MET kinase fusions in pediatric glioblastoma

儿童胶质母细胞瘤中的 MET 激酶融合

基本信息

批准号：
10690229
负责人：
Renee D Read
金额：
$ 2.19万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-27 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10690229
关键词：
Adopted Adult Affect Apoptosis Astrocytes Biological Assay Blood - brain barrier anatomy Brain Diseases C-terminal Cancer Etiology Cell fusion Cell model Cells Child Childhood Childhood Glioblastoma Childhood Glioma Clinical Clinical Research Collaborations Cytokine Signaling Data Development Drug Tolerance Drug resistance Epidermal Growth Factor Receptor Experimental Models FDA approved Female Funding Genetic Transcription Glioma Grant Growth Hippocampus (Brain)Human Immune Immunocompetent Immunosuppression Incidence Inflammation Inflammatory Interferon-beta Interferons Investigation Lead Malignant - descriptor Modeling Mus Mutation N-terminal NF-kappa B Natural Immunity Pathway interactions Patients Pediatric Neoplasm Pharmaceutical Preparations Pharmacology Phosphotransferases Precision therapeutics Primary Brain Neoplasms Process Proteins Proteomics Publishing Receptor Protein-Tyrosine Kinases Research Research Project Grants Resistance Sex Differences Signal Pathway Signal Transduction TLR4 gene Testing Time Toll-Like Receptor Pathway Toll-like receptors Treatment Efficacy Tumor Stem Cells Tumor Tissue Tyrosine Kinase Inhibitor Up-Regulation Variant age related antitumor effect base biological sex childhood cancer mortality epidemiology study experimental study genetic approach improved insight male mouse model mutant neoplastic cell nerve stem cell neurogenesis neuroinflammation new therapeutic target overexpression painful neuropathy precision medicine programs receptor recruit resistance mechanism response small molecule stem stem cell function stem cells stem-like cell therapeutic target transcriptomics treatment strategy tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

ABSTRACT High grade gliomas (HGGs), the most deadly malignant primary brain tumors in children, are incurable with current therapies. To find mutations that drive formation and progression of pediatric HGGs (pHGGs), we genomically characterized patient tumors, and we identified fusion mutations in the MET and ALK receptor tyrosine kinases. Recent comprehensive analyses show that RTK fusions are found in up to 40% of pHGGs, and among the most common are MET, ALK, and NTRK fusions. Our and others’ data show that for many RTK fusions, in which the C-terminal kinase domain is fused to N-terminal regions of other proteins that are normally highly expressed in neuro-glial stem/progenitor cells, indicating that MET fusions are likely overexpressed as a consequence of developmental programs. Our results show that RTK fusions, such as the MET fusions, create constitutively active kinases capable of transforming neural stem cells into pHGG-like tumors. FDA-approved small molecule tyrosine kinase inhibitors (TKIs) exist that penetrate the blood-brain barrier that may benefit pHGG patients with MET and ALK fusions as well as other RTK fusions, and these TKIs are being tested in patients with RTK fusions on an investigational basis. However, despite initial responses, MET fusion pHGG patients can develop resistant tumors. Therefore, to discover TKI resistance mechanisms, we have created our experimental immunocompetent mouse pHGG models for tumors with MET and ALK fusions. Already, our preliminary studies implicate cell-intrinsic innate immunity and inflammatory cytokine signaling pathways in drug tolerance and resistance among pHGG cells with MET fusions. To discover and study resistance mechanisms and to determine if biological sex affects how pHGGs with RTK fusions, we propose to two aims to 1) examine expression and activation of innate immunity pathways in pHGGs with RTK fusions and 2) examine sex differences in innate immunity pathways function in pHGGs with RTK fusions. The results of our research may lead to development of new combination precision treatment strategies for pHGG. 1

抽象的高级别胶质瘤 (HGG) 是儿童中最致命的恶性原发性脑肿瘤，无法治愈为了找到驱动儿科 HGGs (pHGGs) 形成和进展的突变，我们对患者肿瘤进行基因组表征，我们发现了 MET 和 ALK 受体的融合突变最近的综合分析表明，RTK 融合存在于高达 40% 的 pHGG 中，并且其中最常见的是 MET、ALK 和 NTRK 融合，我们和其他人的数据表明，对于许多 RTK 来说。融合，其中 C 端激酶结构域与通常存在的其他蛋白质的 N 端区域融合在神经胶质干/祖细胞中高表达，表明 MET 融合体可能作为我们的结果表明，RTK 融合（例如 MET 融合）会产生影响。能够将神经干细胞转化为 FDA 批准的 pHGG 样肿瘤的组成型活性激酶。小分子酪氨酸激酶抑制剂 (TKI) 可以穿透血脑屏障，可能有益具有 MET 和 ALK 融合以及其他 RTK 融合的 pHGG 患者，这些 TKI 正在接受测试然而，尽管最初有反应，但 MET 融合 pHGG 仍处于研究阶段。因此，为了发现 TKI 耐药机制，我们创建了我们的药物。我们的实验性免疫活性小鼠 pHGG 模型已用于具有 MET 和 ALK 融合的肿瘤。初步研究表明药物中存在细胞内在先天免疫和炎症细胞因子信号通路具有 MET 融合的 pHGG 细胞的耐受性和耐药性发现和研究耐药机制。为了确定生物性别是否影响 pHGG 与 RTK 融合的方式，我们提出两个目标：1) 检查 RTK 融合的 pHGG 中先天免疫途径的表达和激活以及 2) 检查性别 RTK 融合的 pHGG 中先天免疫途径的差异可能是我们的研究结果。导致开发新的 pHGG 组合精准治疗策略。 1