University of Arizona Cancer Center researchers have identified a promising new treatment approach for Merkel cell carcinoma (MCC), a rare but deadly skin cancer, using an existing FDA-approved medication for intestinal worms. The study, published in The Journal of Clinical Investigation, demonstrates that pyrvinium pamoate significantly reduces tumor growth through multiple anticancer mechanisms.
Targeting a Rare but Aggressive Cancer
MCC affects approximately 3,000 people annually in the United States, with incidence rates ranging from 0.3 to 1.6 individuals per million. Despite its rarity, the cancer carries a devastating prognosis. Patients with localized disease have a five-year survival rate of 51%, which plummets to 35% with nodal involvement and just 14% for metastatic disease. More than one-third of patients present with metastatic disease at diagnosis.
Current treatment options include surgery, radiation therapy, chemotherapy, and immunotherapy. However, these approaches benefit only about half of patients with advanced disease, with chemotherapy response rates ranging between 20% and 61%, and immunotherapy showing approximately 50% response rates.
Disrupted Cellular Communication Pathways
The research team, led by Megha Padi, Ph.D., assistant professor in the department of cellular and molecular medicine, used network biology to investigate the molecular mechanisms underlying MCC development. Their analysis revealed significant disruptions in the Wnt signaling pathway, a critical cellular communication system that controls cell growth and development.
"Cancer is a disease of proliferation," Padi explained. "Cells have been growing, duplicating their DNA many times and creating problems all over the genome. A lot of those mutations are not actually what started the cancer to begin with."
In MCC, one type of Wnt signal that encourages cell growth becomes overactive, while another type that helps cells mature and stop dividing is weakened. This imbalance allows cancer cells to continue multiplying unchecked.
Multiple Mechanisms of Action
Pyrvinium pamoate, a known inhibitor of the Wnt pathway, demonstrated the strongest ability to reverse MCC's genetic signature compared with other Wnt-targeting compounds tested in laboratory experiments. The drug worked effectively even at low concentrations, outperforming other agents.
Beyond restoring Wnt signaling balance, the medication operates through several additional mechanisms. It activates p53, a natural tumor-fighting protein, disrupts cancer cell energy production, and triggers a stress response that leads to cancer cell death.
Promising Preclinical Results
In mouse models with human MCC tumors, pyrvinium pamoate significantly reduced tumor growth compared with untreated animals (P < .001). The treated tumors showed decreased levels of proteins that mark actively growing cancer cells. Higher doses produced greater tumor size reduction (P < .001).
"It's a promising amount of tumor regression," Padi noted. "It's not where we want it to be. It's definitely not a miracle drug... We're working now to try to increase its ability to kill the tumor cells to reduce growth."
The drug demonstrated activity against both major forms of MCC: approximately 80% of cases associated with Merkel cell polyomavirus and the remainder caused by sun-induced DNA damage.
Combination Therapy Potential
Researchers are now investigating combinations of pyrvinium pamoate with standard chemotherapies and immunotherapies. "Most MCC patients are now being given immunotherapy as a standard of care, but only 50-60% patients respond," Padi said. "Perhaps the others can be helped by pyrvinium."
The approach builds on the hypothesis that antiparasitic agents could be effective against cancers because tumors behave similarly to parasites. "Parasites and tumors must develop ways to use scarce resources in their host to feed themselves and allow for unlimited multiplication," Padi explained. "If the pathways that they have hijacked to feed themselves are the same, then you get lucky, and you have a tumor type that could be amenable to killing by these antiparasitic drugs."
Broader Applications
Pyrvinium pamoate has already been approved for testing in a clinical trial for pancreatic cancer patients, suggesting that a safe treatment approach for MCC patients may be feasible. The drug has shown potential against multiple cancer types, including colorectal cancer, breast cancer, acute myeloid leukemia, and glioblastoma.
The researchers are particularly excited about potential applications in other neuroendocrine tumors. "We're really excited about possibly bringing our network biology pipeline to all different types of neuroendocrine cancers that can arise in all different tissues of the body," Padi said. "They tend to be more metastatic and more aggressive."
The study authors emphasized that further research is needed to comprehensively characterize the role of Wnt signaling in cancer development and to optimize treatment protocols for developing pyrvinium pamoate as a clinically useful drug for Merkel cell carcinoma.
