CHARACTERIZING AGGRESSIVE GLIOMA COPY NUMBER SUBTYPES

项目摘要/摘要 这份提案描述了一项为期5年的职业发展计划，在该计划中，申请人的最终目标是成为一名 独立的内科医生-科学家，专注于神经病理学的临床实践和专门的研究实验室 对弥漫性胶质瘤的研究。拟议的研究项目将利用以下网址提供的专门知识和资源 华盛顿大学/弗雷德·哈钦森癌症研究中心癌症联盟，该联盟拥有一条经过验证的轨道 培养内科医生-科学家的记录。埃里克·霍兰德博士是胶质瘤和癌症生物学小鼠模型的专家，他将 担任申请者的研究导师。弥漫性胶质瘤是最常见和最恶性的原发肿瘤。 成人的颅内肿瘤。此外，在过去的几十年里，在延长 弥漫性胶质瘤患者的生存，目前还没有有效的靶向治疗方法。一项建议 弥漫性胶质瘤治疗反应差的机制在于瘤内和瘤间的分子和细胞 构成这些肿瘤的异质性。在过去的三年里，申请人在霍兰德博士的实验室工作过 解决胶质瘤中的这种分子异质性，特别是研究体细胞拷贝数的作用 更改(SCNA)。通过对成人胶质瘤队列的拷贝数分析，定义了预后的SCNA亚型 在中位存活率和选择方面的明显差异被发现存在于较小的队列中，这具有一定的意义 关于临床试验设计和对普通人群的适用性。除了这些人类生物标记物项目外，对 临床前胶质瘤小鼠模型一直在进行中，以开始阐明与SCNAs相关的遗传驱动因素 神经胶质瘤。一项这样的研究发现HOXA5是胶质瘤7号染色体增加的驱动因素，HOXA5驱动着 侵袭性胶质瘤表型，包括体内介导的辐射抵抗。结合申请人之前发表的 结合其他初步数据，SCNA亚型的基本生物学将在当前的提案中讨论， 主要通过构建SCNA亚型小鼠脑胶质瘤模型，对其进行功能鉴定(AIM 1)。此外，SCNA亚型特异性反应对标准治疗的组织和细胞后果(目的 2)以及免疫疗法(目标3)的特点。总的来说，候选人在人类和动物方面的背景 研究性和诊断性神经病理学非常适合于这个有指导的研究项目 SCNAs在胶质瘤中的生物学后果，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模型系统，用于研究胶质瘤相关的SCNA和 相关驱动基因在胶质瘤发生中的作用，这将为申请者提供独立的 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.