CHARACTERIZING AGGRESSIVE GLIOMA COPY NUMBER SUBTYPES

侵袭性神经胶质瘤拷贝数亚型的特征

• 批准号: 10226337
• 负责人: Patrick J. Cimino
• 金额: $ 25.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-05-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226337
• 关键词: Abscopal effect; Address; Adult; Adult Glioma; Affect; Animals; Antigens; Automobile Driving; Biological; Biological Markers; Biological Models; Biology; CDK4 gene; CDKN2A gene; CRISPR/Cas technology; Cancer Biology; Cancer Center; Cell Communication; Cell Cycle; Cell Proliferation; Cells; Chemotherapy and/or radiation; Chromosome 12; Clinical; Clinical Trials; Clinical Trials Design; Data; Diagnostic; Diffuse; Down-Regulation; Foundations; Fred Hutchinson Cancer Research Center; Gene Expression Profile; Gene Expression Profiling; Gene Transfer; General Population; Genes; Genetic; Genetic Transcription; Glioblastoma; Glioma; Gliomagenesis; Goals; Heterogeneity; Human; Human Cell Line; Human Chromosomes; Immune; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunologic Techniques; Immunotherapy; Infiltration; Intracranial Neoplasms; Isocitrate Dehydrogenase; Laboratories; Laboratory Research; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MDM2 gene; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Mediating; Mentors; Modeling; Molecular; Mus; Mutation; Outcome; Pathway interactions; Patients; Phenotype; Physicians; Primary Brain Neoplasms; Prognosis; Prognostic Marker; Program Development; Publishing; Radiation therapy; Recording of previous events; Research; Research Project Grants; Resistance; Resources; Role; Sampling; Scientist; Selection Bias; Side; Signal Transduction; Stratification; System; Technology; Testing; Therapeutic; Tissue Sample; Tissues; Treatment outcome; Tumor-infiltrating immune cells; Universities; Washington; Work; base; cancer type; career development; cell type; chemotherapy; chromosome 14 loss; chromosome 7 gain; clinical practice; clinically relevant; cohort; design; experimental study; glioma cell line; human RNA sequencing; improved; in vivo; innovation; macrophage; molecular subtypes; mouse model; mutant; neoplastic cell; nerve stem cell; neuropathology; novel strategies; patient population; pre-clinical; preclinical study; progenitor; prognostic; programs; radiation resistance; response; single-cell RNA sequencing; spatiotemporal; success; targeted treatment; transcriptome sequencing; treatment response; tumor; tumor heterogeneity; tumor-immune system interactions

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.

项目概要/摘要 该提案描述了一个为期 5 年的职业发展计划，其中申请人的最终目标是成为一名 独立医师科学家，专注于神经病理学临床实践，并拥有专门的研究实验室 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，该联盟拥有经过验证的轨道 发展医师科学家的记录。神经胶质瘤和癌症生物学小鼠模型专家 Eric Holland 博士将 担任申请人的研究导师。弥漫性胶质瘤包括最常见和恶性的原发性胶质瘤 成人颅内肿瘤。此外，在过去的几十年里，在延长寿命方面几乎没有取得成功。 弥漫性胶质瘤患者的生存受到影响，目前尚无有效的靶向治疗方法。一项提议 弥漫性胶质瘤治疗反应不佳的机制在于肿瘤内和肿瘤间的分子和细胞 构成这些肿瘤的异质性。过去3年，申请人在Dr. Holland的实验室工作， 解决神经胶质瘤内的这种分子异质性，特别研究体细胞拷贝数的作用 变更（SCNA）。通过成人神经胶质瘤队列的拷贝数分析，定义了预后 SCNA 亚型 中位生存率存在明显差异，并且发现较小的队列中存在选择偏差，这具有重要意义 临床试验设计及其对一般人群的适用性。除了这些人类生物标志物项目之外，还进行了以下研究 临床前神经胶质瘤小鼠模型已经开始着手阐明与 SCNA 相关的遗传驱动因素 神经胶质瘤。一项此类研究确定 HOXA5 是神经胶质瘤中 7 号染色体增益的驱动因素，而 HOXA5 则驱动 侵袭性神经胶质瘤表型，包括介导体内放射抗性。结合申请人之前发表的 与其他初步数据一起，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，对其进行功能表征（Aim 1）。此外，SCNA 亚型特异性反应对标准治疗的有机体和细胞后果（目标 2) 以及免疫疗法（目标 3）将得到表征。总体而言，候选人在人类和动物方面的背景 研究和诊断神经病理学非常适合这个专注于表征的指导研究项目 SCNA 在神经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，该研究还建立了一个模型系统来研究神经胶质瘤相关的 SCNA 和 胶质瘤发生中的相关驱动基因，这将为申请人提供独立的基础 研究计划。

项目成果

Neuropathologic features of central nervous system hemangioblastoma.

• DOI: 10.4132/jptm.2022.04.13
• 发表时间: 2022-05
• 期刊: JOURNAL OF PATHOLOGY AND TRANSLATIONAL MEDICINE
• 影响因子: 2.4
• 作者: Yoda, Rebecca A.;Cimino, Patrick J.
• 通讯作者: Cimino, Patrick J.

Single-cell CUT&Tag analysis of chromatin modifications in differentiation and tumor progression.

• DOI: 10.1038/s41587-021-00865-z
• 发表时间: 2021-07
• 期刊: Nature biotechnology
• 影响因子: 46.9
• 作者: Wu SJ;Furlan SN;Mihalas AB;Kaya-Okur HS;Feroze AH;Emerson SN;Zheng Y;Carson K;Cimino PJ;Keene CD;Sarthy JF;Gottardo R;Ahmad K;Henikoff S;Patel AP
• 通讯作者: Patel AP

Machine learning modeling of genome-wide copy number alteration signatures reliably predicts IDH mutational status in adult diffuse glioma.

• DOI: 10.1186/s40478-021-01295-3
• 发表时间: 2021-12-04
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Nuechterlein N;Shapiro LG;Holland EC;Cimino PJ
• 通讯作者: Cimino PJ

Radiogenomic modeling predicts survival-associated prognostic groups in glioblastoma.

• DOI: 10.1093/noajnl/vdab004
• 发表时间: 2021-01
• 期刊: Neuro-oncology advances
• 作者: Nuechterlein N;Li B;Feroze A;Holland EC;Shapiro L;Haynor D;Fink J;Cimino PJ
• 通讯作者: Cimino PJ