Credentialing murine models for glioblastoma preclinical drug development

胶质母细胞瘤临床前药物开发的小鼠模型认证

基本信息

批准号：
9986359
负责人：
MICHAEL E. BERENS
金额：
$ 47.23万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-13 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9986359
关键词：
ATRX gene Address Allografting Antibodies Antineoplastic Agents BRAF gene Behavior Biological CDKN2A gene Cancer Biology Cell Culture Techniques Cell physiology Cells Chemicals Clinical Clinical Trials Combined Modality Therapy Coupled Credentialing Cultured Cells Disease Drug Combinations Drug Modulation Drug Screening Drug Targeting Drug resistance ERBB2 gene Environment Epidermal Growth Factor Receptor Fatal Outcome Genes Genetic Genetically Engineered Mouse Genome Genomics Glioblastoma Goals Growth Heterogeneity Human Immunoassay MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediating Methods Modeling Molecular Monitor Mus Mutate Mutation NF1 gene Normal Cell Operative Surgical Procedures PIK3CG gene PTEN gene Pathogenesis Pathologic Pathway interactions Patients Penetrance Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Preclinical Drug Development Primary Brain Neoplasms Proteomics Reagent Recurrence Research Personnel Resected Resistance Signal Transduction Specimen TP53 gene Techniques Testing Transplantation Tumor Subtype Validation Work Xenograft Model Xenograft procedure actionable mutation astrocyte progenitor base bcr-abl Fusion Proteins brain cell cell type clinically relevant combat dark matter disorder subtype drug development drug discovery effective therapy exome sequencing feasibility trial human disease human model in vitro Model in vivo individualized medicine inhibitor/antagonist kinase inhibitor leukemia malignant breast neoplasm melanoma mouse model nerve stem cell neuro-oncology novel oligodendrocyte progenitor oncology pre-clinical precision medicine prevent prospective public health relevance resistance mechanism response targeted treatment three dimensional cell culture transcriptome transcriptome sequencing tumor

项目摘要

ABSTRACT Precision medicine promises to revolutionize oncology by targeting drugs to specific mutations. However, targeted drugs have failed to produce durable clinical responses when used as single agents in glioblastoma (GBM), the most common and deadly primary brain tumor. Genetically engineered mouse (GEM) models are essential for functional validation of such mutations, but technical limitations have prevented their widespread use in preclinical cancer drug development. The Miller Lab has developed non- germline GEM (nGEM) models. The Berens Lab has performed comprehensive genomic and chemovulnerability profiling in a genetically diverse and faithful panel of patient-derived human xenograft (PDX) models. The Johnson Lab has developed a novel chemical proteomics method, multiplex inhibitor beads coupled with mass spectrometry (MIB-MS), to assess the activation state of the cellular kinome en masse and has shown that dynamic kinome reprogramming contributes to targeted drug resistance. In this Multi-PI project, we will combine our expertise to address the following Aims: (1) To credential PDX models against human GBM by kinome proteomics; (2) To develop genetically-matched nGEM models from distinct cells of origin; and (3) To credential PDX and nGEM models by dynamic kinome profiling. We will develop a genetically diverse panel of nGEM models with defined driver mutations and cellular origins that will be useful adjunct to PDX for preclinical drug development. We will then credential both PDX and nGEM models against resected GBM specimens using cross-species genome, transcriptome, and kinome, and drug response profiling. Models will be genomically matched to their human counterparts and used to develop rational combination therapies that combat single agent resistance mechanisms in genomically- defined tumor subtypes. This work will therefore help realize the promise of precision medicine in neuro- oncology.

抽象的精准医学有望通过针对特定突变的药物来彻底改变肿瘤学。然而，靶向药物作为单一药物使用时未能产生持久的临床反应胶质母细胞瘤（GBM）是最常见和致命的原发性脑肿瘤。基因工程小鼠（GEM）模型对于此类突变的功能验证至关重要，但技术限制已经阻止了它们在临床前癌症药物开发中的广泛使用。米勒实验室开发了非种系 GEM (nGEM) 模型。贝伦斯实验室进行了全面的基因组和对源自患者的人类异种移植物的遗传多样性和忠实性小组进行化学脆弱性分析 (PDX) 模型。约翰逊实验室开发了一种新型化学蛋白质组学方法——多重抑制剂珠子与质谱 (MIB-MS) 结合，评估细胞激酶组的激活状态 Masse 并表明动态激酶组重编程有助于靶向耐药性。在这个 Multi-PI 项目中，我们将结合我们的专业知识来实现以下目标： (1) 认证 PDX 模型通过激酶组蛋白质组学对抗人类 GBM； (2) 开发基因匹配的nGEM模型不同的起源细胞； (3) 通过动态激酶组分析来验证 PDX 和 nGEM 模型。我们将开发具有明确驱动突变和细胞起源的遗传多样性 nGEM 模型组将成为 PDX 临床前药物开发的有用辅助手段。然后我们将验证 PDX 和 nGEM 使用跨物种基因组、转录组和激酶组针对切除的 GBM 标本建立模型，以及药物反应分析。模型将在基因组上与人类对应物相匹配，并用于开发合理的联合疗法来对抗基因组中的单药耐药机制明确的肿瘤亚型。因此，这项工作将有助于实现神经系统精准医学的前景。肿瘤学。