Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti

鉴定导致原发性 GBM 克隆进化的遗传改变

基本信息

批准号：
8510981
负责人：
Alnawaz Rehemtulla
金额：
$ 45.18万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-05 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510981
关键词：
Accounting Adult Aneuploidy Area Bioinformatics Biopsy Brain Brain Neoplasms Cells Characteristics Chromosomal Gain Chromosomal Loss Chromosomal translocation Clinical Clonal Expansion Data Set Defect Development Diagnostic Neoplasm Staging Disease Early Diagnosis Early treatment Enhancing Lesion Event Evolution Exhibits Genetic Genetically Engineered Mouse Genome Genomic Instability Genomics Glioblastoma Glioma Gliomagenesis Goals Growth Hereditary Disease Heterogeneity Human Human Chromosomes Image Imaging Techniques Individual Instruction Large-Scale Sequencing Lead Lesion Magnetic Resonance Imaging Malignant Glioma Modeling Molecular Molecular Genetics Monitor Mus Mutation Nature Nuclear Atypia Oncogenic Operative Surgical Procedures Outcome PTEN gene Pathogenesis Pathway interactions Pattern Penetrance Periderm Phase Probability Process Proliferating Radiation Radiation therapy Radio Receptor Protein-Tyrosine Kinases Recurrence Resistance Role Signal Pathway Signal Transduction Staging Stem cells TP53 gene Testing The Cancer Genome Atlas Therapeutic Time Tissue Banks Tissues Treatment Efficacy Tumor Suppressor Genes Tumor stage Work base brain cell chemotherapy chromosome 19 loss design genome wide association study improved in vivo insight malignant phenotype mouse model neurosurgery novel outcome forecast preclinical study prevent rapid growth response standard of care stem therapy resistant transcriptomics tumor tumor growth

项目摘要

Primary GBM, accounting for over 90% of human GBMs, develops rapidly or de novo with no prior clinical disease. Large-scale genomic analyses have contributed greatly to the definition of the overall glioma landscape and datasets (TCGA) have enabled the division of GBMs into subclasses based on their genomic, transcriptomic, and signal transduction patterns. Sadly, despite these insights into the genetics of the disease and advances in neurosurgery, radiation and chemotherapy, its dismal prognosis has not changed significantly. Unlike secondary GBM, the order and the timing of the genetic alterations that are acquired remain to be elucidated in primary GBM, and more importantly, how these acquired genetic alterations contribute to aggressive and malignant phenotypes in this devastating disease aren't well understood. Project 2 will utilize the p53'^^^'(R) model which mimics the pathogenesis of adult onset primary GBM with a high degree of nuclear atypia even in the earliest stages of gliomagenesis. The working hypothesis is that the eariiest lesion most likely comprises a small number of oncogenic mutations or amplifications that enables the targeted cell(s) to proliferate beyond normal means. Enhanced proliferation in conjunction with mutations that increase genomic instability may lead to further genomic lesions, including loss of tumor suppressor genes (e.g. Pten), further amplifying proliferation. In Specific Aim 1, we will test the hypothesis that p53 deficiency facilitates the accumulation of critical genetic alterations in the SVZ stem/progenitor cells leading to clonal expansion and primary GBM formation. Acquisition of genetic alterations such as loss of chromosome 19 (harboring Pten) leads to rapid growth and GBM progression. Specific Aim 2 will monitor the response of these evolving tumors to standard of care chemo/radiation therapy, with the goal of defining genetic alterations that result in resistance to therapy, a common feature of GBM. Specific Aim 3 will test the hypothesis that the early stages of gliomagenesis represent the best therapeutic opportunities due to a more limited heterogeneity of clones. The presence of heterogeneous clones within a lesion leads to tumor adaptivity and recurrence an important contributor to therapeutic resistance in glioma. Due to the ability of MRI-PRM (developed in Project 3) to detect areas within the brain that will later develop a contrast enhancing lesion, we will use MRI to identify early genetic alterations in gliomagenesis through precise stereotaxic biopsy of early stage tumors for genomic analysis. We predict that targeted inhibition of key glioma-initiating signaling pathways will significantly enhance outcomes (survival) by preventing recurrence.

原发性 GBM 占人类 GBM 的 90% 以上，在没有先前临床表现的情况下迅速或从头发展疾病。大规模基因组分析对神经胶质瘤的整体定义做出了巨大贡献景观和数据集（TCGA）已经能够根据基因组将 GBM 划分为子类，转录组和信号转导模式。可悲的是，尽管对基因的这些见解随着神经外科、放疗和化疗的进展和疾病的进展，其悲惨的预后并没有改变显著地。与继发性 GBM 不同，获得性基因改变的顺序和时间在原发性 GBM 中仍有待阐明，更重要的是，这些基因改变是如何获得的在这种毁灭性疾病中，导致侵袭性和恶性表型的因素尚不清楚。项目 2 将利用 p53'^^^'(R) 模型，该模型模拟成人发病的原发性 GBM 的发病机制，并具有即使在神经胶质瘤发生的最早阶段，也存在高度的核异型性。工作假设是最早期的病变很可能包含少量致癌突变或扩增，使目标细胞增殖超出正常水平。结合增强增殖增加基因组不稳定性的突变可能导致进一步的基因组损伤，包括肿瘤丧失抑制基因（例如 Pten），进一步放大增殖。在具体目标 1 中，我们将检验假设 p53 缺陷促进 SVZ 干/祖细胞中关键遗传改变的积累导致克隆扩张和原发性 GBM 形成。获得基因改变，例如丧失 19 号染色体（含有 Pten）导致快速生长和 GBM 进展。具体目标 2 将监测这些不断发展的肿瘤对标准化疗/放射治疗的反应，目的是定义导致治疗耐药的基因改变，这是 GBM 的一个常见特征。具体目标3将测试假设神经胶质瘤发生的早期阶段代表了最佳的治疗机会，因为克隆的异质性更有限。病变内异质克隆的存在会导致肿瘤适应性和复发是神经胶质瘤治疗耐药的重要因素。由于有能力 MRI-PRM（在项目 3 中开发）用于检测大脑内随后会形成对比的区域为了增强病变，我们将使用 MRI 通过精确的方法来识别神经胶质瘤发生的早期遗传改变早期肿瘤的立体定向活检用于基因组分析。我们预测，有针对性的抑制关键胶质瘤启动信号通路将通过防止复发来显着提高结果（生存）。