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Translation initiation as a therapeutic target in neuroblastoma

翻译起始作为神经母细胞瘤的治疗靶点

基本信息

批准号：
10577978
负责人：
Rani E. George
金额：
$ 25.88万
依托单位：
DANA-FARBER CANCER INST
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：
2022-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10577978
关键词：
5&apos Untranslated Regions Apoptosis Biogenesis Biological Assay Boston Cell Cycle Progression Cell Line Cell Proliferation Cells Cessation of life Chemistry Childhood Solid Neoplasm Clinical Closure by clamp Development Digit structure Disease Dose Evaluation Exhibits Gene Expression Genes Genetic Transcription Goals Growth Libraries MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Mediating Messenger RNA Modeling N-Myc Protein Neuroblastoma Oncogenes Oncogenic Patients Peptide Initiation Factors Process Property Protein Biosynthesis Protein Synthesis Inhibitors Proteins RNA RNA Helicase RNA immunoprecipitation sequencing Regulation Regulatory Element Research Personnel Resistance Ribosomes Role Scanning Solid Sympathetic Nervous System Testing Therapeutic Transcript Translation Initiation Translational Repression Translations Universities Untranslated Regions Validation addiction analog cancer cell cell growth cellular targeting chemical synthesis childhood cancer mortality clinical application cytotoxic cytotoxicity disorder risk efficacy study established cell line gene function high risk in vivo inhibitor nanomolar neoplastic cell neuroblastoma cell novel novel strategies novel therapeutic intervention overexpression patient derived xenograft model pharmacologic pre-clinical premature prevent protein expression recruit response ribosome profiling scaffold success therapeutic target transcription factor translational potential tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Neuroblastoma (NB) is a pediatric solid tumor of the sympathetic nervous system that accounts for 15% of childhood cancer deaths. Tumor cell amplification of the MYCN transcription factor is seen in half of patients with high-risk disease, where it functions as an oncogenic driver associated with metastatic disease and poor survival. Amplified MYCN functions as a regulator of cell growth by stimulating the expression of genes that function in ribosome biogenesis and regulatory elements of protein translation. We have identified the translation initiation factor eIF4A, an RNA-helicase responsible for overcoming blocks to translation of 5′ untranslated regions (UTRs) to be the predominant regulator of transcript-specific mRNA recruitment in MYCN-overexpressing NB cells. eIF4A is the primary target of the rocaglate class of protein synthesis inhibitors, which inhibit translation initiation in a transcript-specific manner by clamping eIF4A onto polypurine-rich (PP-rich) 5′ UTRs and preventing ribosome scanning. This unique mode of action provides selectivity for highly proliferative cancer cells in which pro-survival transcripts are preferentially enriched in PP- rich leaders. MYCN-associated transcripts rank highly in PP-rich 5′ UTR sequences, the majority of which have critical roles in cell proliferation. From a library screen of amidino-rocaglates (ADRs), novel synthetic rocaglate analogs developed by co-Investigator, Dr John Porco at Boston University, we identified a promising candidate, CMLD012824 that disrupts eIF4A activity, thereby inhibiting translation and inducing selective, dose-dependent cytotoxicity in MYCN-amplified NB cells. We hypothesize that ADR-mediated inhibition of eIF4A would induce robust and selective cytotoxicity in MYCN-amplified NB cells and would prove to be a valid therapeutic strategy in this aggressive cancer. In Aim 1, we will develop potent, highly selective ADRs and newer guanidino-rocaglates (GDRs) that have activity against MYCN- amplified NB cells and exhibit pharmacological properties that enable in vivo efficacy studies. In Aim 2, we will investigate the effects of ADR/GDR inhibition in MYCN-amplified NB cell line and tumor models. The results of these studies will provide preclinical validation of this new class of translation inhibitors for the treatment of MYCN-amplified NB patients, and propel their development towards clinical application. Our findings may also be relevant to other cancers that rely on transcriptional addiction and non-canonical translation initiation mechanisms, thereby broadening the scope of this therapeutic strategy.

项目总结/文摘