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

• 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
• 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' 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

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.

项目摘要/摘要 神经母细胞瘤(NB)是一种儿童交感神经系统实体瘤，占15% 儿童癌症死亡的比例。半数患者肿瘤细胞MYCN转录因子扩增 高风险疾病，其功能是与转移性疾病和贫穷相关的致癌驱动因素 生死存亡。扩增的MYCN通过刺激下列基因的表达而发挥细胞生长调节的作用 核糖体生物发生中的功能和蛋白质翻译的调节元件。我们已经确定了 翻译起始因子eIF4A，一个负责克服5‘端翻译障碍的RNA解旋酶。 非翻译区(UTRs)是转录特异性mRNA募集的主要调控因子 MYCN-过表达的NB细胞。EIF4A是岩酸盐类蛋白质合成的主要靶点 抑制物，通过将eIF4A夹在转录特异性的方式来抑制翻译启动 富含多嘌呤(PP)的5‘UTRs和阻止核糖体扫描。这一独特的行动模式提供了 对高增殖癌细胞的选择性，其中促进生存的转录本优先富含PP- 富有的领袖。MYCN相关的转录本在富含PP的5‘UTR序列中排名很高，其中大多数 在细胞增殖中起关键作用。从氨基-岩藻酸盐(ADR)的库屏幕上，新的合成 由波士顿大学的共同研究员John Porco博士开发的岩酸盐类似物，我们发现了一种 有希望的候选基因CMLD012824可以扰乱eIF4A的活性，从而抑制翻译和诱导 对MYCN扩增的NB细胞的选择性、剂量依赖的细胞毒性。我们假设ADR介导的 抑制eIF4A将在MYCN扩增的NB细胞中诱导强大的和选择性的细胞毒作用 将被证明是这种侵袭性癌症的有效治疗策略。在目标1中，我们将开发 有效的、高度选择性的ADR和较新的具有抗MYCN活性的胍基-岩藻酸盐(GDR)- 扩增的NB细胞，并表现出药理特性，使体内疗效研究。在目标2中，我们 将研究ADR/GDR抑制在MYCN扩增的NB细胞系和肿瘤模型中的作用。这个 这些研究的结果将为这类新的翻译抑制剂提供临床前验证 治疗MYCN扩增的NB患者，推动其向临床应用发展。我们的 这一发现也可能与依赖转录成瘾和非规范的其他癌症有关 翻译启动机制，从而扩大了这一治疗策略的范围。