Precision medicine for pediatric gliomas

The fifth edition of the WHO Classification of Tumors of the Central Nervous System marked a paradigm shift from predominantly histopathological classification toward integrated molecular-pathological definitions. This review summarizes the contemporary molecular landscape of pediatric gliomas, pivotal clinical trial data, current indications for targeted therapies, and major challenges to effective precision treatment, including adaptive resistance and blood-brain barrier penetration.

Sporadic pediatric low-grade gliomas (pLGGs) are characterized by alterations activating the RAS-mitogen-activated protein kinase (MAPK) pathway, particularly BRAF fusions and V600E mutations, enabling the integration of targeted therapies into frontline treatment. Among high-grade tumors, infant-type hemispheric gliomas represent a favorable, fusion-driven subgroup characterized by recurrent receptor tyrosine kinase alterations involving ALK, NTRK1/2/3, ROS1, and MET, with remarkable sensitivity to selective inhibitors. In contrast, pediatric-type diffuse high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs) in older children remain highly refractory and are frequently driven by epigenetic dysregulation associated with histone H3 G34 and H3 K27 alterations.

Targeted therapies have an expanding role in the management of pediatric low- and high-grade gliomas. Further research is particularly needed for pHGGs and DMGs, where outcomes remain unsatisfactory and effective therapeutic options are limited.