Novel Therapeutic Approaches for the Treatment of Neuroblastoma
治疗神经母细胞瘤的新方法
基本信息
- 批准号:10602395
- 负责人:
- 金额:$ 40.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATRX geneAccelerationAffectAgeAntibodiesBindingBiogenesisBiologyCephalicChildChildhood Solid NeoplasmClinical TrialsComplexCyclophosphamideDNADNA DamageDNA Polymerase IDNA RepairDNA biosynthesisDataDatabasesDefectDiagnosisDoseDrug KineticsEvaluationG-QuartetsGenerationsGenomicsGoalsGovernmentGrowthHealthHistonesHumanHuman Cell LineImmunotherapyInterleukin-15Interleukin-2MYCN geneMalignant NeoplasmsMediatingMetabolicMolecularMolecular ChaperonesMolecular Diagnostic TestingMutationNatural Killer CellsNeuroblastomaOncogene ActivationOncogenesOutcomePathway interactionsPatient-Focused OutcomesPatientsPediatric NeoplasmPersonsPhase I/II Clinical TrialPlayPositioning AttributePreclinical TestingProcessPrognosisPublishingRNAReactive Oxygen SpeciesRecurrenceReportingResearchResearch Project GrantsResearch ProposalsRibosomesRoleSaint Jude Children&aposs Research HospitalScheduleSeriesSolid NeoplasmStandardizationStressStructureTestingTherapeuticTopotecanToxic effectTranslatingTranslational ResearchTumor Suppressor Genesantibody-dependent cell cytotoxicitychemotherapyclinically relevantcytokinedesigndisorder riskdrug sensitivityefficacy testingepigenomicsexperiencehigh riskimprovedimproved outcomein vivoinduced pluripotent stem cellinhibitormitochondrial dysfunctionmolecular targeted therapiesmouse modelmultidisciplinarymutantneoplastic cellneuroblastoma cellnovel therapeutic interventionpreventresponsetumortumor growthtumor microenvironment
项目摘要
Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating
mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and
inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis.
Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages
and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated
MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic
reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative
stress. The combination of replicative stress caused by defects in the ATRX–histone chaperone
complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality.
Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor
gene and activation of an oncogene are incompatible. In this proposal, we will exploit this synthetic
lethality to improve outcomes for patients with high-risk and/or recurrent neuroblastoma. Specifically,
we will use molecular targeted therapeutics to perturb ATRX-dependent processes in MYCN amplified
neuroblastomas and to disrupt MYCN-dependent processes in ATRX deficient tumors. In this
translational research proposal, we will target both the tumor cells and the tumor microenvironment.
All published and unpublished data are freely shared through the Childhood Solid Tumor Network to
accelerate discovery on neuroblastoma. The results of these studies will be used to design the next
neuroblastoma clinical trials at St. Jude.
侵袭性癌症通常在生长控制癌基因中具有激活突变,
肿瘤抑制基因的突变。在神经母细胞瘤中,MYCN癌基因的扩增和
ATRX肿瘤抑制基因的失活与高风险疾病和不良预后相关。
在这里,我们表明,ATRX突变和MYCN扩增是相互排斥的所有年龄
和神经母细胞瘤的分期使用人类细胞系和小鼠模型,我们发现,
MYCN表达和ATRX突变是不相容的。MYCN水平升高促进代谢
重编程、线粒体功能障碍、活性氧生成和DNA复制
应力由ATRX-组蛋白伴侣缺陷引起的复制应激的组合
复合物和MYCN介导的代谢重编程诱导的合成致死性。
因此,ATRX和MYCN代表了一个不寻常的例子,
基因和癌基因的激活是不相容的。在本提案中,我们将利用这种合成
致死性,以改善高风险和/或复发性神经母细胞瘤患者的结局。具体地说,
我们将使用分子靶向治疗来干扰MYCN扩增的ATRX依赖性过程,
在神经母细胞瘤中的作用和在ATRX缺陷型肿瘤中破坏MYCN依赖性过程。在这
在转化研究提案中,我们将同时针对肿瘤细胞和肿瘤微环境。
所有已发表和未发表的数据都通过儿童实体瘤网络免费共享,
加速神经母细胞瘤的发现这些研究的结果将用于设计下一个
神经母细胞瘤临床试验
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)
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Michael A Dyer其他文献
Michael A Dyer的其他文献
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{{ truncateString('Michael A Dyer', 18)}}的其他基金
In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas
治疗小儿软组织肉瘤的新型药物组合的体内测试
- 批准号:
10653061 - 财政年份:2021
- 资助金额:
$ 40.24万 - 项目类别:
In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas
治疗小儿软组织肉瘤的新型药物组合的体内测试
- 批准号:
10300360 - 财政年份:2021
- 资助金额:
$ 40.24万 - 项目类别:
In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas
治疗小儿软组织肉瘤的新型药物组合的体内测试
- 批准号:
10437921 - 财政年份:2021
- 资助金额:
$ 40.24万 - 项目类别:
Cell-type– and developmental stage–specific regulation of gene expression in the retina
视网膜中基因表达的细胞类型和发育阶段的特异性调控
- 批准号:
10333227 - 财政年份:2020
- 资助金额:
$ 40.24万 - 项目类别:
Cell-type– and developmental stage–specific regulation of gene expression in the retina
视网膜中基因表达的细胞类型和发育阶段的特异性调控
- 批准号:
9886721 - 财政年份:2020
- 资助金额:
$ 40.24万 - 项目类别:
Novel Therapeutic Approaches for the Treatment of Neuroblastoma
治疗神经母细胞瘤的新方法
- 批准号:
10372856 - 财政年份:2020
- 资助金额:
$ 40.24万 - 项目类别:
Novel Therapeutic Approaches for the Treatment of Neuroblastoma
治疗神经母细胞瘤的新方法
- 批准号:
10737754 - 财政年份:2020
- 资助金额:
$ 40.24万 - 项目类别:
Modeling Retinoblastoma Initiation Using 3D-Retinal Organoids
使用 3D 视网膜类器官模拟视网膜母细胞瘤的发生
- 批准号:
10611878 - 财政年份:2020
- 资助金额:
$ 40.24万 - 项目类别:
Cell-type– and developmental stage–specific regulation of gene expression in the retina
视网膜中基因表达的细胞类型和发育阶段的特异性调控
- 批准号:
10576348 - 财政年份:2020
- 资助金额:
$ 40.24万 - 项目类别:
Modeling Retinoblastoma Initiation Using 3D-Retinal Organoids
使用 3D 视网膜类器官模拟视网膜母细胞瘤的发生
- 批准号:
10165672 - 财政年份:2020
- 资助金额:
$ 40.24万 - 项目类别:
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