Identification and Characterization of Kinase Oncogenes in Glioblastoma

胶质母细胞瘤中激酶癌基因的鉴定和表征

• 批准号: 7385342
• 负责人: LYNDA CHIN
• 金额: $ 21.79万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/7385342
• 关键词: 1-Phosphatidylinositol 3-Kinase; Anchorage-Independent Growth; Astrocytes; Atlases; Behavior; Biochemical; Biological; Biological Assay; Biological Models; Candidate Disease Gene; Cell Line; Cell Proliferation; Cell Survival; Cells; Class; Classification; Clinical; Clinical Trials; Collaborations; Collection; Color; Computer Simulation; Data; Depth; Development; Disease; EGFR Protein Overexpression; Engineering; Epidermal Growth Factor Receptor; Evaluation; Event; Excision; Exhibits; Flowcharts; Funding; Gene Expression Profile; Gene Transfer Techniques; Genes; Genetic; Genetic Screening; Genetically Engineered Mouse; Genome; Genomic Instability; Genomics; Glioblastoma; Glioma; Goals; Human; Immunohistochemistry; In Vitro; Institutes; Invasive; Investigation; Knowledge; Laboratories; Lasers; Lesion; Libraries; Maintenance; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of central nervous system; Mammalian Cell; Maps; Methods; Mining; Modeling; Morphologic artifacts; Mus; Mutate; Mutation; Numbers; Oncogenes; Oncogenic; Operative Surgical Procedures; PIK3CA gene; PTEN gene; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Pilocytic Astrocytoma; Pilot Projects; Platelet-Derived Growth Factor; Play; Pre-Clinical Model; Principal Investigator; Process; Protein Overexpression; Proteins; RNA Interference; Recurrence; Research; Research Personnel; Resected; Resources; Right-On; Role; Sampling; Scanning; Signal Pathway; Signal Transduction; Staging; System; Therapeutic Agents; Therapeutic Intervention; Therapeutic Studies; Time; Tissue Microarray; Translations; Tumor Suppressor Genes; Tumorigenicity; Validation; Work; Yeasts; base; drug development; functional genomics; gain of function; human PIK3CA protein; improved; in vivo; inhibitor/antagonist; insight; loss of function; member; method development; mutant; neoplastic cell; neuropathology; novel; novel therapeutics; outcome forecast; pre-clinical; preclinical study; programs; small molecule; stem; tumor; tumor initiation

Malignant gliomas are the most common and lethal primary central nervous system cancers and are stratified into distinct pathologic grades with well-known biologic behaviors. Although Grade I astrocytomas exhibit defined margins and may be removed surgically, most patients present with tumors that cannot be resected for anatomical reasons or at higher, more invasive stages of disease that preclude complete surgical resection. Work from many laboratories has identified mutations present in a high percentage of glioblastomas including constitutively active mutant epidermal growth factor receptor (EGFR*), inactivating mutations of PTEN, overexpression of platelet-derived growth factor (PDGF), and loss of the cyclindependent kinase 2A (CDKN2A) tumor suppressor gene. However, recent work using genome scale methods to identify regions of copy number aberrations have revealed a bewildering array of recurrent regions of amplification and deletion, presumably targeting yet-to-be-discovered glioma-relevant oncogenes and tumor suppressors. In this project we propose a systematic approach to identify oncogenes beyond those studied in Projects 1 and 2 involved in the pathogenesis of glioblastoma. We will focus on kinase and other potentially targets currently amendable to drug development in order to identify oncogenes with the highest potential for clinical translation. By combining oncogenomics and high throughput RNA interference, we will identify a set of putative oncogenes that are not only amplified in glioblastomas but also necessary for their proliferation and survival. We will then determine the roles of these candidates in tumor initiation and maintenance in functional assays in human and murine models of transformation and determine their expression patterns in patient derived glioblastoma samples. Using unbiased and pathway specific approaches, we will search for small molecule inhibitors targeting the oncogenes identified in these studies and determine the functional relationship of these oncogenes with other signature mutations in glioblastoma pathogenesis as a prelude to preclinical studies. Relevance: Despite progress in defining signature mutations in glioblastoma, the prognosis of patients with glioblastoma remains poor, and we lack curative targeted therapies for this disease. This project will identify and validate glioblastoma-relevant oncogenes, focusing on protein classes amenable,to the development of novel therapeutic agents.

恶性神经胶质瘤是最常见和致命的原发性中枢神经系统癌症， 分层为具有众所周知的生物学行为的不同病理等级。虽然I级星形细胞瘤 表现出明确的边缘，可以通过手术切除，大多数患者的肿瘤无法切除 由于解剖原因或在疾病的更高、更具侵袭性的阶段被切除，从而无法完全切除 手术切除。许多实验室的工作已发现突变存在于高比例的 胶质母细胞瘤包括组成型活性突变表皮生长因子受体 (EGFR*)、失活 PTEN 突变、血小板衍生生长因子 (PDGF) 过度表达以及细胞周期蛋白依赖性缺失 激酶 2A (CDKN2A) 肿瘤抑制基因。然而，最近使用基因组规模的工作 识别拷贝数畸变区域的方法揭示了一系列令人眼花缭乱的反复出现的现象 扩增和缺失区域，可能针对尚未发现的神经胶质瘤相关癌基因 和肿瘤抑制剂。 在这个项目中，我们提出了一种系统方法来识别超出研究范围的致癌基因。 项目1和2涉及胶质母细胞瘤的发病机制。我们将重点关注激酶和其他潜在的 目前可修改药物开发的目标，以确定具有最高潜力的致癌基因 临床翻译。通过结合肿瘤基因组学和高通量 RNA 干扰，我们将确定一组 推定的癌基因不仅在胶质母细胞瘤中扩增，而且是其增殖所必需的 和生存。然后我们将确定这些候选者在肿瘤发生和维持中的作用 在人类和小鼠转化模型中进行功能测定并确定它们的表达模式 患者来源的胶质母细胞瘤样本。使用公正和特定途径的方法，我们将寻找 针对这些研究中确定的癌基因的小分子抑制剂，并确定其功能 这些癌基因与胶质母细胞瘤发病机制中其他特征突变的关系作为前奏 临床前研究。 相关性：尽管在定义胶质母细胞瘤特征突变方面取得了进展，但患者的预后 胶质母细胞瘤的治疗效果仍然较差，而且我们缺乏针对这种疾病的有效靶向治疗方法。该项目将 识别并验证与胶质母细胞瘤相关的癌基因，重点关注适合的蛋白质类别 开发新型治疗剂。