Novel mouse models using MADR-GESTALT technology to accelerate glioma research

使用 MADR-GESTALT 技术加速神经胶质瘤研究的新型小鼠模型

• 批准号: 10271987
• 负责人: Linda M Liau
• 金额: $ 21.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271987
• 关键词: Affect; Alternative Splicing; BRCA1 gene; Basic Science; Brain; Brain Neoplasms; CDK4 gene; CDKN2A gene; Cancer Patient; Chemotherapy and/or radiation; Child; Childhood Glioma; Chromatin; Clinical; Cytotoxic T-Lymphocytes; Development; Engineering; Gene Expression; Germ-Line Mutation; Glioblastoma; Glioma; Goals; Histones; Human; Immune Evasion; Immunocompetent; Immunotherapeutic agent; Immunotherapy; Laboratories; MHC Class I Genes; Malignant neoplasm of brain; Modeling; Morbidity - disease rate; Mosaicism; Mus; Mutation; Oncogenic; PTEN gene; Pathogenicity; Patients; Preclinical Testing; Predisposition; Proteins; Research; Research Project Grants; Role; Scientist; System; T cell therapy; T-Cell Receptor; Technology; Testing; Therapeutic; Time; Translating; Translational Research; Tyrosine Kinase Receptor Inhibition; Vaccines; Variant; Work; Yeasts; antigen binding; clinical care; clinically significant; efficacy testing; epidermal growth factor receptor VIII; experimental study; genome editing; immune checkpoint blockade; improved; in vivo; in vivo Model; mouse model; mutant; neoantigens; next generation sequencing; novel; novel therapeutic intervention; recombinase; small molecule inhibitor; standard of care; targeted treatment; tumor; tumor microenvironment; tumorigenesis

ABSTRACT (Project) The proposed experiments leverage novel mouse models created using MADR-GESTALT technology. These models will enhance information derived from in vivo experiments and are being applied in the following aims. Aim 1: Evaluate rational combinations of brain penetrant receptor tyrosine kinase inhibition and immunotherapy for study in new mouse models of oncogenically similar glioblastoma. This project will investigate mechanisms of immune evasion following treatment with immune-based therapy, and develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor micro-environment. Immunocompetent models that accurately recapitulate the known dominant oncogenic drivers in human GBM are crucial to this work. We propose to use the MADR-GESTALT system to create models of EGFRvIII and CDK4/6-driven GBM in order to test how small molecule inhibitors can be effectively paired with active vaccines and checkpoint blockade immunotherapy. Aim 2: Establish a moderate-throughput, high-fidelity, patient-specific in vivo modeling platform using MADR in order to understand pathogenicity of novel germline variants, their effects on gene expression, and their contribution to pHGG susceptibility. This project seeks to determine the role of novel germline mutations in pediatric glioma. The MADR technology will be used to develop mouse models to determine the potential of these germline mutations to contribute to tumorigenesis. The mice will be analyzed for time to tumor development, progression, and survival. Aim 3: Evaluate the therapeutic potential of TCR-engineered cytotoxic T cells in H3G34R/V HGG. Previous research has identified a small number of tumor-associated neoantigens that are presented on class I MHC and are bound by antigen-specific T cell receptors in H3F3A mutant glioblastoma. H3F3A mutant and wild-type models will be used to further delve into the mechanisms by which these particular mutations affect oncogenesis in H3G34R glioblastoma, and will be used for pre-clinical testing of the efficacy of TCR-engineered adoptive T cell transfer as targeted therapy for H3F3A mutant glioblastoma.

摘要（项目） 所提出的实验利用了使用MADR-GESTALT技术创建的新型小鼠模型。这些 这些模型将增强从体内实验中获得的信息，目前正用于以下目的。 目的1：评价脑渗透受体酪氨酸激酶抑制剂与免疫治疗的合理组合 用于在致癌性相似的胶质母细胞瘤的新小鼠模型中进行研究。本项目将研究 免疫治疗后的免疫逃避，并制定合理的组合， 免疫抑制策略，以克服脑肿瘤微环境的免疫抑制环境。 准确概括人类GBM中已知的显性致癌驱动因素的免疫活性模型 对于这项工作至关重要。我们建议使用MADR-GESTALT系统来创建EGFRvIII模型， CDK 4/6驱动的GBM，以测试小分子抑制剂如何与活性疫苗有效配对 和检查点阻断免疫疗法。 目的2：建立一个中等通量，高保真度，患者特异性的体内建模平台，使用MADR， 为了了解新的生殖系变异的致病性，它们对基因表达的影响，以及它们的 对pHGG敏感性的贡献。该项目旨在确定新的生殖系突变的作用， 小儿神经胶质瘤MADR技术将用于开发小鼠模型，以确定 这些生殖系突变有助于肿瘤发生。将分析小鼠的肿瘤形成时间 发展、进展和生存。 目的3：评价TCR工程化细胞毒性T细胞在H3 G34 R/V HGG中的治疗潜力。先前 研究已经鉴定了少量的肿瘤相关的新抗原，其存在于I类MHC上， 被H3 F3 A突变型胶质母细胞瘤中的抗原特异性T细胞受体结合。H3 F3 A突变体和野生型 模型将用于进一步深入研究这些特殊突变影响肿瘤发生的机制 在H3 G34 R胶质母细胞瘤中，并将用于临床前测试TCR工程过继性T 细胞转移作为H3 F3 A突变型胶质母细胞瘤的靶向治疗。