Dissolving clusters of cancer cells to prevent metastases

Certain tumour types do not remain at their point of origin but spread throughout the body and form metastases. This is because the primary tumour continuously releases cancer cells into the blood. These circulating tumour cells (CTCs) can join together into small clusters of up to a dozen cells and settle in other organs. There, the clusters grow into larger tumours, known as metastases. Metastatic tumours are still a major medical problem: every year, around seven million people worldwide die from them.

One example of such a spreading tumour is breast cancer. As soon as the primary tumour forms metastases, the chances of survival decrease drastically. Tens of thousands of women worldwide still die of metastatic breast cancer. Oncologists are therefore looking for ways to weaken or destroy the clusters in order to prevent the formation of metastases.

Significantly reduced risk of metastases

In a new study, which has just been published in the journal Nature Medicine, a team of researchers from ETH Zurich, the University Hospitals of Basel and Zurich, and the Basel-Land Cantonal Hospital, shows a new, promising approach.

In a clinical study, the researchers administered the drug digoxin at a low and safe dosage for one week to nine patients with metastatic breast cancer.

The result: the number of cells per cluster decreased significantly ¨C by an average of 2.2 cells. Given that typical cluster sizes are only a handful of cells, this means a significant reduction in the risk of metastases. The smaller the clusters, the less able they are to successfully produce metastases. ¡°Breast cancer metastasis depends on CTC clusters¡±, explains principal investigator Nicola Aceto, Professor of Molecular Oncology at ETH Zurich. "The larger they are, the more successful they are."

The Achilles' heel of CTC clusters are the sodium-potassium pumps (also known as Na+/K+-ATPases), which are located in the membranes of tumour cells and are responsible for transporting sodium out of the cells and potassium into them. Digoxin blocks these ion pumps and thus suppresses the ion exchange. The cells therefore absorb more calcium from the outside of the cell membrane. This weakens the cohesion of the cancer cells in the cluster, causing them to fall apart.

However, digoxin alone does not eliminate the existing tumour. The agent would have to be administered in combination with other substances that kill existing cancer cells.

Researchers hope to optimise the active ingredient

The active ingredient digoxin originally comes from the foxglove plant (Digitalis sp.) and is usually used for heart conditions such as heart failure. The ETH researchers discovered in 2019 that digoxin could also be effective in the context of breast cancer. They carried out an extensive screening in which they systematically tested more than 2,400 different substances in cell cultures to find active agents against clusters of circulating tumour cells (CTCs).

In the next step, the researchers want to develop new molecules based on digoxin that are even better at dissolving the CTC clusters. The ETH spin-off, Page Therapeutics is already working on this solution.

Aceto also wants to expand his research to other types of cancer that spread, such as prostate, colorectal or pancreatic cancer, as well as melanoma. Initial experiments in his laboratory have already begun.

The study is a prime example of outstanding cooperation between ETH Zurich and various hospitals, including the University Hospitals of Basel and Zurich and the Basel-Land Cantonal Hospital. The hospital partners recruited the patients and conducted the clinical trials.