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Updated: Dec 22, 2025

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EWS-FLI1-regulated Serine Synthesis and Exogenous Serine are Necessary for Ewing Sarcoma Cellular Proliferation and

Sameer H Issaq1, Arnulfo Mendoza2, Ria Kidner2

  • 1Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland. issaqsh@mail.nih.gov.

Molecular Cancer Therapeutics
|May 7, 2020
PubMed

Insights

Targeting serine metabolism, crucial for Ewing sarcoma growth, shows therapeutic promise. Inhibiting PHGDH or combining NAMPT and PHGDH inhibitors significantly reduced tumor development in preclinical models.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Ewing sarcoma's genomic landscape is increasingly understood, yet targeted therapies remain limited.
  • The oncogenic transcription factor EWS-FLI1 influences Ewing sarcoma cell metabolism by regulating 3-phosphoglycerate dehydrogenase (PHGDH).
  • PHGDH is the rate-limiting enzyme in de novo serine synthesis, a pathway implicated in cancer cell growth.

Purpose of the Study:

  • To investigate the role of serine metabolism in Ewing sarcoma tumorigenesis.
  • To evaluate the therapeutic potential of targeting serine metabolism in preclinical Ewing sarcoma models.
  • To explore novel drug combinations for Ewing sarcoma treatment.

Main Methods:

  • PHGDH knockdown and its effect on Ewing sarcoma cell proliferation and xenograft tumor growth.
  • Treatment with the PHGDH inhibitor NCT-503.
  • Combination therapy involving nicotinamide phosphoribosyltransferase (NAMPT) inhibition and NCT-503.
  • Assessment of Ewing sarcoma cell proliferation and tumorigenesis under serine deprivation.

Main Results:

  • PHGDH knockdown decreased Ewing sarcoma cell proliferation and inhibited xenograft tumor growth.
  • NCT-503 treatment resulted in a dose-dependent decrease in cellular proliferation.
  • Combined NAMPT and NCT-503 inhibition synergistically abolished Ewing sarcoma cell proliferation and tumor growth.
  • Serine deprivation inhibited Ewing sarcoma cell proliferation and tumorigenesis, highlighting dependence on both de novo synthesis and exogenous serine.

Conclusions:

  • Serine metabolism is critical for Ewing sarcoma tumorigenesis.
  • Targeting metabolic dependencies, specifically serine metabolism, represents a promising therapeutic strategy for Ewing sarcoma.
  • A combination strategy targeting NAMPT and PHGDH may offer broader clinical applications in other PHGDH-overexpressing cancers.

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