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：
Antonio Iavarone
金额：
$ 36.93万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
https://reporter.nih.gov/project-details/8866153
关键词：
Aftercare Architecture Area Atlases Automation Biopsy Cells Clinical Code Complementary DNA DNA Data Analyses Data Set Dependency Devices Disease Dissection Drug resistance Epigenetic Process Evolution Excision Failure Frequencies Gene Expression Profile Genes Genetic Genetic Transcription Genetic Variation Genome Genomic DNA Genomics Glioblastoma Heterogeneity Human In Vitro Individual Libraries Malignant - descriptor Malignant Neoplasms Maps Medical Messenger RNA Methods Microfabrication Microfluidics Modeling Mus Mutation Natural Selections Operative Surgical Procedures Outcome Patients Pattern Pharmaceutical Preparations Phylogenetic Analysis Population Population Control Primary Neoplasm Reagent Receptor Protein-Tyrosine Kinases Relapse Relative (related person)Reporting Research Resistance Sampling Solid Neoplasm Specimen Staging Structure System The Cancer Genome Atlas Therapeutic Time Tissues Treatment Failure Tumor Tissue Validation Work cancer genome combinatorial cost driving force drug sensitivity epigenetic variation exome in vivo inhibitor/antagonist insight medical specialties neglect new technology oncology pressure research study small molecule tool treatment strategy tumor tumor 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抽象的实体瘤中越来越多的证据表明耐药性和治疗失败的原因是疾病过程中抗性亚克隆的自然选择。肿瘤内异质性和癌症亚克隆多样性是肿瘤药物相对于其他医学药物失败率高的关键驱动力药物应用于稳定的体细胞基因组而不是不稳定的基因组的专业人类癌症。在这项提案中，我们重点关注一种最无法治愈且具有遗传异质性的肿瘤（人类胶质母细胞瘤），预测和验证标志着启动的驱动程序改变的情况，创始人个体患者的进化和治疗适应。我们将开发和应用新技术恶性神经胶质瘤组织内单个细胞的高通量转录和基因组分析。我们的目前的系统能够进行单细胞 mRNA 捕获、cDNA 条形码和芯片上扩增，生成扩增子可直接转换为标准的合并测序文库。我们将采用相同的设备从单个细胞中大规模并行地在芯片上捕获基因组 DNA，以进行全基因组扩增和外显子组捕获。接下来，我们将在原位小鼠和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。该提案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任何固体即将发生的进化运动存在一组确定的选择压力时的肿瘤。这些信息将具有非常宝贵的意义破译不断变化的肿瘤依赖性并提供最准确的治疗预测。