Researchers at the Vall d’Hebron Research Institute (VHIR) have identified a therapeutic strategy, using existing drugs, which has been shown to effective in animal models for one type of melanoma currently untreated.
The study, published in ‘Nature Communications, was carried out in collaboration with the Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, and the Rovira Virgili University (URV) and the Pere Virgili Health Research Institute (IISPV), Tarragona.
Melanoma is a complex and heterogeneous type of skin cancer, in which the response to treatment is limited, especially in some tumor subtypes.
In the world are diagnosed 325,000 new cases of melanoma each year, disease that causes about 90,000 deaths annually.
One of the common subtypes of this skin cancer is caused by mutations in NRAS, a protein related to cell malignancy that is altered in 25% of melanoma cases.
His treatment is currently limited due to the difficulty involved in developing targeted therapies against NRAS.
For this study, the investigators examined the characteristics of metabolism of melanoma cells.
The tumors require a high glucose consumption to obtain energy and to manufacture components such as proteins or nucleic acids, necessary to generate a new malignant cell and spread the cancer.
In the case of NRAS-mutated melanomas, these are. especially dependent on glucose for energy generation compared to other subtypes.
Results of the work.
The results of the work show that, when glucose is removed from the environment, the cells of this melanoma subtype activate pathways of survival signaling other than those that are activated under normal conditions.
One of the proteins that are activated in this situation is. BRAF, factor that facilitates tumor growth.
The investigators found that, under these conditions, the drug sorafenib, which has been used for years for other indications, is able to inhibit this mechanism and thus prevents the survival of the cancer cell.
“The discovery lies in the fact that the cells of this subtype of melanoma are. inelastic to use fuels other than glucose, which makes them vulnerable and, in an attempt to survive, they end up being sensitive to a drug indicated for other diseases (sorafenib) which, when applied, the cells die,” explains the head of the Biomedical Research in Melanoma group at VHIR, Juan Ángel Recio.
The researchers analyzed the effect of this strategy on. animal models, which were implanted with tumor cells from patients. The experiment confirmed that, when administered with a compound capable of block glucose together with the drug sorafenib, the mice’s tumors improved. “The effects were striking because not only did the tumors shrink, but in some cases they even went as far as completely disappear.” Recio pointed out.
The advantage of this work is that it employs an already approved drug, sorafenib, together with a strategy of glucose consumption reduction of the tumor which has also been previously tested in clinical studies.
“An important part of this study is a drug repositioning already approved for human use, which speeds up the process for transferring it to patients, because the toxicity tests are already done and do not have to be repeated, and this is a great advantage,” Recio pointed out.
The next step is to test this combination in humans by means of a clinical trial for which VHIR researchers are seeking funding, in addition to recruiting the hundred or so patients that a study of these characteristics requires, explained the researcher.