Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated...

Area of Science:

• Oncology
• Metabolic pathways
• Molecular biology

Background:

• Ewing sarcoma (EWS) is a primary bone cancer in young adults with poor prognosis for metastatic disease.
• Current chemotherapy has not improved survival for metastatic EWS, highlighting the need for novel treatments.
• Targeting metabolic differences between cancer and normal cells presents a promising therapeutic avenue.

Purpose of the Study:

• To investigate the role of one-carbon metabolism in EWS.
• To identify and validate novel therapeutic targets within this metabolic pathway.
• To assess the efficacy of targeting one-carbon metabolism in preclinical EWS models.

Main Methods:

• Analysis of one-carbon metabolism gene expression in EWS patient data.
• Genetic and pharmacological inhibition of serine hydroxymethyltransferase 2 (SHMT2).
• Assessment of EWS cell proliferation, colony formation, and nucleotide levels.
• Evaluation of tumor growth in an EWS xenograft model.
• Inhibition of dihydrofolate reductase (DHFR) using Pralatrexate.

Main Results:

• Elevated expression of one-carbon metabolism genes correlates with reduced survival in EWS patients.
• Inhibition of mitochondrial SHMT2 significantly reduces EWS cell proliferation and colony formation by depleting glycine and purine nucleotides.
• Pharmacological inhibition of DHFR also profoundly inhibits EWS growth.
• Genetic depletion of SHMT2 markedly impairs tumor growth in vivo.
• EWS cells are dependent on the mitochondrial, but not cytoplasmic, arm of one-carbon metabolism.

Conclusions:

• Upregulation of one-carbon metabolism is a key vulnerability in Ewing sarcoma.
• Targeting SHMT2 or other nodes in the one-carbon metabolic pathway offers a promising therapeutic strategy for EWS.
• This study establishes one-carbon metabolism as a targetable pathway for improving EWS treatment outcomes.