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.

项目概要/摘要神经母细胞瘤（NB）是一种小儿交感神经系统实体瘤，占 15% 儿童癌症死亡的一半患者中观察到 MYCN 转录因子的肿瘤细胞扩增。患有高风险疾病，它作为与转移性疾病和贫困相关的致癌驱动因素扩增的 MYCN 通过刺激基因的表达来发挥细胞生长调节剂的作用。我们已经确定了核糖体生物合成中的功能和蛋白质翻译的调节元件。翻译起始因子 eIF4A，一种负责克服 5' 翻译障碍的 RNA 解旋酶非翻译区 (UTR) 是转录特异性 mRNA 募集的主要调节因子 MYCN 过表达的 NB 细胞是 rocaglate 类蛋白质合成的主要靶标。抑制剂，通过将 eIF4A 夹在转录本特异性的方式上来抑制翻译起始富含多聚嘌呤（PP）的 5' UTR 并防止核糖体扫描，这种独特的作用模式提供了这种独特的作用。对高度增殖的癌细胞具有选择性，其中促生存转录本优先富集于 PP- 丰富的前导序列在富含 PP 的 5'UTR 序列中排名靠前，其中大部分序列。从新型合成脒基罗卡格拉特 (ADR) 文库筛选中起重要作用。 rocaglate 类似物是由波士顿大学的联合研究员 John Porco 博士开发的，我们发现了有前途的候选者 CMLD012824 可破坏 eIF4A 活性，从而抑制翻译并诱导 MYCN 扩增的 NB 细胞中的选择性、剂量依赖性细胞毒性我们一直在努力解决 ADR 介导的问题。抑制 eIF4A 会在 MYCN 扩增的 NB 细胞中诱导强效和选择性的细胞毒性，在目标 1 中，我们将开发一种有效的治疗策略。有效、高选择性的 ADR 和新型胍基罗卡格拉酸盐 (GDR)，具有抗 MYCN- 活性在目标 2 中，我们扩增了 NB 细胞并表现出可进行体内功效研究的药理学特性。将研究 ADR/GDR 抑制对 MYCN 扩增的 NB 细胞系和肿瘤模型的影响。这些研究的结果将为这种新型翻译抑制剂的临床前验证提供依据治疗 MYCN 扩增的 NB 患者，并推动其向临床应用发展。研究结果也可能与依赖转录成瘾和非经典的其他癌症有关翻译起始机制，从而扩大了这种治疗策略的范围。