MET kinase fusions in pediatric glioblastoma

儿童胶质母细胞瘤中的 MET 激酶融合

• 批准号: 10756382
• 负责人: Renee D Read
• 金额: $ 3.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10756382
• 关键词: Adhesions; Adopted; Adult; Apoptosis; Astrocytes; Automobile Driving; Biological Process; Blocking Antibodies; Brain; Brain Diseases; C-terminal; Cancer Etiology; Cells; Child; Childhood Glioblastoma; Childhood Glioma; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cytokine Signaling; Cytoplasmic Protein; Data; Development; Doctor of Philosophy; Drug Tolerance; Drug resistance; Experimental Models; FDA approved; Genetic; Genomics; Glioma; Goals; Growth; IRAK4 gene; Immune; Immunocompetent; Immunosuppression; In Vitro; Inflammation; Inflammatory; Interferon Receptor; Interferons; Invaded; Lesion; Malignant - descriptor; Mediating; Modeling; Mutation; N-terminal; Natural Immunity; Neoplasm Metastasis; Oncogenic; Pathway interactions; Patients; Pediatric Neoplasm; Pharmaceutical Preparations; Phosphotransferases; Precision therapeutics; Primary Brain Neoplasms; Process; Proliferating; Proteins; Proteomics; Publishing; RNA Interference; Receptor Protein-Tyrosine Kinases; Research; Resistance; Resistance development; STAT1 gene; Signal Pathway; Signal Transduction; TBK1 gene; TLR4 gene; TP53 gene; Testing; Therapeutic Agents; Tissues; Toll-like receptors; Treatment Efficacy; Tumor Promotion; Tumor Stem Cells; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Variant; Xenograft procedure; antitumor effect; astrocyte progenitor; autocrine; blood-brain barrier penetration; brain tissue; cell type; chemokine; childhood cancer mortality; cytokine; differential expression; effective therapy; experimental study; extracellular; genetic approach; human model; improved; in vivo; insight; kinase inhibitor; migration; mouse model; mutant; neoplastic cell; nerve stem cell; neural; new therapeutic target; novel therapeutics; overexpression; paracrine; pharmacologic; precision medicine; predicting response; predictive marker; prevent; programs; protein protein interaction; recruit; resistance mechanism; response; small molecule; stem cell model; stem cells; stem-like cell; synergism; therapeutic evaluation; therapeutic target; therapy design; transcriptomics; treatment strategy; tumor; tumor microenvironment; tumor progression; tumorigenesis

ABSTRACT High grade gliomas (HGGs), the most deadly malignant primary brain tumors in children, and are incurable with current therapies. To find mutations that drive formation and progression of pediatric HGGs (pHGGs), we genomically characterized over 25 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 and ALK fusions, found in more than 10% of pHGGs. 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 quickly developed resistant secondary tumors. Therefore, we are using our experiments MET fusion models, which include patient-derived pHGG tumor stem cells and xenografts as well as immunocompetent pHGG mouse models, to discover TKI resistance mechanisms. Already, our preliminary studies implicate cell-intrinsic innate immunity and inflammatory cytokine signaling in TKI drug tolerance and emergence of resistance among pHGG cells with MET fusions. To discover and study resistance mechanisms for MET and other RTK fusions in pHGG, we propose to two aims to 1) examine interactions between RTK fusions, RTK kinase inhibitors, and inflammatory cytokine signaling pathways and their effectors in vitro and in vivo in the brain using our robust MET fusion models, and to 2) test synergy between RTK kinase inhibitors and inflammatory pathway inhibition using pharmacologic and genetic approaches. We will use additional models of RTK fusions pHGGs to determine if our observations are generalizable among pHGGs with RTK fusions. The results of our research may lead to development of new combination precision treatment strategies for pHGG.

摘要 高级别胶质瘤(HGG)是儿童最致命的原发脑肿瘤，是 用目前的治疗方法无法治愈。寻找驱动儿童HGG形成和进展的突变 (PHGGS)，我们对超过25种肿瘤进行了基因组学特征分析，并确定了MET和ALK的融合突变。 受体酪氨酸激酶。最近的综合分析表明，高达40%的人发现了RTK融合 最常见的是MET和ALK融合，在超过10%的PHGG中发现。我们的和 其他人的数据表明，对于许多RTK融合，其中C-末端的激酶域被融合到N-末端 在神经胶质干细胞/祖细胞中正常高表达的其他蛋白质的区域，表明 作为发展计划的结果，MET融合基因可能过度表达。我们的结果表明，RTK 融合，例如MET融合，创造了能够转化神经干细胞的结构性活性激酶 转化为PHGG样瘤。FDA批准的小分子酪氨酸激酶抑制剂(TKI)可以穿透 血脑屏障，可能有利于MET和ALK融合以及其他RTK融合的PHGG患者，以及 这些TKI正在研究的基础上在RTK融合的患者中进行测试。然而，尽管最初 反应中，MET融合PHGG患者迅速发展为耐药继发肿瘤。因此，我们正在使用 我们的实验符合融合模型，其中包括患者来源的PHGG肿瘤干细胞和异种移植 并建立免疫活性PHGG小鼠模型，探讨TKI耐药机制。已经，我们的 TKI药物涉及细胞固有免疫和炎性细胞因子信号转导的初步研究 MET融合的PHGG细胞对MET的耐受性和耐药性的出现。发现和研究抗药性 在PHGG中，MET和其他RTK融合的机制，我们提出了两个目的：1)检查相互作用 RTK融合、RTK激酶抑制剂和炎症细胞因子信号通路及其效应物之间的关系 使用我们健壮的MET融合模型，在体外和体内脑组织中，并2)测试RTK激酶之间的协同作用 使用药理学和遗传学方法的抑制剂和炎症途径抑制。我们将使用 RTK融合PHGGS的其他模型，以确定我们的观察结果是否可在PHGGS中推广 RTK融合。我们的研究结果可能会导致新的组合精密治疗的发展 PHGG的策略。