Joan Seoane, co-director of the Preclinical and Translational Research Program at the Vall d’Hebron Institute of Oncology (VHIO).
According to recent statistics, the malignant melanoma is the main death cause by skin cancer, more than 57,000 estimated fatal cases in 2020 all over the world. As the incidence of melanoma is increasing, the need to develop more effective and specific treatments to improve outcomes for these patients is of paramount importance.
An investigation published in Cancer Research directed by Joan Seoaneco-director of the Preclinical and Translational Research Program of the Vall d’Hebron Institute of Oncology (VHIO), with the support of the Spanish Association Against Cancer, has demonstrated the effectiveness of C1aa potent BRAF inhibitor that can cross the blood-brain barrier and penetrate the brain, achieving better results in preclinical models than the drugs currently used, so it might become a effective treatment pathway for patients with BRAF V600E/K mutated brain metastatic melanoma.
“Our investigations have shown surprising activity in brain metastatic models. C1a achieved more effective exposure in the brain compartment and superior results compared to other BRAF inhibitors. Our results have supported the clinical validation of this new agent in the setting of existing therapies, and patients are already being recruited for a clinical trial that will test this compound. A positive result from the trial might provide a therapeutic alternative for patients with melanoma brain metastases”, adds Joan Seoane, research professor at Icrea and co-director of the VHIO Preclinical and Translational Research Program.
Los Tumors eventually become resistant to targeted treatments. In response to this predictable phenomenon, the researchers also studied the resistance mechanisms to help prevent the tumor from escaping the action of C1a, and tried to identify a possible combination treatment strategy to further prolong antitumor responses.
The immune system, involved in resistant tumors
Analysis of tumors that manifested a recurrence following being treated with C1a showed that MAPK reactivation is the main mechanism of resistance in both peripheral and metastatic brain settings and that BRAF kinase domain duplication is the dominant factor in resistance.
“These contributions will help identify biomarkers of response to treatment and, ultimately, to guide the stratification of patients in clinical trials”, says Ester Bonfill Teixidor, first co-author of this study and member of the Gene Expression and Cancer Group of the VHIO, led by Joan Seoane.
In order to identify the mechanisms involved in resistance to C1a, a transcriptomic analysis of the resistant tumors and the appearance of an inflammatory phenotype was observed, indicating a clear implication of the immune system. Considering that immune checkpoint inhibitors (ICIs) are already used clinically to treat melanoma, the researchers explored a combined approach with C1a and anti-PD1 antibody.
The results showed that C1a also promotes potent antitumor responses when combined with anti-PD1 and drastically reduces the appearance of recurrences and resistance to C1a treatment. Therefore, the therapeutic combination of C1a with blockade of immune checkpoints might give new hope to this patient population.
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