Molecular targeted therapies for pediatric low-grade gliomas: current perspectives and future directions

Abstract Pediatric low-grade gliomas (pLGGs) are a heterogeneous group of tumors characterized by frequent activation of the mitogen-activated protein kinase (MAPK) signaling pathway, often driven by a single oncogenic alteration. Recent advances in molecular profiling have identified actionable alterations involving BRAF, FGFR, NF1, and receptor tyrosine kinases, leading to the development of genotype-directed molecular targeted therapies. Clinical trials of BRAF, MEK, and RAF inhibitors have demonstrated substantial antitumor activity, and targeted therapy is increasingly being incorporated into the treatment of pLGGs. However, because patients with pLGGs generally have favorable long-term survival and may exhibit prolonged periods of tumor stability as part of their natural history, several challenges remain regarding the optimal use of these agents. These include patient selection, timing of treatment initiation, treatment duration, long-term toxicities, and tumor regrowth after treatment discontinuation. In particular, rapid tumor regrowth, referred to as rebound, may occur after discontinuation of MAPK pathway inhibitors, although its risk factors and optimal preventive strategies remain unclear. Furthermore, the effects of prolonged pathway inhibition on the natural history and oncogene-induced senescence of pLGGs are unknown. This review summarizes the molecular landscape and current evidence for genotype-directed therapies in pLGGs and discusses the clinical challenges associated with their long-term implementation. Future treatment strategies should therefore focus on optimizing the timing and duration of targeted therapy while considering long-term toxicities, patient growth and development, and the natural history of pLGGs.