New strategy against a subtype of melanoma that was untreatable

Melanoma is a complex and heterogeneous cancer in which the response to treatment is limited, especially in some tumor subtypes.

A study led by the Melanoma Biomedical Research group of the Vall d’Hebron Research Institute (VHIR) in Barcelona, ​​in which the Rovira i Virgili University (URV) of Tarragona has also participated, has identified a strategy that increases the effect of an existing treatment against the cells of a type of melanoma. The study, published in the academic journal Nature Communications, has been carried out in collaboration with the Dermatology Service of the Vall d’Hebron University Hospital, the Breast Cancer and Melanoma group of the Vall d’Hebron Institute of Oncology (VHIO) , the Pere Virgili Health Research Institute (IISPV) in Tarragona, and the Bellvitge Biomedical Research Institute (IDIBELL), located in Hospitalet de Llobregat and which is part of the CERCA institution of the Generalitat of Catalonia.

One of the most common subtypes of melanoma is caused by mutations in NRAS, a protein related to cell malignancy that presents alterations in 25% of cases. Its treatment is currently limited due to the difficulty of developing therapies directed against NRAS. “In this work we contribute to understanding the role of NRAS in melanoma, which is essential to find therapeutic strategies against this tumor subtype,” explains Juan Ángel Recio, head of the VHIR Melanoma Biomedical Research group.

In the study, the researchers examined the characteristics of melanoma cell metabolism. Tumors require a high consumption of glucose to obtain energy, but above all to manufacture components such as proteins or nucleic acids and generate a new cell. In the case of NRAS-mutated melanomas, and using metabolomic techniques, the researcher at the URV’s Department of Electronic, Electrical and Automatic Engineering, Òscar Yanes, who is also part of the IISPV and the Diabetes Network Biomedical Research Center and Associated Metabolic Diseases (CIBERDEM) in Spain, helped demonstrate that these are especially glucose-dependent compared to other subtypes, since they have difficulty using other alternative energy sources to make up for the absence of glucose.

Oscar Yanes. (Photo: URV / IISPV)

The results of the work show that, when glucose is removed from the environment, the cells of this subtype of melanoma activate survival signaling pathways that are different from those activated under normal conditions. One of the proteins that are activated in this situation is BRAF, which allows cells to function normally despite adverse conditions. It was also verified that, under these conditions, the drug sorafenib, which has been used for years for other indications, is capable of inhibiting this mechanism and, therefore, prevents cell survival. “By eliminating glucose, we managed to make melanoma cells sensitive to treatment with sorafenib and to die very quickly”, affirm Juan Ángel Recio and Kimberley McGrail, researchers from the Melanoma Biomedical Research group. “In this way, we can use existing drugs, which facilitates and speeds up the process until their clinical use, since, in the case of sorafenib, it is already approved for use in humans,” adds the researcher.

Lastly, the research also analyzed the effect of this strategy in animal models in which tumor cells from patients were implanted. In this case, to simulate the lack of glucose in the tumor cells, a compound capable of imitating glucose was used, but it cannot be metabolized in the same way and blocks its use. Since tumor cells need more energy than healthy cells, they are more likely to take up glucose and therefore also take up more of this compound, which simulates a lack of glucose. It was confirmed that, by administering sorafenib together with this substance, the volume of the tumor in the mice is reduced and in some cases it may even disappear. “For its use in humans, there are strategies already proven in clinical studies to reduce glucose consumption in the tumor. The next step will be to test this combination in humans,” concludes Recio. (Source: URV)