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Soo Park, MD
Soo Park, MD
Posted: Tuesday, May 13, 2025
A multidisciplinary research team has identified pyrvinium pamoate, a U.S. Food and Drug Administration–approved anthelmintic, as a potential therapeutic candidate for Merkel cell carcinoma (MCC).
MCC can arise from either ultraviolet-induced DNA damage or integration of Merkel cell polyomavirus (MCPyV). With a 5-year survival rate of 51% for localized disease and only 14% for metastatic cases, MCC carries a poor prognosis. While immunotherapy has improved outcomes for some patients, response rates are limited, and resistance frequently develops.
“Addressing this knowledge gap and identifying alternative treatment options with improved efficacy is of the utmost importance in the pursuit of better outcomes for patients with MCC,” wrote the study authors.
Investigators utilized integrative genomic, molecular, and in vivo analyses to explore pyrvinium pamoate’s effects on MCC tumorigenesis.
Using RNA sequencing of MCPyV T antigen–induced fibroblasts, they found significant changes in Wnt signaling pathways. Canonical Wnt genes (eg, WNT3, TCF7, and TCF3) were upregulated, while noncanonical Wnt genes (eg, WNT5A, WNT5B, and WNT16) were downregulated. This expression pattern was also observed in MCC tumor samples and suggests that suppression of noncanonical and activation of canonical Wnt signaling may contribute to MCC progression, according to the investigators.
To target Wnt dysregulation, the team screened compounds using LINCS L1000 data. Pyrvinium pamoate was identified as the most effective Wnt-targeting compound because it significantly reversed the MCC gene expression signature (P_adj = 8.9 × 10⁻⁹, odds ratio = 1.97). In vitro, pyrvinium pamoate inhibited MCC cell growth at concentrations as low as 100 nM and reduced expression of the proliferation marker Ki67.
Pyrvinium pamoate also inhibited the canonical Wnt pathway by reducing T-cell factor (TCF) activity and upregulated noncanonical Wnt ligands (WNT5A/B), and suppressed neuroendocrine markers such as ATOH1 and SOX2. These effects were confirmed by RNA-seq, RT-qPCR, and Western blotting.
Additional mechanisms of pyrvinium pamoate were noted, including:
In an MCC xenograft model using MKL-1 cells, pyrvinium pamoate treatment significantly slowed tumor growth in NSG mice (P < .001). Treated tumors also showed reduced expression of ATOH1 and Ki67. Dose-escalation studies confirmed efficacy with minimal toxicity at lower doses.
“It is possible that MCC tumors must suppress noncanonical Wnts to remain in a proliferative progenitor-like cell state, while maintaining canonical Wnt (or TCF) activity at a level that supports proliferation. However, further experiments are needed to determine how noncanonical Wnt ligands are suppressed during MCC development,” the authors wrote.
They concluded, “Our research has shown that the Wnt signaling pathway plays a functional role in maintaining the neuroendocrine features of Merkel cell carcinoma. Furthermore, we have demonstrated the potential of pyrvinium pamoate as an antitumor agent that targets multiple vulnerabilities of MCC. Further studies are needed to comprehensively characterize the role of Wnt signaling on cancer hallmarks and to optimize treatment protocols for the development of pyrvinium pamoate as a clinically useful drug for MCC.”
Disclosures: No conflicts of interest were reported.
The Journal of Clinical Investigation
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