Identification and Characterization of Kinase Oncogenes in Glioblastoma

恶性胶质瘤是最常见和最致命的原发中枢神经系统癌症， 分成不同的病理级别，具有众所周知的生物学行为。尽管I级星形细胞瘤 表现出明确的边缘，可以通过手术切除，大多数患者的肿瘤不能 因解剖学原因或在更高、更具侵袭性的疾病阶段切除 手术切除。许多实验室的工作已经确定了在很高比例的 胶质母细胞瘤，包括成分活性突变的表皮生长因子受体(EGFR*)，失活 PTEN突变、血小板衍生生长因子(PDGF)过表达和细胞周期依赖性基因缺失 蛋白激酶2A(CDKN2A)抑癌基因。然而，最近使用基因组规模的工作 识别拷贝数异常区域的方法揭示了一系列令人困惑的复发性 扩增和缺失区域，可能针对尚未发现的胶质瘤相关癌基因 和肿瘤抑制因子。 在这个项目中，我们提出了一种系统的方法来识别那些在 蛋白1和蛋白2参与了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 目前可修改的药物开发靶点，以确定具有最高潜力的癌基因 临床翻译。通过结合癌基因组学和高通量RNA干扰，我们将识别一组 可能的癌基因不仅在胶质母细胞瘤中扩增，而且对其增殖也是必要的 和生存。然后我们将确定这些候选基因在肿瘤启动和维持中的作用 在人和小鼠转化模型中的功能分析并确定其在 患者来源的胶质母细胞瘤样本。使用不偏不倚和路径特定的方法，我们将搜索 以这些研究中确定的癌基因为靶点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标志性突变的关系 临床前研究。 相关性：尽管在确定胶质母细胞瘤标志性突变方面取得了进展，但患者的预后 胶质母细胞瘤的发病率仍然很低，我们缺乏针对这种疾病的根治性靶向治疗。这个项目将 识别和验证与胶质母细胞瘤相关的癌基因，重点是服从于 新型治疗剂的开发。

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.