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:
- 金额:$ 45.18万
- 依托单位:
- 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:
- 关键词:AccountingAdultAneuploidyAreaBioinformaticsBiopsyBrainBrain NeoplasmsCellsCharacteristicsChromosomal GainChromosomal LossChromosomal translocationClinicalClonal ExpansionData SetDefectDevelopmentDiagnostic Neoplasm StagingDiseaseEarly DiagnosisEarly treatmentEnhancing LesionEventEvolutionExhibitsGeneticGenetically Engineered MouseGenomeGenomic InstabilityGenomicsGlioblastomaGliomaGliomagenesisGoalsGrowthHereditary DiseaseHeterogeneityHumanHuman ChromosomesImageImaging TechniquesIndividualInstructionLarge-Scale SequencingLeadLesionMagnetic Resonance ImagingMalignant GliomaModelingMolecularMolecular GeneticsMonitorMusMutationNatureNuclear AtypiaOncogenicOperative Surgical ProceduresOutcomePTEN genePathogenesisPathway interactionsPatternPenetrancePeridermPhaseProbabilityProcessProliferatingRadiationRadiation therapyRadioReceptor Protein-Tyrosine KinasesRecurrenceResistanceRoleSignal PathwaySignal TransductionStagingStem cellsTP53 geneTestingThe Cancer Genome AtlasTherapeuticTimeTissue BanksTissuesTreatment EfficacyTumor Suppressor GenesTumor stageWorkbasebrain cellchemotherapychromosome 19 lossdesigngenome wide association studyimprovedin vivoinsightmalignant phenotypemouse modelneurosurgerynoveloutcome forecastpreclinical studypreventrapid growthresponsestandard of carestemtherapy resistanttranscriptomicstumortumor 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.
占人类GBM的90%以上的初级GBM,迅速发展或从头开始而没有先前的临床
疾病。大规模的基因组分析对整体神经胶质瘤的定义做出了巨大贡献
景观和数据集(TCGA)已根据其基因组将GBMS分为子类别
转录组和信号转导模式。可悲的是,尽管对遗传学的见解
疾病和神经外科,放射和化学疗法的进展,其惨淡的预后没有改变
显著地。与次级GBM不同,获取的遗传改变的顺序和时机
在初级GBM中仍然有待阐明,更重要的是,这些获得的遗传改变了
在这种毁灭性疾病中有助于侵略性和恶性表型。
项目2将利用p53'^^^'(R)模型,该模型模拟了成人发作的初级GBM的发病机理
高度的核亚典现象,即使在神经胶质作用的最早阶段也是如此。工作的假设是
最具痛苦的病变很可能包括少数的致癌突变或放大的病变
使目标细胞能够超越正常均值。增强的增殖与
增加基因组不稳定性的突变可能导致进一步的基因组病变,包括肿瘤的丧失
抑制基因(例如PTEN),进一步扩大增殖。在特定目标1中,我们将检验假设
p53缺乏促进了SVZ茎/祖细胞中关键遗传改变的积累
导致克隆扩张和主要GBM形成。获取遗传改变,例如丢失
19染色体(藏有PTEN)导致快速生长和GBM进展。具体目标2将监视
这些不断发展的肿瘤对护理标准化学/放射治疗的反应,目的是定义
遗传改变会导致对治疗的抗性,这是GBM的共同特征。特定目标3将测试
神经胶作用的早期阶段是由于A代表最佳治疗机会的假设
克隆的异质性更有限。病变内的异质克隆的存在导致肿瘤
适应性和复发是神经胶质瘤治疗性抗性的重要促进者。由于能力
MRI-PRM(在项目3中开发)检测大脑内将形成对比的区域
增强病变,我们将使用MRI通过精确确定神经胶质作用的早期遗传改变
早期肿瘤的立体定位活检进行基因组分析。我们预测针对密钥的抑制
胶质瘤发射信号通路将通过预防复发来显着提高预后(存活)。
项目成果
期刊论文数量(0)
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Alnawaz Rehemtulla其他文献
Alnawaz Rehemtulla的其他文献
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{{ truncateString('Alnawaz Rehemtulla', 18)}}的其他基金
HTS for FADD kinase inhibitors using molecular imaging
使用分子成像对 FADD 激酶抑制剂进行 HTS
- 批准号:
7502826 - 财政年份:2008
- 资助金额:
$ 45.18万 - 项目类别:
Proj 2: Molecular Imaging of Cell Surface Receptors in Cancer
项目 2:癌症细胞表面受体的分子成像
- 批准号:
7490305 - 财政年份:2008
- 资助金额:
$ 45.18万 - 项目类别:
HTS for FADD kinase inhibitors using molecular imaging
使用分子成像对 FADD 激酶抑制剂进行 HTS
- 批准号:
7682117 - 财政年份:2008
- 资助金额:
$ 45.18万 - 项目类别:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
Phospho-FADD 的分子成像及其在治疗耐药中的作用
- 批准号:
8069987 - 财政年份:2007
- 资助金额:
$ 45.18万 - 项目类别:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
Phospho-FADD 的分子成像及其在治疗耐药中的作用
- 批准号:
7465392 - 财政年份:2007
- 资助金额:
$ 45.18万 - 项目类别:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
Phospho-FADD 的分子成像及其在治疗耐药中的作用
- 批准号:
7299155 - 财政年份:2007
- 资助金额:
$ 45.18万 - 项目类别:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
Phospho-FADD 的分子成像及其在治疗耐药中的作用
- 批准号:
7624236 - 财政年份:2007
- 资助金额:
$ 45.18万 - 项目类别:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
Phospho-FADD 的分子成像及其在治疗耐药中的作用
- 批准号:
7843603 - 财政年份:2007
- 资助金额:
$ 45.18万 - 项目类别:
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