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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

摘要