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：
10359745
负责人：
Michael A Dyer
金额：
$ 40.24万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
https://reporter.nih.gov/project-details/10359745
关键词：
ATRX gene Affect Age Antibodies Binding Biogenesis Biology Child Childhood Solid Neoplasm Clinical Trials Complex Cyclophosphamide DNA DNA Damage DNA Polymerase I DNA Repair DNA biosynthesis Data Databases Defect Diagnosis Dose Drug Kinetics Evaluation G-Quartets Generations Genomics Goals Government Growth Health Histones Human Human Cell Line Immunotherapy Interleukin-15 Interleukin-2 MYCN gene Malignant Neoplasms Mediating Metabolic Molecular Molecular Chaperones Molecular Diagnostic Testing Mutation Natural Killer Cells Neuroblastoma Oncogene Activation Oncogenes Outcome Pathway interactions Patient-Focused Outcomes Patients Pediatric Neoplasm Persons Phase I/II Clinical Trial Play Positioning Attribute Preclinical Testing Process Prognosis Publishing RNA Reactive Oxygen Species Recurrence Reporting Research Research Project Grants Research Proposals Ribosomes Role Saint Jude Children&apos s Research Hospital Schedule Series Solid Neoplasm Standardization Structure Testing Therapeutic Topotecan Toxic effect Translating Translational Research Tumor Suppressor Genes antibody-dependent cell cytotoxicity chemotherapy clinically relevant cytokine design disorder risk drug sensitivity efficacy testing epigenomics experience high risk improved improved outcome in vivo induced pluripotent stem cell inhibitor mitochondrial dysfunction molecular targeted therapies mouse model multidisciplinary mutant neoplastic cell neuroblastoma cell novel therapeutic intervention prevent replication stress response tumor tumor growth tumor 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.

侵略性癌症通常在生长控制的肿瘤中具有激活突变和灭活肿瘤抑制基因的突变。在神经母细胞瘤中，霉菌癌基因的扩增和 ATRX肿瘤抑制基因的失活与高风险疾病和预后不良相关。在这里，我们表明ATRX突变和MYCN扩增在所有年龄段都相互排斥和神经母细胞瘤的阶段。使用人类细胞系和鼠标模型，我们发现升高 MYCN表达和ATRX突变不兼容。升高的MYCN水平促进代谢重编程，线粒体功能障碍，反应性氧的产生和DNA复制性压力。由ATRX-组蛋白链中缺陷引起的复制应力的组合 MYCN介导的代谢重编程引起的复合物和这种复合物导致合成致死性。因此，ATRX和MYCN代表一个不寻常的例子，其中肿瘤抑制剂失活癌基因的基因和激活是不兼容的。在此提案中，我们将利用此合成致命性可改善高危和/或复发性神经母细胞瘤患者的结局。具体来说，我们将使用分子靶向疗法在MYCN放大器中扰动ATRX依赖性过程神经母细胞瘤并破坏ATRX缺乏肿瘤中MYCN依赖性过程。在这个翻译研究建议，我们将同时针对肿瘤细胞和肿瘤微环境。通过儿童实体肿瘤网络自由共享所有发布和未发表的数据加速对神经母细胞瘤的发现。这些研究的结果将用于设计下一个圣裘德的神经母细胞瘤临床试验。