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Digoxin Effectively Reduces Circulating Tumor Cell Clusters in Metastatic Breast Cancer, Study Finds
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Key Takeaways
- Digoxin treatment led to a significant reduction in circulating tumor cell cluster size in metastatic breast cancer patients.
- CTC clusters are predictive of poor prognosis and have higher metastatic capacity compared to individual CTCs.
Digoxen is the active ingredient found in the foxglove plant and is commonly used to treat heart failure.
Treatment with digoxin (Digitek; Mylan Pharmaceuticals Inc) led to partial deterioration of circulating tumor cell (CTC) clusters in women with metastatic breast cancer (MBC), according to study results published by researchers from ETH Zurich in Nature Medicine. The agent had encouraging results, meeting its primary end point of mean cluster size reduction in a single-arm, exploratory study (NCT03928210).1
Vial of digoxin solution for intravenous administration | Image Credit: © luchschenF - stock.adobe.com
Despite significant advancements in treatments, a need for improved therapeutic approaches and alternatives remains for patients with MBC who have worse outcomes. Historically, therapies and agents used in treatment of breast cancer (BC) are cytotoxic rather than being designed to interview with the mechanisms underlying metastasis.2
Presence of CTCs has been established as a predictive indicator of poor prognosis in patients with BC. CTCs are living cells that shed from primary and metastatic lesions into the bloodstream and circulate, lending to the spread of disease and development of lesions in other parts of the body. Preclinical research has found that clusters of CTCs have significantly higher metastatic capacity compared with individual CTCs, as well as identified vulnerabilities that would lead to development of drugs to target these clusters, disrupt their aggregation, and inhibit their ability to seed metastatic tumors.2
“Breast cancer metastasis depends on CTC clusters," Nicola Aceto, principal investigator and professor of Molecular Oncology at ETH Zurich, said in an article by ETH Zurich. "The larger they are, the more successful they are."3
Their study focused on digoxen, an active ingredient originally from the foxglove plant. It is commonly used for treatment of heart failure, but a 2019 study showed it was also effective in the BC treatment paradigm. In a screening of over 2400 FDA approved drugs, researchers found that Na+/K+ ATPase inhibitors, such as cardiac glycosides, dissolved CTC clusters into single cells, leading to metastasis suppression in mouse models.2,3
To further explore the ability of Na+/K+ ATPase inhibitors to disrupt CTC clusters, researchers initiated a multicentric, prospective, first-in-human proof-of-concept, single-arm, therapeutic exploratory phase 1 study. They aimed to determine whether treatment with the Na+/K+ ATPase inhibitor digoxin could reduce mean CTC cluster size. The study included 9 patients who were administered digoxin daily at a maintenance dose of 0.7–1.4 ng ml−1 serum level.2
The researchers reported that the study met its primary end point of mean cluster size reduction, demonstrating a reduction of −2.2 cells per cluster upon treatment (P = 0.003). Additionally, they identified that digoxin therapy was associated with downregulation of cell-to-cell adhesion and cell-cycle-related genes, according to transcriptome profiling.2
The initial findings are promising and represent the first in-human proof that digoxin treatment leads to a partial CTC cluster dissolution. These results highlight a potential new approach to targeting metastasis, but further research is needed to validate efficacy and safety in larger trials. If confirmed, Na+/K+ ATPase inhibitors like digoxin could offer a novel therapeutic strategy for patients with MBC, addressing a critical unmet need in metastatic disease management.
