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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.

髓母细胞瘤是小儿最常见的恶性脑肿瘤。经过手术、放疗和化疗，五年生存率为60-70%。幸存者表现出严重的身体和认知障碍，往往无法独立生活。髓母细胞瘤存在于四个不同的分子亚群（WNT，SHH，组3、组4）。一个无法治愈的SHH驱动的肿瘤亚组显示MYCN转录扩增因子我们如何在髓母细胞瘤中靶向N-myc？N-myc调节蛋白质合成的能力与其致癌潜力和与mTOR丝氨酸-苏氨酸激酶的相互作用。我们假设N- myc劫持由mTOR丝氨酸苏氨酸激酶调节的翻译机制以驱动转化; 并且靶向翻译控制代表了N-myc驱动的癌症的治疗策略。采用核糖体分析技术，我们惊讶地发现，除了作为蛋白质的全球调节器的作用，在合成中，N-myc与mTOR相互作用以调节属于折叠机器的13种mRNA的翻译，对于N-myc驱动的髓母细胞瘤功能重要。N-myc基因调控细胞凋亡的机制翻译这些特定的mRNA子集来驱动肿瘤发生，以及这些潜在的脆弱性是否如何利用这些技术来开发靶向治疗仍然是一个悬而未决的问题。在本提案中，我们将机械地剖析N-myc如何劫持其致癌活性的翻译机制。使用新颖我们将分别评估eIF 4 E和eIF 4A在我们的N-myc驱动的基因表达中的重要性。基因工程小鼠（GEM）模型。我们还将测试针对eIF 4A和eIF 4 E的新临床药物，分析GEM模型和患者来源的原位异种移植物。成功实现这些目标将描述N-myc如何与mTOR相互作用以调节翻译靶点的关键子集，并阐明在N-myc驱动的髓母细胞瘤中的药物机制。