In normal cells, voltage models provide a model for orderly growth. But with cancer, the opposite happens. Marked by a break in the normal electrical patterns generated by cells, they lose their specialized functions, begin to grow in a tumor and spread and disrupt the functioning of other tissues – metastases. As of yet, there is no clinically available treatment that specifically targets the process of metastasis, which remains the leading cause of death in cancer patients.
Now, researchers at Tufts University have found that manipulating blood pressure patterns in tumor cells using ion channel blockers already approved by the FDA as treatments for other diseases can actually dramatically reduce Tumor cell invasion in a dish and metastasis in an animal model of breast cancer.
The discovery that drugs already approved for other conditions can slow or stop metastasis could lead to an accelerated path to approval for cancer treatment.
“This is an unexplored but highly opportunistic strategy for the treatment of cancer,” said Madeleine Oudin, the Tiampo family’s assistant professor of biomedical engineering at Tufts University School of Engineering and corresponding author of the study. “Ion channels, which regulate the bioelectric properties of cells, are the second most common target for existing pharmaceuticals, so we have a relatively large set of ready-to-use drugs that could be reused for cancer treatment. “
To test their treatment strategy, the Tufts research team focused on triple negative breast cancer (TNBC), a disease subtype that accounts for about 15% of all breast cancer cases. The likelihood of metastasis for TNBC is greater than that of all other breast cancer subtypes, and because TNBC is associated with a poor prognosis at five years, scientists are focusing their efforts on controlling it.
The researchers were able to show that manipulating the stress properties of breast cancer cells can have a significant effect on their progression to metastasis, reducing the number of metastatic sites in mouse lungs by about 50%.
The cells of the body create a natural tension across their membranes, caused by ion channels that actively push or passively allow positive and negative ions to enter and exit the cell. Mike Levin, Professor Vannevar Bush in the Department of Biology, collaborator on this study, has worked for many years to dissect the role of electrical properties in cellular behavior in model organisms. When Oudin joined Tufts, they received funding through the Tufts Collaborates program, which helps support collaborations between faculty from different schools to tackle exciting new areas of research.
Although there are a variety of channels that cause the movement of positively charged sodium, calcium and potassium ions, as well as negatively charged chloride ions, potassium ion channels tend to dominate in generating voltage across the cell membrane. . When Tufts researchers genetically overexpressed potassium ion channels in tumor cells, the interior of the cells became more negatively charged, and the voltage imbalance resulted in increased tumor growth and metastasis, both within the cells. plated and animal models.
The researchers’ therapeutic strategy took the opposite approach: blocking potassium ion channels led to a restoration of more normal voltages for cells, decreased invasion of tumor cells and a significant reduction in metastases.
Four FDA-approved potassium ion channel blockers were selected, and all had similar efficacy in killing tumor cells. One drug, amiodarone, had the greatest effect on normalizing cell tensions and was selected to see how well it would work in treating breast cancer in mice. The researchers found that the drug, approved for the treatment of cardiac arrhythmias, reduced the ability of tumors to spread as cells break off and travel to other parts of the body.
By examining the genes triggered by the change in blood pressure, they discovered a number of molecular pathways involved in cell movement. The effects of the drug blocking the ion channels were consistent with restricting the movement of the cells so that they did not move away and develop new tumors.
The Tufts team will continue to explore the effects of ion channel blockers on cancer in animal models, in combination with existing standard treatments like chemotherapy. Since amiodarone and similar drugs are already approved for use in humans, phase I clinical trials in small groups of cancer patients may begin in the near future.