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

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 与目前的疗法。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 酪氨酸激酶。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 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 发展计划的结果。我们的结果表明，RTK 融合（例如 MET 融合）可以创建 能够将神经干细胞转化为 pHGG 样肿瘤的组成型活性激酶。 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 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 在研究的基础上进行 RTK 融合的患者。然而，尽管有初步反应，MET 融合 pHGG 患者可能会出现耐药肿瘤。因此，为了发现 TKI 耐药机制，我们创建了我们的 具有 MET 和 ALK 融合肿瘤的实验性免疫活性小鼠 pHGG 模型。已经，我们的 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 pHGG 中先天免疫途径功能的差异。我们的研究结果可能 导致开发新的 pHGG 组合精准治疗策略。 1