Medication for heart conditions improves melanoma treatment

A collaborative study led by IRB Barcelona, Navarrabiomed and the Institute of Neurosciences CSIC-UMH shows that the administration of ranolazine, a drug currently used to treat heart conditions, improves the efficacy of current therapies for melanoma in mouse models of the disease.

In most cases, patients with melanoma respond well to therapies directed against one of the key genes in tumour progression, namely BRAF. However, they soon develop resistance to these therapies and the tumours grow back. In addition, clinical studies suggest that these patients show a poorer response to immunotherapy.

The new study, published in the journal Nature Metabolism, has provided a deeper understanding of the role of fatty acid metabolism in the development of resistance to BRAF inhibitors and demonstrated the capacity of ranolazine to slow down tumour progression. The drug increases the visibility of melanoma cells to the immune system, thereby improving response to immunotherapies and increasing the ability of lymphocytes to control tumour growth.

The research was coordinated from the Navarrabiomed Biomedical Research Center by Dr Imanol Arozarena Martinicorena, Head of the Cancer Signalling unit. Navarrabiomed designed and managed the development of the project, and also carried out experiments related to resistance to targeted therapies and how ranolazine affects the immunogenicity of melanoma cells.

“This study demonstrates that it is possible to pharmacologically reorganise the metabolism of the tumour cell to improve the effect of targeted therapies and immunotherapies,” Arozarena said. “The next challenge is to demonstrate the clinical effect of these combinations in patients and study the potential of ranolazine in other types of cancer. To do this, we need to better understand how this drug acts both in tumour cells and in the immune system.”

The Institute of Neurosciences CSIC-UMH — a joint centre of the Spanish National Research Council (CSIC) and Miguel Hernández University — conducted the immunotherapy trials with mice and the study of immune cells in the tumour microenvironment.

“Immunotherapy has established itself as a fundamental therapeutic strategy for melanoma and other types of cancer,” said Dr Berta Sánchez-Laorden, principal investigator of the Institute’s Cellular Plasticity in Development and Disease group. “Despite this, many patients do not respond optimally to these treatments. This work shows the beneficial impact of the combination of ranolazine with immunotherapy in preclinical models of melanoma, thus supporting its possible application in patients.”

Scientists at IRB Barcelona performed single-cell RNA sequencing analyses, which have revealed in detail the effect of ranolazine on the metabolic state of tumour cells. Dr Salvador Aznar Benitah, who leads IRB Barcelona’s Stem Cells and Cancer lab, said, “We suspected that fatty acid metabolism was crucial in the most aggressive forms of melanoma, but being able to confirm this with a drug already approved for use in humans is highly relevant. Hopefully, these results can pave the way to change clinical practice.”

The development of future clinical trials to validate and confirm the action of ranolazine in cancer patients will be facilitated by the fact that it has already been approved for use in humans and is already being administered in clinical practice to treat chronic angina.

Image caption: Treatment with ranolazine increases the number of antitumour lymphocytes that infiltrate the tumour and favour the action of immunotherapy. NK-type antitumour lymphocytes are stained in green and tumour cells in blue.