Some tumor types spread throughout the body and develop metastases instead of staying at their original location. This occurs because the main tumor constantly releases cancer cells into the blood. After settling in other organs, these circulating tumor cells (CTCs) can form tiny clusters of up to 12 cells.
The clusters there develop into metastases, which are bigger tumors. Approximately seven million people worldwide lose their lives to metastatic tumors each year, making them a serious medical concern.
Breast cancer is one instance of a tumor that spreads like this. The chances of survival sharply decline once the primary tumor develops metastases. Metastatic breast cancer continues to claim the lives of tens of thousands of women worldwide. To stop metastases from forming, oncologists are searching for methods to weaken or eliminate the clusters.
Significantly Reduced Risk of Metastases
A group of researchers from ETH Zurich, the University Hospitals of Basel and Zurich, and the Basel-Land Cantonal Hospital demonstrated a novel and promising method in a recent study published in the journal Nature Medicine.
Around nine patients with metastatic breast cancer were given digoxin at a low and safe dosage for one week as part of a clinical study.
As a result, there were, on average, 2.2 fewer cells per cluster, which was a significant decrease. This indicates a substantial decrease in the risk of metastases, as typical cluster sizes are only a few cells. The likelihood that a cluster will successfully produce metastases decreases with cluster size.
Breast cancer metastasis depends on CTC clusters. The larger they are, the more successful they are.”
Nicola Aceto, Professor and Study Principal Investigator, Eidgenössische Technische Hochschule Zürich
The sodium-potassium pumps, also referred to as Na+/K+-ATPases, are the weak point of CTC clusters. They are found in tumor cell membranes and are in charge of moving potassium into and sodium out of the cells. Digoxin suppresses ion exchange by blocking these ion pumps.
As a result, the cells take up more calcium from the cell membrane, and the cancer cells in the cluster become less cohesive and disintegrate.
Digoxin by itself, however, cannot remove the current tumor. The agent would need to be used in conjunction with other drugs that destroy cancer cells that are already present.
Researchers Hope to Optimize the Active Ingredient
The foxglove plant (Digitalis sp.) is the source of digoxin, an active ingredient typically used to treat heart conditions like heart failure. According to research from ETH in 2019, digoxin may also be useful in the treatment of breast cancer.
To identify active agents against clusters of circulating tumor cells (CTCs), they conducted a thorough screening in which they methodically examined over 2,400 distinct compounds in cell cultures.
The researchers' next goal is to create digoxin-based compounds that are even more effective at breaking down CTC clusters. Page Therapeutics, an ETH spin-off, is already developing this solution.
In addition to melanoma, Aceto hopes to broaden his research to include other cancers that spread, like prostate, colorectal, or pancreatic cancer. In his lab, preliminary experiments have already started.
The study illustrates the excellent collaboration between ETH Zurich and several hospitals, such as the Basel-Land Cantonal Hospital and the University Hospitals of Basel and Zurich. The hospital partners recruited the patients for the clinical trials.
Source:
Journal reference:
Kurzeder, C., et al. (2025) Digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer: a proof-of-concept trial. Nature Medicine. doi.org/10.1038/s41591-024-03486-6.