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：
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
项目类别：
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

项目摘要

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.

抽象的高级神经胶质瘤（HGGS），儿童最致命的恶性原发性脑肿瘤，是目前的疗法无法治愈。找到驱动小儿HGG形成和进展的突变（PHGGS），我们在25个肿瘤上进行基因表征，我们在Met和Alk中鉴定了融合突变受体酪氨酸激酶。最近的全面分析表明，RTK融合量最多可在40％ PHGG，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显示，对于许多RTK融合了，其中C末端激酶结构域与N末端融合通常在神经胶质/祖细胞中高度表达的其他蛋白质区域，表明由于发展计划的结果，MET融合可能过表达。我们的结果表明RTK 融合（例如MET融合）产生了能够转化神经干细胞的组成型活性激酶进入类似Phgg的肿瘤。 FDA批准的小分子酪氨酸激酶抑制剂（TKI）存在穿透可能使MET和ALK融合以及其他RTK融合的PHGG患者受益的血脑屏障以及这些TKI在研究基础上对RTK融合的患者进行了测试。但是，dospite初始反应，遇到融合PHGG患者很快就会出现抗性继发性肿瘤。因此，我们正在使用我们的实验符合融合模型，其中包括患者衍生的PHGG肿瘤干细胞和异种移植物作为以及免疫能力的PHGG小鼠模型，以发现TKI抗性机制。已经，我们的初步研究暗示了TKI药物中的细胞中性先天免疫和炎症细胞因子信号传导 PHGG细胞中具有MET融合的耐受性和抗性的出现。发现和研究抵抗力 PHGG中MET和其他RTK融合的机制，我们提出了两个目标，以检查相互作用在RTK融合，RTK激酶抑制剂和炎性细胞因子信号通路及其作用之间使用我们强大的MET融合模型在大脑中的体外和体内，至2）在RTK激酶之间测试协同作用使用药物和遗传方法的抑制剂和炎症途径抑制作用。我们将使用 RTK Fusions Phggs的其他模型，以确定我们的观察结果是否可以在PHGG中推广 RTK融合。我们的研究结果可能导致新组合精度治疗的发展 PHGG的策略。