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Updated: Jun 18, 2025

A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
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Pharmacologic Inhibition of EIF4A Blocks NRF2 Synthesis to Prevent Osteosarcoma Metastasis

Michael M Lizardo1, Christopher Hughes1, Yue Z Huang1

  • 1Department of Molecular Oncology, BC Cancer Agency, Part of the Provincial Health Services Authority, Vancouver, British Columbia, Canada.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 30, 2024
PubMed
Abstract

Insights

Targeting eukaryotic initiation factor 4A1 (EIF4A1) effectively inhibits osteosarcoma (OS) metastasis. This approach blunts the NRF2 antioxidant response, offering a promising therapeutic strategy for metastatic OS.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis

Background:

  • Metastatic osteosarcoma (OS) lacks effective therapies.
  • Targeting mRNA translation is a promising strategy for OS.
  • Selective translation supports cytoprotective protein synthesis in harsh microenvironments.

Purpose of the Study:

  • To assess eukaryotic translation factor expression in OS.
  • To evaluate EIF4A1 inhibitors for antimetastatic activity in OS.
  • To identify pathways affected by EIF4A1 inhibition.

Main Methods:

  • Assessed eukaryotic translation factor expression in OS.
  • Utilized metastatic OS cell lines and patient-derived xenograft (PDX) models.
  • Evaluated EIF4A1 inhibitors for antiproliferative, pro-apoptotic, and antimetastatic effects.
  • Performed proteomics to identify affected pathways.

Main Results:

  • Eukaryotic initiation factor 4A1 (EIF4A1) was highly expressed in OS.
  • CR-1-31B, an EIF4A1 inhibitor, showed nanomolar cytotoxicity and inhibited OS metastasis.
  • CR-1-31B blocked NRF2 upregulation, mimicking genetic NRF2 inactivation.
  • The clinical-grade inhibitor zotatifin also blocked NRF2 synthesis and OS metastasis.

Conclusions:

  • Pharmacologic targeting of EIF4A1 effectively inhibits OS metastasis.
  • Inhibition of EIF4A1 blunts the NRF2 antioxidant response.
  • EIF4A1 inhibition represents a viable therapeutic strategy for metastatic OS.

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