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

基本信息

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
项目类别：
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

项目摘要

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）拟议的实验利用了使用 MADR-GESTALT 技术创建的新型小鼠模型。这些模型将增强从体内实验中获得的信息，并应用于以下目标。目标1：评估脑渗透受体酪氨酸激酶抑制和免疫治疗的合理组合用于研究致癌性相似的胶质母细胞瘤的新小鼠模型。该项目将研究机制免疫逃避治疗后的免疫治疗，并开发合理的组合克服脑肿瘤微环境的免疫抑制环境的免疫治疗策略。免疫活性模型可准确概括人类 GBM 中已知的主要致癌驱动因素对这项工作至关重要。我们建议使用 MADR-GESTALT 系统创建 EGFRvIII 和 CDK4/6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。目标 2：使用 MADR 建立中等通量、高保真度、患者特异性的体内建模平台为了了解新种系变异的致病性、它们对基因表达的影响以及它们的作用 pHGG 敏感性的贡献。该项目旨在确定新型种系突变在小儿神经胶质瘤。 MADR技术将用于开发小鼠模型以确定其潜力这些种系突变有助于肿瘤发生。将分析小鼠的肿瘤时间发展、进步和生存。目标 3：评估 TCR 工程细胞毒性 T 细胞在 H3G34R/V HGG 中的治疗潜力。以前的研究已鉴定出少量呈递于 I 类 MHC 和肿瘤相关新抗原在 H3F3A 突变胶质母细胞瘤中与抗原特异性 T 细胞受体结合。 H3F3A突变型和野生型模型将用于进一步深入研究这些特定突变影响肿瘤发生的机制 H3G34R 胶质母细胞瘤，并将用于 TCR 工程过继性 T 疗效的临床前测试细胞转移作为 H3F3A 突变胶质母细胞瘤的靶向治疗。