CHARACTERIZING AGGRESSIVE GLIOMA COPY NUMBER SUBTYPES

项目总结/摘要 该提案描述了一个为期5年的职业发展计划，申请人的最终目标是成为一名 独立的医生，科学家，专注于神经病理学的临床实践和研究实验室， 弥漫性神经胶质瘤的研究。拟议的研究项目将利用现有的专业知识和资源， 华盛顿大学/弗雷德哈钦森癌症研究中心癌症联盟， 发展物理科学家的记录。神经胶质瘤和癌症生物学小鼠模型专家埃里克·霍兰德博士将 担任申请人的研究导师。弥漫性神经胶质瘤包括最常见和恶性的原发性 成人颅内肿瘤。此外，在过去几十年里， 弥漫性胶质瘤患者的生存率，目前还没有有效的靶向治疗方法。一个提议的 弥漫性胶质瘤治疗反应差的机制在于肿瘤内和肿瘤间的分子和细胞 异质性组成了这些肿瘤。在过去的3年里，申请人在荷兰博士的实验室工作， 解决胶质瘤内的这种分子异质性，特别是研究体细胞拷贝数的作用 变更（SCNA）。通过成人胶质瘤队列的拷贝数分析，确定了预后SCNA亚型 中位生存率和选择偏差存在明显差异，这表明 临床试验设计和对一般人群的适用性。沿着这些人类生物标志物项目， 临床前神经胶质瘤小鼠模型已经在进行中，开始阐明与SCNA相关的遗传驱动因素， 胶质瘤一项这样的研究将HOXA 5确定为神经胶质瘤中7号染色体获得的驱动因子，HOXA 5驱动神经胶质瘤细胞的增殖。 侵袭性胶质瘤表型，包括介导体内放射抗性。结合申请人先前公布的 与其他初步数据一起工作，SCNA亚型的基础生物学将在当前提案中得到解决， 主要通过构建SCNA亚型胶质瘤小鼠模型，其将被功能表征（Aim 1）。此外，SCNA亚型特异性反应对标准治疗的生物和细胞后果（目的 2)以及免疫疗法（目标3）将被表征。总的来说，候选人的人类和动物背景 调查和诊断神经病理学非常适合这个指导研究项目，重点是表征 神经胶质瘤中SCNAs的生物学后果，并可能产生治疗这种恶性肿瘤的新方法。 重要的是，这项研究还建立了一个研究神经胶质瘤相关SCNA的模型系统， 相关的驱动基因，这将为申请人提供独立的基础， 研究计划。

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year career development program in which the applicant’s ultimate goal is to become an independent physician-scientist with a focused clinical practice in neuropathology and a research laboratory dedicated to the study of diffuse gliomas. The proposed research project will capitalize on the expertise and resources available at the University of Washington/Fred Hutchinson Cancer Research Center Cancer Consortium, which has a proven track record of developing physician-scientists. Dr. Eric Holland, an expert in mouse models of glioma and cancer biology, will serve as the applicant’s research mentor. Diffuse gliomas comprise the most common and malignant primary intracranial neoplasms in adults. Furthermore, over the last several decades there has been little success in prolonging the survival of patients with diffuse glioma, and there is yet to be effective targeted therapies. One proposed mechanism for poor treatment response of diffuse glioma lies in the intra- and inter-tumoral molecular and cellular heterogeneity that make up these tumors. Over the last 3 years, the applicant has worked in Dr. Holland’s laboratory to address this molecular heterogeneity within glioma, specifically investigating the role of somatic copy number alterations (SCNAs). Through copy number profiling across adult glioma cohorts, prognostic SCNA subtypes were defined with clear differences in median survival and selection biases were found to exist in smaller cohorts, having implications on clinical trial design and applicability to the general population. Along with these human biomarker projects, studies of pre-clinical glioma mouse models have been underway to begin to elucidate genetic drivers associated with SCNAs in glioma. One such study identified HOXA5 as being a driver of chromosome 7 gain in glioma, with HOXA5 driving an aggressive glioma phenotype including mediating radioresistance in vivo. Combining the applicant’s previously published work with other preliminary data, the underlying biology of SCNA subtypes will be addressed in the current proposal, primarily through the construction of SCNA subtype glioma mouse models, which will be functionally characterized (Aim 1). Additionally, the organismal and cellular consequences of SCNA subtype-specific responses to standard therapy (Aim 2) as well as immunotherapy (Aim 3) will be characterized. Overall, the candidate’s background in human and animal investigative and diagnostic neuropathology is well-suited for this mentored research project focused on characterizing biological consequences of SCNAs in gliomas and may yield novel approaches for the treatment of this malignancy. Importantly, the proposed research also establishes a model system for studying glioma-associated SCNAs and associated driver genes in gliomagenesis, which will provide the applicant with the foundation for an independent research program.