Project 2: Dissection of clonal architecture and evolution in solid tumors
项目 2:实体瘤克隆结构和进化的剖析
基本信息
- 批准号:8866153
- 负责人:
- 金额:$ 36.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-19 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:AftercareArchitectureAreaAtlasesAutomationBiopsyCellsClinicalCodeComplementary DNADNAData AnalysesData SetDependencyDevicesDiseaseDissectionDrug resistanceEpigenetic ProcessEvolutionExcisionFailureFrequenciesGene Expression ProfileGenesGeneticGenetic TranscriptionGenetic VariationGenomeGenomic DNAGenomicsGlioblastomaHeterogeneityHumanIn VitroIndividualLibrariesMalignant - descriptorMalignant NeoplasmsMapsMedicalMessenger RNAMethodsMicrofabricationMicrofluidicsModelingMusMutationNatural SelectionsOperative Surgical ProceduresOutcomePatientsPatternPharmaceutical PreparationsPhylogenetic AnalysisPopulationPopulation ControlPrimary NeoplasmReagentReceptor Protein-Tyrosine KinasesRelapseRelative (related person)ReportingResearchResistanceSamplingSolid NeoplasmSpecimenStagingStructureSystemThe Cancer Genome AtlasTherapeuticTimeTissuesTreatment FailureTumor TissueValidationWorkcancer genomecombinatorialcostdriving forcedrug sensitivityepigenetic variationexomein vivoinhibitor/antagonistinsightmedical specialtiesneglectnew technologyoncologypressureresearch studysmall moleculetooltreatment strategytumortumor progression
项目摘要
TITLE
Project 2: Dissection of clonal architecture and evolution in solid tumors
ABSTRACT
Increasing evidence in solid tumors suggests that drug resistance and therapeutic failure results from
natural selection of resistant subclones during the disease course. Intra-tumor heterogeneity and cancer
subclonal diversity is the key driving force of the high failure rate of oncology drugs relative to other medical
specialties where drugs are applied to stable somatic genomes rather than the unstable genomes found in
human cancer. In this proposal, we focus on one of the most incurable and genetically heterogeneous tumors
(human glioblastoma), to predict and validate the landscape of driver alterations that mark initiation, founder
evolution, and therapy adaptation within individual patients. We will develop and apply novel technologies for
high-throughput transcription and genomic analysis of individual cells within malignant glioma tissues. Our
current system is capable of single cell mRNA capture, cDNA barcoding, and on-chip amplification, generating
amplicons for direct conversion into a standard, pooled sequencing library. We will adapt the same device for
massively parallel, on-chip capture of genomic DNA from individual cells for whole genome amplification and
exome capture. Next, we will functionally validate the single-cell glioma models in orthotopic mouse and
human systems in vitro and in vivo. The successful outcome of this proposal will be to deliver an integrated
computational-experimental pipeline that will be able to predict the forthcoming evolutionary moves of any solid
tumor in the presence of a defined set of selective pressures. This information will be of invaluable significance
to decipher evolving tumor dependencies and provide the most accurate therapeutic predictions.
标题
项目2:实体瘤克隆结构和进化的剖析
摘要
越来越多的证据表明,实体瘤的耐药性和治疗失败的原因是
抗病亚系的自然选择。肿瘤内异质性与癌症
亚克隆多样性是肿瘤药物相对于其他药物的高失败率的关键驱动力。
这些专业将药物应用于稳定的体细胞基因组,而不是不稳定的基因组,
人类癌症在这个建议中,我们关注的是一种最难治愈的遗传异质性肿瘤。
(人类胶质母细胞瘤),以预测和验证标志着启动的驱动程序改变的景观,创始人
进化和个体患者内的治疗适应。我们将开发和应用新技术,
高通量转录和恶性神经胶质瘤组织内单个细胞的基因组分析。我们
目前的系统能够单细胞mRNA捕获、cDNA条形码化和芯片上扩增,
用于直接转化成标准的合并的测序文库的扩增子。我们将采用相同的设备,
大规模并行芯片上捕获来自单个细胞的基因组DNA用于全基因组扩增,
外显子组捕获接下来,我们将在原位小鼠中对单细胞胶质瘤模型进行功能验证,
体外和体内的人体系统。这一建议的成功结果将是提供一个综合的
计算实验管道,将能够预测未来的任何固体的进化运动,
在一组确定的选择性压力的存在下治疗肿瘤。这一信息将具有非常重要的意义
以破译不断演变的肿瘤依赖性,并提供最准确的治疗预测。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Antonio Iavarone其他文献
Antonio Iavarone的其他文献
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{{ truncateString('Antonio Iavarone', 18)}}的其他基金
Evolution and targeting of the functional states of glioblastoma
胶质母细胞瘤功能状态的进化和靶向
- 批准号:
10467181 - 财政年份:2022
- 资助金额:
$ 36.93万 - 项目类别:
Evolution and targeting of the functional states of glioblastoma
胶质母细胞瘤功能状态的进化和靶向
- 批准号:
10651751 - 财政年份:2022
- 资助金额:
$ 36.93万 - 项目类别:
Evolution and targeting of the functional states of glioblastoma
胶质母细胞瘤功能状态的进化和靶向
- 批准号:
10729932 - 财政年份:2022
- 资助金额:
$ 36.93万 - 项目类别:
Oncogenic mechanisms, molecular stratification and therapeutic targets of brain tumors
脑肿瘤的致癌机制、分子分层和治疗靶点
- 批准号:
10493186 - 财政年份:2021
- 资助金额:
$ 36.93万 - 项目类别:
Oncogenic mechanisms, molecular stratification and therapeutic targets of brain tumors
脑肿瘤的致癌机制、分子分层和治疗靶点
- 批准号:
10729917 - 财政年份:2021
- 资助金额:
$ 36.93万 - 项目类别:
Oncogenic mechanisms, molecular stratification and therapeutic targets of brain tumors
脑肿瘤的致癌机制、分子分层和治疗靶点
- 批准号:
10299894 - 财政年份:2021
- 资助金额:
$ 36.93万 - 项目类别:
Oncogenic mechanisms, molecular stratification and therapeutic targets of brain tumors
脑肿瘤的致癌机制、分子分层和治疗靶点
- 批准号:
10675651 - 财政年份:2021
- 资助金额:
$ 36.93万 - 项目类别:
The Huwe1 ubiquitin ligase regulates mitosis, genomic stability and oncogenesis.
Huwe1 泛素连接酶调节有丝分裂、基因组稳定性和肿瘤发生。
- 批准号:
10188467 - 财政年份:2019
- 资助金额:
$ 36.93万 - 项目类别:
The role of the LZTR1 ubiquitin ligase in stem cells and cancer
LZTR1 泛素连接酶在干细胞和癌症中的作用
- 批准号:
9262886 - 财政年份:2015
- 资助金额:
$ 36.93万 - 项目类别:
The role of the LZTR1 ubiquitin ligase in stem cells and cancer
LZTR1 泛素连接酶在干细胞和癌症中的作用
- 批准号:
9067257 - 财政年份:2015
- 资助金额:
$ 36.93万 - 项目类别:
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