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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：
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/10602395
关键词：
ATRX gene Acceleration Affect Age Antibodies Binding Biogenesis Biology Cephalic 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 Stress 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 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.

侵袭性癌症通常具有生长控制癌基因的激活突变和失活。肿瘤抑制基因的突变。在神经母细胞瘤中，MYCN癌基因和 ATRX肿瘤抑制基因的失活与高危疾病和不良预后相关。在这里，我们表明ATRX突变和MYCN扩增在所有年龄段都是相互排斥的神经母细胞瘤分期。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复制压力。ATRX-组蛋白伴侣蛋白缺陷引起的复制应激组合复合体和MYCN介导的代谢重编程导致的合成致死。因此，ATRX和MYCN代表了一个不寻常的例子，其中肿瘤抑制因子的失活基因和癌基因的激活是不相容的。在这个提案中，我们将利用这种合成致命性以改善高危和/或复发神经母细胞瘤患者的预后。具体来说，我们将使用分子靶向治疗来扰乱MYCN扩增的ATRX依赖过程神经母细胞瘤和在ATRX缺乏的肿瘤中干扰MYCN依赖的过程。在这翻译研究建议，我们将同时针对肿瘤细胞和肿瘤微环境。所有已发布和未发布的数据都通过儿童实体肿瘤网络免费共享，以加快神经母细胞瘤的发现。这些研究的结果将被用来设计下一个圣犹大的神经母细胞瘤临床试验。