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:
  • 金额:
    $ 25.88万
  • 依托单位:
  • 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

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

项目成果

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Rani E. George其他文献

Rani E. George的其他文献

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{{ truncateString('Rani E. George', 18)}}的其他基金

Cell lineage as an indicator of immune response in neuroblastoma
细胞谱系作为神经母细胞瘤免疫反应的指标
  • 批准号:
    10647815
  • 财政年份:
    2022
  • 资助金额:
    $ 25.88万
  • 项目类别:
Cell lineage as an indicator of immune response in neuroblastoma
细胞谱系作为神经母细胞瘤免疫反应的指标
  • 批准号:
    10467445
  • 财政年份:
    2022
  • 资助金额:
    $ 25.88万
  • 项目类别:
Transcriptional CDKs as therapeutic targets in MYC-dependent cancers
转录 CDK 作为 MYC 依赖性癌症的治疗靶点
  • 批准号:
    9898326
  • 财政年份:
    2016
  • 资助金额:
    $ 25.88万
  • 项目类别:
Transcriptional CDKs as therapeutic targets in MYC-dependent cancers
转录 CDK 作为 MYC 依赖性癌症的治疗靶点
  • 批准号:
    9106921
  • 财政年份:
    2016
  • 资助金额:
    $ 25.88万
  • 项目类别:
The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma
ALK 受体酪氨酸激酶作为神经母细胞瘤的治疗靶点
  • 批准号:
    8206709
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma
ALK 受体酪氨酸激酶作为神经母细胞瘤的治疗靶点
  • 批准号:
    8409812
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma
ALK 受体酪氨酸激酶作为神经母细胞瘤的治疗靶点
  • 批准号:
    8785831
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma
ALK 受体酪氨酸激酶作为神经母细胞瘤的治疗靶点
  • 批准号:
    8040502
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma
ALK 受体酪氨酸激酶作为神经母细胞瘤的治疗靶点
  • 批准号:
    8720860
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma
ALK 受体酪氨酸激酶作为神经母细胞瘤的治疗靶点
  • 批准号:
    8598861
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:

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