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: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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

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 高级别胶质瘤是儿童最致命的原发脑肿瘤，是无法治愈的。 用目前的治疗方法。为了找到驱动儿童HGGs(PHGGs)形成和进展的突变，我们 患者肿瘤的基因组特征，我们确定了MET和ALK受体的融合突变 酪氨酸激酶。最近的综合分析表明，高达40%的PHGG中发现了RTK融合，以及 其中最常见的是MET、ALK和NTRK融合。我们和其他人的数据显示，对于许多RTK 融合，在这种融合中，C末端的激酶结构域与其他蛋白质的N末端区域融合，而正常情况下 在神经胶质干细胞/祖细胞中高度表达，表明MET融合可能作为一种 发展计划的后果。我们的结果表明，RTK融合，如MET融合，创造了 能够将神经干细胞转化为PHGG样肿瘤的结构性活性激酶。FDA批准 小分子酪氨酸激酶抑制剂(TKI)可以穿透血脑屏障，可能有益于 接受MET和ALK融合以及其他RTK融合的PHGG患者，这些TKI正在进行测试 在研究基础上进行RTK融合的患者。然而，尽管最初有反应，MET融合PHGG 患者可能会患上抗药性肿瘤。因此，为了发现TKI的抵抗机制，我们创建了我们的 MET和ALK融合的实验性免疫活性小鼠PHGG肿瘤模型。已经，我们的 药物中涉及细胞固有免疫和炎性细胞因子信号通路的初步研究 MET融合的PHGG细胞的耐受性和耐药性。发现和研究抗性机制 为了确定生物性别是否会影响PHGGs与RTK的融合，我们提出了两个目标来研究 RTK融合基因在PHGGs中的表达和激活及2)性别鉴定 RTK融合的PHGG天然免疫通路功能的差异。我们的研究结果可能 导致针对PHGG的新的组合精密治疗策略的开发。 1