Novel Therapeutic Approaches for the Treatment of Neuroblastoma

治疗神经母细胞瘤的新方法

• 批准号: 10372856
• 负责人: Michael A Dyer
• 金额: $ 8.96万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 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/10372856
• 关键词: ATRX gene; Age; Child; Childhood Solid Neoplasm; Clinical Trials; Complex; DNA biosynthesis; Data; Defect; Generations; Growth; Histones; Human Cell Line; MYCN gene; Malignant Neoplasms; Mediating; Metabolic; Molecular Chaperones; Mutation; Neuroblastoma; Oncogene Activation; Oncogenes; Pathway interactions; Patient-Focused Outcomes; Process; Prognosis; Publishing; Reactive Oxygen Species; Recurrence; Research Proposals; Saint Jude Children' s Research Hospital; Translating; Translational Research; Tumor Suppressor Genes; design; disorder risk; high risk; improved outcome; mitochondrial dysfunction; molecular targeted therapies; mouse model; mutant; neoplastic cell; novel therapeutic intervention; replication stress; tumor; tumor microenvironment

PROJECT SUMMARY 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.

项目总结