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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：
10672311
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/10672311
关键词：
5&apos Untranslated Regions Acute Binding Biology Brain Cell Death Induction Cell Line Cell Survival Cessation of life Chemotherapy and/or radiation Child Childhood 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 Heterozygote 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 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 cancer cell cancer genome cognitive disability cohort genetic approach high risk human model improved in vivo inhibitor insight loss of function medulloblastoma mouse model novel novel therapeutics patient stratification pharmacologic 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.

髓母细胞瘤是儿童最常见的恶性脑肿瘤。手术后，放疗和