Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti
Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti
批准号:
9327972
负责人:
Alnawaz Rehemtulla
金额:
$45.82万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-09-05 至 2019-06-30
关键词:
AccountingAdultAneuploidyAreaBioinformaticsBiopsyBrainBrain NeoplasmsCellsCharacteristicsChromosomal GainChromosomal LossChromosomal translocationClinicalClonal ExpansionDNA Sequence AlterationData SetDefectDevelopmentDiseaseEarly DiagnosisEarly treatmentEnhancing LesionEventEvolutionExhibitsGeneticGenetically Engineered MouseGenomeGenomic InstabilityGenomicsGlioblastomaGliomaGliomagenesisGoalsGrowthHereditary DiseaseHeterogeneityHumanHuman ChromosomesImageImaging TechniquesIndividualInstructionLarge-Scale SequencingLeadLesionMRI ScansMagnetic Resonance ImagingMalignant GliomaModelingMolecularMonitorMorphologyMusMutationNatureNuclear AtypiaOncogenicOperative Surgical ProceduresOutcomePTEN genePathogenesisPathway interactionsPatternPenetrancePeridermPhaseProbabilityProcessProliferatingRadiationRadiation therapyRadioReceptor Protein-Tyrosine KinasesRecurrenceResistanceRoleSignal PathwaySignal TransductionStem cellsTP53 geneTestingThe Cancer Genome AtlasTherapeuticTissue BanksTissuesTreatment EfficacyTumor Suppressor GenesTumor stagebasebrain cellbrain parenchymachemotherapychromosome 19 lossdesigngenome-wide analysisgenomic signatureimprovedimproved outcomein vivoinsightmalignant phenotypemolecular targeted therapiesmouse modelneurosurgerynoveloutcome forecastpreclinical trialpreventradioresistantrapid growthresponsestandard of carestemsurvival outcometargeted agenttherapy resistanttranscriptomicstumortumor growthtumor heterogeneity
中文摘要
原发基底膜占人类基底膜的90%以上,发展迅速或从头开始,无临床先例。
疾病。大规模的基因组分析对整个胶质瘤的定义做出了很大贡献。
景观和数据集(TCGA)使基于其基因组将GBM划分为亚类成为可能,
转录和信号转导模式。可悲的是,尽管有这些对人类基因的洞察
疾病和神经外科、放射和化疗的进展,其令人沮丧的预后没有改变
意义重大。与继发性GBM不同,获得的基因改变的顺序和时间
在原发的GBM中仍有待阐明,更重要的是,这些获得性基因改变是如何
在这种毁灭性疾病中,导致侵袭性和恶性表型的原因尚不清楚。
项目2将利用P53‘^’(R)模型,该模型模拟成人起病的原发性GBM的发病机制。
即使在胶质瘤形成的最早阶段,核的异型性也很高。工作假说是
最早期的病变很可能包括少量的致癌突变或扩增
使靶细胞(S)以超出正常方式增殖。加强扩散,与
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,包括肿瘤的丧失
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缺乏促进SVZ干/祖细胞中关键基因改变的积累
导致克隆扩张和原发基底膜的形成。获得遗传改变,如丢失
19号染色体(含有Pten)导致快速生长和GBM进展。《特定目标2》将监控
这些不断演变的肿瘤对标准护理放化疗的反应,目的是确定
导致治疗抵抗的基因改变,这是GBM的常见特征。《特定目标3》将进行测试
认为胶质瘤发生的早期阶段代表最佳治疗机会的假说是由于
克隆的异质性更有限。病变内存在异质克隆会导致肿瘤。
适应性和复发性是胶质瘤治疗抵抗的重要因素。由于有能力
MRI-PRM(在项目3中开发)用于检测大脑中稍后会形成对比的区域
增强损伤,我们将使用MRI来识别胶质瘤形成的早期基因变化,通过精确的
用于基因组分析的早期肿瘤的立体定位活检。我们预测,靶向抑制关键
启动神经胶质瘤的信号通路将通过预防复发显著提高预后(存活率)。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Core C: Radiosensitization Core
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批准号:10554477
-
项目类别:
-
资助金额:$12.12万
-
财政年份:2023
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Task Specific Project 3
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批准号:7728718
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项目类别:
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资助金额:$4.77万
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财政年份:2008
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负责人:Alnawaz Rehemtulla
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依托单位:
HTS for FADD kinase inhibitors using molecular imaging
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批准号:7502826
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项目类别:
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资助金额:$6.84万
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财政年份:2008
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负责人:Alnawaz Rehemtulla
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依托单位:
Proj 2: Molecular Imaging of Cell Surface Receptors in Cancer
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批准号:7490305
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项目类别:
-
资助金额:$27.65万
-
财政年份:2008
-
负责人:Alnawaz Rehemtulla
-
依托单位:
HTS for FADD kinase inhibitors using molecular imaging
-
批准号:7682117
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项目类别:
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资助金额:$20.86万
-
财政年份:2008
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负责人:Alnawaz Rehemtulla
-
依托单位:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
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批准号:8069987
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项目类别:
-
资助金额:$27.99万
-
财政年份:2007
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
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批准号:7465392
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项目类别:
-
资助金额:$28.86万
-
财政年份:2007
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
-
批准号:7299155
-
项目类别:
-
资助金额:$28.88万
-
财政年份:2007
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
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批准号:7624236
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项目类别:
-
资助金额:$28.86万
-
财政年份:2007
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Molecular Imaging of Phospho-FADD and its role in resistance to therapy
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批准号:7843603
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项目类别:
-
资助金额:$28.86万
-
财政年份:2007
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Devel. of Mol. Imaging Tools for Non-Invasive Monitoring of Drug Target Interact.
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批准号:7214533
-
项目类别:
-
资助金额:$37.29万
-
财政年份:2006
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti
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批准号:8510981
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项目类别:
-
资助金额:$45.18万
-
财政年份:2001
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Devel. of Mol. Imaging Tools for Non-Invasive Monitoring of Drug Target Interact.
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批准号:8318546
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项目类别:
-
资助金额:$40.35万
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财政年份:2001
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Devel. of Mol. Imaging Tools for Non-Invasive Monitoring of Drug Target Interact.
-
批准号:8104197
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项目类别:
-
资助金额:$39.92万
-
财政年份:2001
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti
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批准号:8745102
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项目类别:
-
资助金额:$42.68万
-
财政年份:2001
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Devel. of Mol. Imaging Tools for Non-Invasive Monitoring of Drug Target Interact.
-
批准号:7799203
-
项目类别:
-
资助金额:$42.26万
-
财政年份:2001
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti
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批准号:8903706
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项目类别:
-
资助金额:$43.96万
-
财政年份:2001
-
负责人:Alnawaz Rehemtulla
-
依托单位:
Devel. of Mol. Imaging Tools for Non-Invasive Monitoring of Drug Target Interact.
-
批准号:7595882
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项目类别:
-
资助金额:$41.11万
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财政年份:2001
-
负责人:Alnawaz Rehemtulla
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依托单位:
MOLECULAR MEDIATORS OF RADIATION-INDUCED APOPTOSIS
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批准号:2647826
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项目类别:
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资助金额:$16.01万
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财政年份:1998
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负责人:Alnawaz Rehemtulla
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依托单位:
MOLECULAR MEDIATORS OF RADIATION-INDUCED APOPTOSIS
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批准号:6137673
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项目类别:
-
资助金额:$15.97万
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财政年份:1998
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负责人:Alnawaz Rehemtulla
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依托单位:
海外基金