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MET kinase fusions in pediatric glioblastoma

MET kinase fusions in pediatric glioblastoma
儿童胶质母细胞瘤中的 MET 激酶融合
批准号:
10690229
负责人:
Renee D Read
金额:
$2.19万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-27 至 2023-11-30
关键词:
AdoptedAdultAffectApoptosisAstrocytesBiological AssayBlood - brain barrier anatomyBrain DiseasesC-terminalCancer EtiologyCell fusionCell modelCellsChildChildhoodChildhood GlioblastomaChildhood GliomaClinicalClinical ResearchCollaborationsCytokine SignalingDataDevelopmentDrug ToleranceDrug resistanceEpidermal Growth Factor ReceptorExperimental ModelsFDA approvedFemaleFundingGenetic TranscriptionGliomaGrantGrowthHippocampus (Brain)HumanImmuneImmunocompetentImmunosuppressionIncidenceInflammationInflammatoryInterferon-betaInterferonsInvestigationLeadMalignant - descriptorModelingMusMutationN-terminalNF-kappa BNatural ImmunityPathway interactionsPatientsPediatric NeoplasmPharmaceutical PreparationsPharmacologyPhosphotransferasesPrecision therapeuticsPrimary Brain NeoplasmsProcessProteinsProteomicsPublishingReceptor Protein-Tyrosine KinasesResearchResearch Project GrantsResistanceSex DifferencesSignal PathwaySignal TransductionTLR4 geneTestingTimeToll-Like Receptor PathwayToll-like receptorsTreatment EfficacyTumor Stem CellsTumor TissueTyrosine Kinase InhibitorUp-RegulationVariantage relatedantitumor effectbasebiological sexchildhood cancer mortalityepidemiology studyexperimental studygenetic approachimprovedinsightmalemouse modelmutantneoplastic cellnerve stem cellneurogenesisneuroinflammationnew therapeutic targetoverexpressionpainful neuropathyprecision medicineprogramsreceptorrecruitresistance mechanismresponsesmall moleculestemstem cell functionstem cellsstem-like celltherapeutic targettranscriptomicstreatment strategytumortumor growthtumor microenvironmenttumor progressiontumorigenesis

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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
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Human Organoid Models for Pediatric High-Grade Gliomas
  • 批准号:
    10727450
  • 项目类别:
  • 资助金额:
    $43.04万
  • 财政年份:
    2023
  • 负责人:
    Renee D Read
  • 依托单位:
Verteporfin as a YAP/TAZ inhibitor for treatment of glioblastoma
  • 批准号:
    10737348
  • 项目类别:
  • 资助金额:
    $57.75万
  • 财政年份:
    2023
  • 负责人:
    Renee D Read
  • 依托单位:
MET kinase fusions in pediatric glioblastoma
  • 批准号:
    10373782
  • 项目类别:
  • 资助金额:
    $23.48万
  • 财政年份:
    2021
  • 负责人:
    Renee D Read
  • 依托单位:
MET kinase fusions in pediatric glioblastoma
  • 批准号:
    10756382
  • 项目类别:
  • 资助金额:
    $3.76万
  • 财政年份:
    2021
  • 负责人:
    Renee D Read
  • 依托单位:
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