TRK inhibition for pediatric and adult central nervous system tumors: Early promise and future questions.

Abstract

Central nervous system (CNS) tumors are the most common cause of cancer-related death in children. Despite significant treatment advances, survival rates for several tumor types (including diffuse midline glioma and other high-grade gliomas, as well as most recurrent tumors) remain poor, and current multimodal therapies, including surgery, radiation therapy, and cytotoxic chemotherapy carry a high risk of treatment-related morbidities. There is therefore a critical need to translate recent discoveries on the biological and genetic basis of pediatric CNS tumors into improvement in clinical care for these patients. Comprehensive analysis (including genome, transcriptome, and epigenome) of diverse CNS tumors has led to a heightened understanding of the spectrum and frequency of disease-specific tumorigenic genetic events underlying common pediatric tumor types, including low-grade glioma,1 high-grade glioma,2 medulloblastoma,3 and ependymoma.4 These discoveries have led to improved classification of pediatric CNS tumors through definition of key molecular events and are being successfully incorporated into the care of patients with selected tumor types. As one example, recent reports have confirmed the activity of the MEK inhibitor selumetinib for patients with both neurofibromatosis type 1 (NF1)-associated and non-NF1-associated low-grade glioma,5,6 establishing selumetinib as a therapeutic option for these patients.