One of the biggest challenges in the fight against melanoma - a malignant tumour that originates from the cells responsible for the synthesis of pigments that determine skin colour - is the treatment of advanced cases that cannot be resolved surgically. The pharmacological treatment that more than 50 percent of melanoma patients with metastases receive is based on the use of an inhibitor of a particular enzyme often associated with other drugs. However, 6-12 months after initial tumor remission, drug resistance is observed in almost every case.
New developments on the subject come from a research led by a team from the Department of Experimental and Clinical Biomedical Sciences "Mario Serio" which identified a new marker responsible for drug resistance: uPAR, a membrane receptor. The study, funded by the Italian Cancer Research Association (AIRC) and the Ente Cassa di Risparmio di Firenze, was recently published in the journal EBioMedicine ["EGFR / uPAR interaction as druggable target to overcome vemurafenib acquired resistance in melanoma cells" https : //doi.org/10.1016/j.ebiom.2018.12.024] and sees the participation of the "Giovanni Paolo II" Scientific Institute of Hospitalization and Care in Bari.
"More than half of the patients with advanced melanomas (non-operable or metastatic) have a particular genetic mutation (BRAF) that leads to the synthesis of a permanently active protein, in which the replacement of a single amino acid is responsible for the uncontrolled proliferation of the cancer cell," specifies Anna Laurenzana, the first author of the article and member of the team coordinated by Mario Del Rosso and Gabriella Fibbi. "These patients are treated with targeted therapies, that is, with specific inhibitors of the mutated protein. These inhibitors generate a rapid response with the disappearance of metastases within a few months. Unfortunately, these treatments cause in almost all patients the onset of an acquired resistance to the drug with consequent reappearance of the tumor in an even more aggressive form."
The team found that relapsing patients express high levels of the uPAR receptor, a molecule involved in cell movement, even before drug treatment. "Although the number of patients considered is limited - explains Laurenzana - our study suggests that uPAR expression could provide a predictive value towards determining the patient's response to therapies based on BRAF inhibitors".
Based on this evidence, the researchers generated in the laboratory a line of human melanoma cells resistant to drug therapy and, treating it with a small peptide capable of blocking uPAR activity, they re-sensitized these cells to the inhibitory action of the drug, causing a halting of the growth and progression of the tumour. "
We are only at the beginning of our research path," the scientist comments. "It would be necessary to finance a screening on a larger number of biopsies before the treatment in order to give the most appropriate combined therapy."
