Discovering And Modeling Genetic Events Driving Glioblastoma Pathogenesis

发现和模拟驱动胶质母细胞瘤发病机制的遗传事件

基本信息

批准号：
7385339
负责人：
RONALD ANTHONY DEPINHO
金额：
$ 37.88万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-10 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7385339
关键词：
Address Adult Alleles Antibodies Apoptosis Astrocytes Astrocytoma Automobile Driving Belief Biochemical Biological Biological Models Brain Brain Neoplasms Bypass Candidate Disease Gene Caspase Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Line Cell Proliferation Cells Cessation of life Classification Clinical Color Combined Modality Therapy Complement Condition Data Depth Development Diffuse Disease Disease Progression EGFR inhibition Embryo End Point Engineering Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Evaluation Event Excision Exons Exposure to Extinction (Psychology)Facility Construction Funding Category Failure Feedback Foundations Funding Gene Mutation Genes Genetic Genetic Markers Genetic Models Genomics Genotype Glioblastoma Glioma Gliomagenesis Goals Grant Histopathology Human Immunohistochemistry In Vitro Incidence Injection of therapeutic agent Intracranial Neoplasms Investments Knock-in Mouse Knock-out Lesion Maintenance Malignant Glioma Malignant Neoplasms Mitochondria Modeling Molecular Mus Mutation Necrosis Neoplasms Oncogenes Oncogenic PDGFRB gene PTEN gene Pathogenesis Pattern Phenocopy Phenotype Play Positioning Attribute Pre-Clinical Model Primary Neoplasm Principal Investigator Property Protein Overexpression Proteins Proteomics RNA Interference Range Rate Reagent Receptor Protein-Tyrosine Kinases Recurrence Refractory Relative (related person)Resistance Resolution Resources Role Sampling Signal Pathway Signal Transduction Site Specimen System Testing Tetanus Helper Peptide Therapeutic Time Tissue Model Transgenes Transgenic Organisms Treatment Protocols Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Derived Validation Work angiogenesis base caspase-3 comparative drug development drug discovery genetic element human disease in vivo inhibitor/antagonist metaplastic cell transformation mouse model neoplastic cell nestin protein novel novel therapeutics postnatal pre-clinical programs receptor expression research study response transcriptomics tumor tumor xenograft

Address Adult Alleles Antibodies Apoptosis Astrocytes Astrocytoma Automobile Driving Belief Biochemical Biological Biological Models Brain Brain Neoplasms Bypass Candidate Disease Gene Caspase Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Line Cell Proliferation Cells Cessation of life Classification Clinical Color Combined Modality Therapy Complement Condition Data Depth Development Diffuse Disease Disease Progression EGFR inhibition Embryo End Point Engineering Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Evaluation Event Excision Exons Exposure to Extinction (Psychology)Facility Construction Funding Category Failure Feedback Foundations Funding Gene Mutation Genes Genetic Genetic Markers Genetic Models Genomics Genotype Glioblastoma Glioma Gliomagenesis Goals Grant Histopathology Human Immunohistochemistry In Vitro Incidence Injection of therapeutic agent Intracranial Neoplasms Investments Knock-in Mouse Knock-out Lesion Maintenance Malignant Glioma Malignant Neoplasms Mitochondria Modeling Molecular Mus Mutation Necrosis Neoplasms Oncogenes Oncogenic PDGFRB gene PTEN gene Pathogenesis Pattern Phenocopy Phenotype Play Positioning Attribute Pre-Clinical Model Primary Neoplasm Principal Investigator Property Protein Overexpression Proteins Proteomics RNA Interference Range Rate Reagent Receptor Protein-Tyrosine Kinases Recurrence Refractory Relative (related person)Resistance Resolution Resources Role Sampling Signal Pathway Signal Transduction Site Specimen System Testing Tetanus Helper Peptide Therapeutic Time Tissue Model Transgenes Transgenic Organisms Treatment Protocols Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Derived Validation Work angiogenesis base caspase-3 comparative drug development drug discovery genetic element human disease in vivo inhibitor/antagonist metaplastic cell transformation mouse model neoplastic cell nestin protein novel novel therapeutics postnatal pre-clinical programs receptor expression research study response transcriptomics tumor tumor xenograft

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项目摘要

Glioblastoma multiforme(GBM) is universally lethal and lacks durable responses to all targeted and conventional therapies tested to date including inhibitors of its signature lesion, EGFR. We believe that clinical progress will derive from a more comprehensive view of the underlying genetics of GBM and an intensive functional and clinical validation of targets in physiologically relevant preclinical model systems. Project 1 experiments are directed towards understanding tHe role of various signature mutations and several newly discovered cancer genes in the development of GBM and how these genetic factors influence GBM's tumor biological properties and their responses to therapy. We have developed a mouse model of high-grade glioma engineered with the same mutations encountered in human primary GBM: conditional activated EGFR knock-in as well as conditional Ink4a/Arf and Pten knockout alleles. As a result of our high resolution genomic and proteomic studies, we have also identified many new oncogenes (e.g., Bcl2L12) and tumor suppressor genes (e.g., p18INK4C) as well as a repertoire of novel functionally active receptor tyrosine kinases (RTKs) with notably distinct co-expression patterns. Remarkably, we have preliminary evidence showing that some of these co-expressed RTKs can functionally substitute for EGFR signaling upon treatment with EGFR inhibitors and that dual inhibition of EGFR and other RTKs yields dramatic biochemical and biological responses for the first time. These advances, together with our new mouse model and equivalent human systems, provide a strong foundation to validate several key genes in GBM pathogenesis with the goal of identifying the best targets and combination therapies for this disease. To accomplish these goals, we will work with Projects 2 and 3 and all of the Cores, to refine our high-grade glioma model (Gradell/lll) with additional key alleles. Specifically, OHT-responsive GFAP-CreER and tet-inducible transgenic strategies will be utilized to enable somatic alteration of PTEN, p18lnk4c, and/or Bcl2L12 in the adult brain, and hence provide an opportunity to assess whether these alleles alone or in combination can drive progression in the setting of EGFR activation and Ink4a/Arf deficiency. These models will be subjected to extensive characterization on the tumor biological, molecular and genomic levels and will be used to test the role of Bcl2L12 and certain RTKs including MET in the response to EGFR inhibition. With regard to RTKs, significant initial effort will be directed towards defining the role of MET in GBM pathogenesis and its ability to provide a bypass mechanism in the setting of EGFR inhibition. Along similar lines, genetic and pharmacologic strategies as well as mouse and human model systems will be used to determine whether several RTKs co-expressed and activated in GBM can drive the development of GBM and provide a basis for resistance to RTK therapy.

胶质母细胞瘤多形（GBM）普遍致命，缺乏对所有目标和目标的持久反应迄今为止已测试的常规疗法包括其签名病变的抑制剂EGFR。我们相信临床进展将源于对GBM和A的潜在遗传学的更全面的看法生理相关的临床前模型系统中靶标的密集功能和临床验证。项目1实验是针对理解各种签名突变和几个新发现的癌症基因在GBM的发展中以及这些遗传因素如何影响 GBM的肿瘤生物学特性及其对治疗的反应。我们已经开发了一个鼠标模型在人类初级GBM中遇到相同突变的高级神经胶质瘤：条件激活的EGFR敲入以及有条件的INK4A/ARF和PTEN敲除等位基因。由于我们高解决基因组和蛋白质组学研究，我们还确定了许多新的癌基因（例如Bcl2l12）和肿瘤抑制基因（例如P18INK4C）以及新型功能活性受体酪氨酸的曲目具有明显不同的共表达模式的激酶（RTK）。值得注意的是，我们有初步证据表明这些共表达的RTK可以在功能上替代EGFR信号传导用EGFR抑制剂治疗以及对EGFR和其他RTK的双重抑制作用可产生戏剧性的生化和生物学反应首次。这些进步以及我们的新鼠标模型和等效的人类系统，为验证GBM发病机理中的多个关键基因提供了坚实的基础目的是确定该疾病的最佳靶标和组合疗法。完成这些目标，我们将与项目2和3和所有核心合作，以完善我们的高级神经胶质瘤模型（gradell/lll）带有其他密钥等位基因。具体而言，OHT响应的GFAP-CREER和TET-CRIBLECERE 转基因策略将用于实现PTEN，P18LNK4C和/或BCL2L12的躯体改变成人大脑，因此提供了一个机会，可以评估这些等位基因单独或组合是否可以在EGFR激活和INK4A/ARF缺乏症的设置中驱动进程。这些模型将受到在肿瘤生物学，分子和基因组水平上进行广泛的表征，并将用于测试 BCl2L12和包括某些RTK在对EGFR抑制的响应中的作用。关于 rtks，将针对定义MET在GBM发病机理及其ITS中的作用的大量初步努力。在EGFR抑制的情况下提供旁路机制的能力。沿着类似的线，遗传和药理策略以及小鼠和人类模型系统将用于确定是否是否在GBM中共表达和激活的几个RTK可以推动GBM的发展，并提供基础抗RTK治疗。