shan Jiguang Wang Tao Jiang Beijing Neurosurgical Institute Capital Medical UniversityBeijing 100050China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100050China Divison of Life Science Department of Chemical and Biological EngineeringCenter for Systems Biology and Human Healthand State Key Laboratory of Molecular NeuroscienceThe Hong Kong University of Science and TechnologyHong KongChina China National Clinical Research Center for Neurological Diseases Beijing 100050China Division of Life Science Hong Kong University of Science and TechnologyHong KongChina Center of Brain Tumor Beijing Institute for Brain DisordersBeijing 100069China Department of Radiotherapy Beijing Tiantan HospitalCapital Medical UniversityBeijing 100050China

Glioma is the most common lethal tumor of the human brain.The median survival of patients with primary World Health Organization grade IV glioma is only 14.6 months.The World Health Organization classification of tumors of the central nervous system categorized gliomas into lower-grade gliomas and glioblastomas.Unlike primary glioblastoma that usually develop de novo in the elderly,secondary glioblastoma enriched with an isocitrate dehydrogenase mutant typically progresses from lower-grade glioma within 5-10 years from the time of diagnosis.Based on various evolutional trajectories brought on by clonal and subclonal alterations,the evolution patterns of glioma vary according to different theories.Some important features distinguish the normal brain from other tissues,e.g.,the composition of the microenvironment around the tumor cells,the presence of the blood-brain barrier,and others.The underlying mechanism of glioma recurrence and evolution patterns of glioma are different from those of other types of cancer.Several studies correlated tumor recurrence with tumor heterogeneity and the immune microenvironment.However,the detailed reasons for the progression and recurrence of glioma remain controversial.In this review,we introduce the different mechanisms involved in glioma progression,including tumor heterogeneity,the tumor microenvironment and drug resistance,and their pre-clinical implements in clinical trials.This review aimed to provide new insights into further clinical strategies for the treatment of patients with recurrent and secondary glioma.

关键词： glioma evolution mechanism strategies tumor heterogeneity secondary glioma

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Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma

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Frontiers of Medicine 2023年第2期17卷 240-262页

作者： Jing Feng Zheng Zhao Yanfei Wei zhaoshi bao Wei Zhang Fan Wu Guanzhang Li Zhiyan Sun Yanli Tan Jiuyi Li Yunqiu Zhang Zejun Duan Xueling Qi Kai Yu Zhengmin Cong Junjie Yang Yaxin Wang Yingyu Sun Fuchou Tang Xiaodong Su Chuan Fang Tao Jiang Xiaolong Fan Beijing Key Laboratory of Gene Resource and Molecular Development Laboratory of Neuroscience and Brain DevelopmentBeijing Normal UniversityBeijing 100875China Beijing Neurosurgical Institute Beijing 100070China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Department of Pathology Affiliated Hospital of Hebei UniversityBaoding 071000China Gendya Biotechnology Ltd. Beijing 100176China Center of Growth Metabolism&Aging Key Laboratory of Bio-Resource and Eco-Environment of Ministry of EducationCollege of Life SciencesSichuan UniversityChengdu 610065China Department of Pathology Sanbo Brain HospitalCapital Medical UniversityBeijing 100093China Biodynamic Optical Imaging Center(BIOPIC) School of Life SciencesPeking UniversityBeijing 100871China Department of Neurosurgery Affiliated Hospital of Hebei UniversityBaoding 071000China Hebei Key Laboratory of Precise Diagnosis and Treatment of Glioma Baoding 071000China Chinese Glioma Genome Atlas Network(CGGA) Beijing 100070China College of Life Sciences Sichuan Normal UniversityChengdu 610101China

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.

关键词： glioma progression molecular classification EM PM subtyping intratumor heterogeneity

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Chinese Glioma Genome Atlas(CGGA):A Comprehensive Resource with Functional Genomic Data from Chinese Glioma Patients

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Genomics, Proteomics & Bioinformatics 2021年第1期19卷 1-12页

作者： Zheng Zhao Ke-Nan Zhang Qiangwei Wang Guanzhang Li Fan Zeng Ying Zhang Fan Wu Ruichao Chai Zheng Wang Chuanbao Zhang Wei Zhang zhaoshi bao Tao Jiang Beijing Neurosurgical Institute Capital Medical UniversityBeijing 100070China Department of Neurosurgery The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310009China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Center of Brain Tumor Beijing Institute for Brain DisordersBeijing 100069China China National Clinical Research Center for Neurological Diseases Beijing 100070China

Gliomas are the most common and malignant intracranial tumors in adults.Recent studies have revealed the significance of functional genomics for glioma pathophysiological studies and treatments.However,access to comprehensive genomic data and analytical platforms is often limited.Here,we developed the Chinese Glioma Genome Atlas(CGGA),a user-friendly data portal for the storage and interactive exploration of cross-omics data,including nearly 2000 primary and recurrent glioma samples from Chinese cohort.Currently,open access is provided to whole-exome sequencing data(286 samples),mRNA sequencing(1018 samples)and microarray data(301 samples),DNA methylation microarray data(159 samples),and microRNA microarray data(198 samples),and to detailed clinical information(age,gender,chemoradiotherapy status,WHO grade,histological type,critical molecular pathological information,and survival data).In addition,we have developed several tools for users to analyze the mutation profiles,mRNA/microRNA expression,and DNA methylation profiles,and to perform survival and gene correlation analyses of specific glioma subtypes.This database removes the barriers for researchers,providing rapid and convenient access to high-quality functional genomic data resources for biological studies and clinical applications.CGGA is available at http://***.

关键词： Glioma Functional genomics Chinese Glioma Genome Atlas Chinese cohort Database

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MET fusions and splicing variants convergently defne a subgroup of glioma sensitive to MET inhibitors

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Holistic Integrative Oncology 2022年第1期1卷 244-254页

作者： Ke-Nan Zhang Zheng Zhao Jing Chen zhaoshi bao Rui-Chao Chai Zhiyan Sun Lingxiang Wu Zhiliang Wang Hanjie Liu Quanhua Mu Huimin Hu Fan Zeng Zheng Wang Guanzhang Li Yuanhao Chang Qiangwei Wang Fan Wu Ying Zhang Yuqing Liu Chunjie Jiang Ulf Dietrich Kahlert Do-Hyun Nam Wei Zhang Chunsheng Kang Jiguang Wang Rongjie Tao Qianghu Wang Tao Jiang Beijing Neurosurgical Institute Capital Medical UniversityBeijingChina Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Department of Bioinformatics Nanjing Medical UniversityNanjingJiangsuChina Department of Chemical and Biological Engineering Divison of Life ScienceCenter for Systems Biology and Human Healthand State Key Laboratory of Molecular NeuroscienceThe Hong Kong University of Science and TechnologyHong KongChina Division of Diabe‑tes Endocrinologyand MetabolismDepartment of MedicineBaylor College of MedicineHoustonTXUSA Molecular and Experimental Surgery Faculty of Medicine and University Medicine MagdeburgMagdeburgGermany Institute for Refractory Cancer Research Samsung Medical CenterSeoulRepublic of Korea Department of Health Science&Technology Samsung Advanced Institute for Health Sciences&Technology(SAIHST)Sungkyunkwan UniversitySeoulRepublic of Korea Department of Neurosurgery Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea Laboratory of Neuro‑Oncology Ministry of Education and Tianjin CityTianjin Neurological InstituteTianjin Medical University General HospitalKey Laboratory of PostNeuro Injury Neuro-Repair and Regeneration in Central Nervous SystemTianjinChina Departments of Neurosurgery Shandong Cancer Hospital and InstituteShandong UniversityJinanShandongChina Center of Brain Tumor Beijing Institute for Brain DisordersBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina Research Unit of Accurate Diagnosis Treatmentand Translational Medicine of Brain TumorsChinese Academy of Medical SciencesBeijingChina

Purpose:Our previous study has shown that PTPRZ1-MET(ZM)fusion is a viable target for MET inhibitors in gliomas.However,the diversity and prevalence of somatic MET alterations in difuse gliomas are still elusive and need to be extensively characterized for identifying novel therapeutic targets.Methods:Totally,1,350 glioma patients and 31 patient-derived cells were collected from the Chinese Glioma Genome Atlas(CGGA)and published data.All kinds of MET fusions and/or splicing variants(MET F/SVs)were identifed by bioinformatical methods.Single-cell RNA sequencing(scRNA-seq)were used for validation.In vitro experiments of drug resistance were conducted for the possibility of MET-targeted treatment.Results:MET F/SVs but not genomic amplifcation,were highly enriched in the secondary glioblastomas(sGBM)and marked worse prognosis.Further molecular and scRNA-seq analysis revealed that MET F/SVs were induced in the course of glioma evolution and highly associated with MET overexpression.Subsequent in vitro and the clinical study showed that cells and patients harboring MET F/SVs have better response to MET inhibitors.Conclusion:Our fndings expanded the percentage of gliomas with abnormal MET alterations and suggested that a subgroup of gliomas harboring MET F/SVs may beneft from MET-targeted therapy.

关键词： MET variation Secondary glioblastoma Biomarker MET inhibitor Precision neuro-oncology

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CACA guidelines for holistic integrative management of glioma

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Holistic Integrative Oncology 2022年第1期1卷 292-317页

作者： Daiming Fan Tao Jiang Wenbin Ma Chuanlu Jiang Yongping You Ying Mao Xiaoguang Qiu Chunsheng Kang Gang Li Qing Mao Xuejun Yang Zhiyong Qin Zhixiong Liu Weimin Wang Xinting Wei Wenbin Li Yunhui Liu Rutong Yu Xinguang Yu Dezhi Kang Yonggao Mou Lei Wang Wei Zhang zhaoshi bao Ruichao Chai baoshi Chen Xing Fan Shengyu Fang Guanzhang Li Lianwang Li Shouwei Li Xing Liu Yanwei Liu Xia Shan Liang Wang Yinyan Wang Yu Wang Zheng Wang Zhiliang Wang Chenxing Wu Wei Yan Pei Yang Gan You Chuanbao Zhang Zhong Zhang Zheng Zhao Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityNo.119 South 4th Ring West RoadFengtai DistrictBeijing 100070China

Glioma of the brain is a kind of tumor originating from neuroglial cells.It is the most common primary intracranial tumor,accounting for~30%of all central nervous system tumors and 80% of malignant brain tumors.Glioma is characterized by high disability and recurrence rates.The disease seriously threatens the life of patients,afects their quality of life,and brings a heavy economic and psychological burden to patients,families,and society.With the progression of molecular genetic testing technology and the completion of various clinical trials,the classifcation scheme for glioma is increasingly well established.Diagnosis and treatment regimens,including traditional and new regimens,are becoming increasingly specialized and standardized.The purpose is to develop a clinical diagnosis and treatment guideline for glioma in the Chinese population suitable for Chinese doctors and the general population based on domestic and international glioma research progress.Thus,domestic practitioners in the feld can obtain current information and provide better service to patients with glioma,promoting the development of domestic clinical medicine and basic research on glioma.

关键词： Glioma Clinical guideline Holistic integrative medicine

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造血系细胞特异蛋白1基因在脑胶质瘤中的表达及其意义

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中华神经外科杂志 2021年第5期37卷 516-522页

作者：张莹黄华曾凡保肇实首都医科大学北京市神经外科研究所100070 首都医科大学附属北京天坛医院神经外科 100070

目的分析造血系细胞特异蛋白1(HCLS1)基因在脑胶质瘤中的表达特征及其意义。方法收集中国脑胶质瘤基因组图谱(CGGA)计划数据库的两套mRNA测序数据及其临床资料(CGGA325数据集325例,CGGA693数据集693例)。分析HCLS1在不同世界卫生组织(W... 详细信息

目的分析造血系细胞特异蛋白1(HCLS1)基因在脑胶质瘤中的表达特征及其意义。方法收集中国脑胶质瘤基因组图谱(CGGA)计划数据库的两套mRNA测序数据及其临床资料(CGGA325数据集325例,CGGA693数据集693例)。分析HCLS1在不同世界卫生组织(WHO)病理学分级、异柠檬酸脱氢酶(IDH)突变状态、2016年中枢神经系统肿瘤分类、O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)启动子甲基化状态的脑胶质瘤患者中的表达特征。根据HCLS1表达量的中位数,将患者分为高表达组和低表达组,绘制Kaplan-Meier生存曲线,采用log-rank检验比较不同HCLS1表达水平患者的生存差异。采用单因素和多因素Cox回归分析判断脑胶质瘤患者总生存期的影响因素。收集2007年1月至2015年10月首都医科大学附属北京天坛医院神经外科收治的脑胶质瘤患者的脑胶质瘤样本和生存信息(实验组1共27例,实验组2共17例),实验组1采用实时荧光定量聚合酶链式反应(qRT-PCR)检测HCLS1的表达量,实验组2采用免疫组织化学染色检测HCLS1蛋白的表达情况,并计算免疫组织化学染色评分。采用生物信息学方法分析HCLS1的生物学功能。结果在CGGA325数据集中,HCLS1的表达量随WHO病理学级别(Ⅱ~Ⅳ级)的升高而增加(F=30.29,P<0.001);HCLS1在IDH野生型中的表达量高于IDH突变型(t=8.51,P<0.001);依据2016年的中枢神经系统肿瘤分类,3组低级别脑胶质瘤患者中,HCLS1表达量在IDH突变+1p/19q联合缺失组最低(F=23.61,P<0.001),而两组高级别脑胶质瘤患者中,HCLS1在IDH野生组的表达高于IDH突变组(P<0.001);MGMT启动子非甲基化者的HCLS1表达量高于甲基化者(P=0.001);HCLS1高表达组患者的总生存期短于低表达组(P<0.001)。HCLS1的上述表达特征在CGGA693数据集中得到了验证。多因素Cox回归分析结果显示,HCLS1表达量是影响脑胶质瘤患者总生存期的独立危险因素(HR=1.951,95%CI:1.307~2.910,P=0.001)。qRT-PCR结果显示,HCLS1的表达量随WHO病理学级别的升高而增加(F=11.11,P<0.001)。免疫组织化学染色评分结果显示,HCLS1蛋白在WHOⅡ~Ⅳ级组织样本中的评分依次为(1.33±0.21)分、(3.40±0.87)分及(7.67±0.88)分,组间差异有统计学意义(F=21.88,P<0.001)。实验组1和2中,HCLS1基因和蛋白高表达患者的总生存期均短于低表达者(均P<0.05)。生物信息学分析提示,HCLS1可能与脑胶质瘤细胞的免疫反应有关。结论HCLS1的表达量与脑胶质瘤的恶性程度及患者的生存期有关,可作为判断患者预后的潜在指标。

关键词：神经胶质瘤基因预后免疫造血系细胞特异蛋白1

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DLX5基因表达及潜在调控机制预示胶质母细胞瘤不良预后

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中国微侵袭神经外科杂志 2019年第8期24卷 364-369页

作者：保肇实王强威王永志首都医科大学附属北京天坛医院神经外科 100070 北京市神经外科研究所分子病理室 100070

目的初步探究人类无远端同源框基因家族5 (distal-less homeobox,DLX 5)是否与胶质瘤病人预后相关及可能机制。方法采用来自中国脑胶质瘤基因图谱数据库(CGGA)的83个原发胶质母细胞瘤(primary glioblastoma multiform,pGBM)病人进行全... 详细信息

目的初步探究人类无远端同源框基因家族5 (distal-less homeobox,DLX 5)是否与胶质瘤病人预后相关及可能机制。方法采用来自中国脑胶质瘤基因图谱数据库(CGGA)的83个原发胶质母细胞瘤(primary glioblastoma multiform,pGBM)病人进行全基因组表达芯片检测。结果在m RNA表达谱中鉴定出两组样本(称为G1组和G2组)。G1组富集基因主要与神经细胞分化和发育有关,G2组富集基因主要发挥免疫功能。在所有相关富集基因中,DLX5与病人预后显著相关(P <0.001,OR=1.255)。在83例pGBM病人中,DLX5高表达病人中位生存期47.8周,DLX5低表达病人中位生存期72.9周,DLX5高表达病人生存率较低(P <0.01)。在长生存期pGBM病人中,DLX5甲基化水平较高,且mi RNA表达水平与DLX5表达量有明显相关性。结论 DLX5高表达可作为pGBM病人不良预后标志物,为pGBM病人药物研发提供潜在靶点。

关键词：胶质母细胞瘤中国脑胶质瘤基因组数据库全转录基因芯片预后分析

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继发胶质母细胞瘤基因突变全景图指导下的靶向MET的脑肿瘤临床试验

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科学新闻 2019年第2期 51-51页

作者： Huimin Hu Quanhua Mu zhaoshi bao Yiyun Chen Yanwei Liu Jing Chen Kuanyu Wang Zheng Wang Yoonhee Nam Biaobin Jiang Jason K.Sa.Hee-Jin Cho Nam-Gu Her Chuanbao Zhang Zheng Zhao Ying Zhang Fan Zeng Fan Wu Xun Kang Yuqing Liu Zenghui Qian Zhiliang Wang Ruoyu Huang Qiangwei Wang Wei Zhang Xiaoguang Qiu Wenbin Li Do-Hyun Nam 樊小龙王吉光江涛北京师范大学生命科学院香港科技大学北京市神经外科研究所

文章简介低级别胶质瘤几乎全部会进展到高级别的继发胶质母细胞瘤,且该进展过程的机制并不明晰,也没有阻止进展的治疗手段。通过研究188例继发胶质母细胞瘤的基因突变全景图,研究人员发现TP53突变、体细胞超突变、MET14外显子跳跃、PTPR... 详细信息

文章简介低级别胶质瘤几乎全部会进展到高级别的继发胶质母细胞瘤,且该进展过程的机制并不明晰,也没有阻止进展的治疗手段。通过研究188例继发胶质母细胞瘤的基因突变全景图,研究人员发现TP53突变、体细胞超突变、MET14外显子跳跃、PTPRZ1-MET融合基因及MET扩增显

关键词：胶质母细胞瘤外显子跳跃临床试验 MET 基因突变肿瘤临床

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