Wnt/β-catenin signaling is a therapeutic target in anaplastic thyroid carcinoma

Endocrine. 2024 Oct;86(1):114-118. doi: 10.1007/s12020-024-03887-0. Epub 2024 May 28.

Abstract

Background: Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that has consistently shown Wnt/β-catenin (canonical) signaling activation in various study populations. There are currently no targetable treatments for BRAF-wildtype ATC and a lack of effective treatment for BRAFV600EATC. Our aim is to identify whether Wnt inhibitors could be potential therapeutic agents for ATC patients with limited treatment options.

Methods: In this Institutional Review Board-approved study, we utilize a cohort of 32 ATCs and 20 non-neoplastic multinodular goiters (MNG). We also use 4 ATC spheroid cell lines (THJ-16T, THJ-21T, THJ-29T, and THJ-11T) and two primary patient-derived ATC organoid cultures (VWL-T5 and VWL-T60). Finally, we use a murine xenograft mouse model of ATC for in vivo treatment studies.

Results: Using a large patient cohort, we demonstrate that this near-universal Wnt signaling activation is associated with ligand expression- rather than being mutationally-driven. We show that pyrvinium pamoate, a potent Wnt inhibitor, exhibits in vitro efficacy against both ATC cell lines and primary patient-derived ATC organoids VWL-T5 (p < 0.05) and VWL-T60 (p < 0.01) Finally, using a murine xenograft model of ATC, we show that pyrvinium significantly delays the growth of ATC tumors in THJ-16T (p < 0.005) and THJ-21T (p < 0.001).

Conclusions: We tested Wnt inhibitor treatment, both in vitro and in vivo, as a potential novel therapy for this highly lethal disease. Future large-scale studies utilizing multiple Wnt inhibitors will lay the foundation for the development of these novel therapies for patients with ATC.

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Pyrvinium Compounds* / pharmacology
  • Pyrvinium Compounds* / therapeutic use
  • Thyroid Carcinoma, Anaplastic* / drug therapy
  • Thyroid Carcinoma, Anaplastic* / metabolism
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / metabolism
  • Thyroid Neoplasms* / pathology
  • Wnt Signaling Pathway* / drug effects
  • Wnt Signaling Pathway* / physiology
  • Xenograft Model Antitumor Assays

Substances

  • Pyrvinium Compounds
  • pyrvinium
  • Antineoplastic Agents