Remodeling the translatome in N-myc mediated medulloblastoma and its therapeutic implications

N-myc 介导的髓母细胞瘤中翻译组的重塑及其治疗意义

基本信息

批准号：
10522626
负责人：
Davide Ruggero
金额：
$ 66.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522626
关键词：
5&apos Untranslated Regions Acute Binding Biology Brain Cell Death Cell Line Cell Survival Cessation of life Chemotherapy and/or radiation Child Childhood Malignant Brain Tumor Childhood Medulloblastomas Clinical Codon Nucleotides Cognition Complex Cytotoxic Chemotherapy Data Development Disease Excision FRAP1 gene Gene Expression Genetic Genetically Engineered Mouse Growth Human Knockout Mice LoxP-flanked allele MYCN gene Malignant Neoplasms Mediating Membrane Proteins Messenger RNA Molecular Mus Oncogenes Oncogenic Operative Surgical Procedures Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Protein Biosynthesis Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-myc RNA RNA Cap-Binding Proteins RNA Helicase Radiation Regulation Regulatory Element Research Resistance Resolution Role SHH gene Signal Pathway Specificity Spinal Cord Structure Subgroup Survivors Technology Testing Therapeutic Time Transcript Translations Untranslated Regions Xenograft procedure base cancer cell cancer genome cognitive disability cohort genetic approach high risk human model improved in vivo inhibitor insight loss of function medulloblastoma novel novel therapeutics patient stratification physically handicapped ribosome profiling targeted treatment therapeutic target tool transcription factor translation factor translatome tumor tumorigenesis

项目摘要

Medulloblastoma is the most common malignant pediatric brain tumor. After surgery, radiation and chemotherapy, five-year survival is 60-70% overall. Survivors show severe physical and cognitive disabilities, often unable to live independently. Medulloblastoma exists in four distinct molecular subgroups (WNT, SHH, Group3, Group 4). An incurable subgroup of SHH driven tumors show amplification of the MYCN transcription factor. How can we target N-myc in medulloblastoma? N-myc’s ability to regulate protein synthesis is tied both to its oncogenic potential and to interactions with the mTOR serine-threonine kinase. We hypothesize that N- myc hijacks the translational machinery regulated by the mTOR serine threonine kinase to drive transformation; and that targeting translation control represents a therapeutic strategy for N-myc driven cancers. Employing ribosome profiling technology, we surprisingly found that in addition to roles as a global regulator of protein synthesis, N-myc interacts with mTOR to regulate translation of 13 mRNAs belonging to the folding machinery, functionally important for N-myc driven medulloblastoma. The mechanisms by which N-myc directs the translation of these specific subsets of mRNAs to drive tumorigenesis and whether these potential vulnerabilities can be leveraged to develop targeted therapies remain outstanding questions. In this proposal, we will mechanistically dissect how N-myc hijacks the translational machinery for its oncogenic activity. Using novel genetic approaches, we will separately evaluate the importance of eIF4E and eIF4A in our N-myc driven genetically engineered mouse (GEM) models. We will also test new clinical drugs against eIF4A and eIF4E, analyzing GEM models, and patient derived orthotopic xenografts. Successful completion of these aims will delineate how N-myc interacts with mTOR to regulate key subsets of translational targets, and elucidates druggable mechanisms in N-myc driven medulloblastoma.

髓母细胞瘤是继手术、放射和治疗之后最常见的恶性儿童脑肿瘤。化疗后，五年生存率总体为 60-70% 幸存者表现出严重的身体和认知障碍，髓母细胞瘤存在于四个不同的分子亚组中（WNT、SHH、第 3 组、第 4 组）SHH 驱动肿瘤的不可治愈亚组显示 MYCN 转录扩增。我们如何才能在髓母细胞瘤中靶向 N-myc 调节蛋白质合成的能力？由于其致癌潜力以及与 mTOR 丝氨酸-苏氨酸激酶的相互作用，我们认为 N- 很重要。 myc 劫持由 mTOR 丝氨酸苏氨酸激酶调节的翻译机制来驱动转化；靶向翻译控制代表了 N-myc 驱动的癌症的治疗策略。核糖体分析技术，我们惊讶地发现，除了作为蛋白质的全局调节剂的作用合成，N-myc 与 mTOR 相互作用，调节属于折叠机制的 13 个 mRNA 的翻译，对于 N-myc 驱动的髓母细胞瘤具有重要的功能 N-myc 指导的机制。这些特定 mRNA 子集的翻译是否驱动肿瘤发生以及这些潜在的脆弱性是否可以利用来开发靶向治疗仍然悬而未决的问题。使用新颖的方法机械地剖析 N-myc 如何劫持转化机制的致癌活性。遗传方法，我们将分别评估 eIF4E 和 eIF4A 在我们的 N-myc 驱动中的重要性我们还将针对 eIF4A 和 eIF4E 测试新的临床药物，分析 GEM 模型和患者来源的原位异种移植物将成功完成这些目标。描述 N-myc 如何与 mTOR 相互作用来调节翻译靶标的关键子集，并阐明 N-myc 驱动的髓母细胞瘤中的药物机制。