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Updated: May 27, 2025

A Model for Perineural Invasion in Head and Neck Squamous Cell Carcinoma
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Blockade of the PGE2 Pathway Inhibits the Growth of PTEN-Deficient HNSCC Tumors

Jacqueline P Nguyen1, Shorook Na'ara1, Liam C Woerner1

  • 1Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, California.

Molecular Cancer Therapeutics
|February 20, 2025
PubMed

Insights

Aspirin inhibits head and neck squamous cell carcinoma (HNSCC) growth in PTEN-deficient tumors. Targeting EP2/EP4 receptors with TPST-1495 enhances anti-PD1 therapy effectiveness in HNSCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • PI3K signaling is frequently altered in head and neck squamous cell carcinoma (HNSCC).
  • PTEN loss or PIK3CA alterations lead to increased PI3K signaling, promoting tumor growth and immunosuppression via COX2 and prostaglandin E2 (PGE2).
  • The role of PGE2 in PTEN-deficient HNSCC and its interaction with EP2/EP4 receptors require further investigation.

Purpose of the Study:

  • To investigate PGE2 signaling in PTEN-deficient HNSCC.
  • To evaluate the efficacy of aspirin and a dual EP2/EP4 antagonist (TPST-1495) in preclinical HNSCC models.
  • To assess the potential of EP2/EP4 antagonism to enhance anti-PD1 immunotherapy.

Main Methods:

  • Utilized PTEN knockout and PIK3CA-altered HNSCC cell lines and tumor models in immunocompetent mice.
  • Assessed PGE2 signaling pathways and the impact of therapeutic interventions.
  • Administered aspirin, TPST-1495, or anti-PD1 immunotherapy, alone or in combination.

Main Results:

  • Aspirin selectively inhibited the growth of PTEN knockout HNSCC tumors.
  • TPST-1495 demonstrated significant tumor growth inhibition.
  • TPST-1495 substantially enhanced the antitumor activity of anti-PD1 immunotherapy.

Conclusions:

  • Non-steroidal anti-inflammatory drugs (NSAIDs) exhibit antitumor activity in PTEN-deficient and PI3K-altered HNSCC.
  • Targeting EP2/EP4 receptors represents a promising strategy to augment existing anti-PD1 therapies for HNSCC.
  • These findings suggest novel therapeutic avenues for PI3K pathway-altered HNSCC.

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