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:10690229
- 负责人:
- 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
- 起止时间:2022-09-27 至 2023-11-30
- 项目状态:已结题
- 来源:
- 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
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Renee D Read其他文献
Renee D Read的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Renee D Read', 18)}}的其他基金
Human Organoid Models for Pediatric High-Grade Gliomas
儿童高级别胶质瘤的人体类器官模型
- 批准号:
10727450 - 财政年份:2023
- 资助金额:
$ 2.19万 - 项目类别:
Verteporfin as a YAP/TAZ inhibitor for treatment of glioblastoma
维替泊芬作为 YAP/TAZ 抑制剂治疗胶质母细胞瘤
- 批准号:
10737348 - 财政年份:2023
- 资助金额:
$ 2.19万 - 项目类别:
MET kinase fusions in pediatric glioblastoma
儿童胶质母细胞瘤中的 MET 激酶融合
- 批准号:
10373782 - 财政年份:2021
- 资助金额:
$ 2.19万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 2.19万 - 项目类别:
MET kinase fusions in pediatric glioblastoma
儿童胶质母细胞瘤中的 MET 激酶融合
- 批准号:
10532158 - 财政年份:2021
- 资助金额:
$ 2.19万 - 项目类别:
Mechanisms of RIOK2 function in glioblastoma
RIOK2在胶质母细胞瘤中的功能机制
- 批准号:
10232051 - 财政年份:2017
- 资助金额:
$ 2.19万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
8668168 - 财政年份:2012
- 资助金额:
$ 2.19万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
8504550 - 财政年份:2012
- 资助金额:
$ 2.19万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
8450950 - 财政年份:2012
- 资助金额:
$ 2.19万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
7707429 - 财政年份:2009
- 资助金额:
$ 2.19万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 2.19万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 2.19万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 2.19万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 2.19万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 2.19万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 2.19万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 2.19万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 2.19万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 2.19万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 2.19万 - 项目类别:
Grant-in-Aid for Scientific Research (C)