Medicina di precisione nelle malattie rare: il caso della Neurofibromatosi di tipo 1. Analisi di dati clinici e trascrittomica

Background In the past decade, researchers have endeavored to discover effective drugs for managing plexiform neurofibromas (PNs) associated with neurofibromatosis type 1 (NF1), seeking alternatives to often unsatisfactory surgical interventions. Selumetinib, an oral MEK inhibitor, is a the first drug approved for use in children with NF1 and inoperable, symptomatic PN. Predicting patient responses to Selumetinib remains a challenge. This study aimed to identify a molecular blood signature that could distinguish potential responders from non-responders and facilitate tailored therapies Materials and Methods The study enrolled NF1 patients receiving Selumetinib therapy and conducted extensive monitoring, including clinical assessments and volumetric analysis of PNs through MRI. Selumetinib was provided for compassionate use, and side effects were closely monitored. Additionally, transcriptomic analysis of peripheral blood cells compared patient data before and after treatment with that of healthy controls. Results All patients (13) with NF1 and PNs treated con Selumetinib had significant reductions in PN size, with 35% of patients experiencing tumor shrinkage exceeding 20%. Selumetinib demonstrated a favorable safety profile, with manageable side effects. Transcriptomic analysis identified genes associated with the MEK pathway, showing downregulation of genes such as DUSP6, SPP1, and SIGLEC15 and 16, while genes related to immune response, like CD22 and CD79A, were upregulated Conclusion The findings emphasize the clinical utility of Selumetinib in halting PN growth and shed light on potential mechanisms underlying its effectiveness and side effects. Further research is essential to better understand the immune system's role and develop biomarkers for personalized NF1 treatment