A BRAF fusion occurs when BRAF joins with another gene, removing some of its normal controls. The most common example is KIAA1549::BRAF, although other rare fusions occur. These alterations are especially common in pilocytic astrocytomas.

In the United States, tovorafenib (Ojemda), a type II RAF inhibitor, received accelerated approval in 2024 for children six months and older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or a BRAF V600 mutation. Research continues into additional ways to target fusion-driven tumors safely and effectively.

BRAF V600E occurs in a smaller subset of pLGGs and is enriched in tumors including ganglioglioma and pleomorphic xanthoastrocytoma. It activates MAPK differently from a BRAF fusion—and that difference matters.

For children one year and older with BRAF V600E-mutated LGG who require systemic therapy, the FDA has approved dabrafenib plus trametinib. One medicine inhibits mutant BRAF; the other inhibits MEK downstream. Treatments designed for BRAF V600E should not be assumed to work for BRAF fusions, and some BRAF inhibitors can paradoxically activate signaling in fusion-driven tumors.

Neurofibromatosis type 1 is a genetic condition caused by a germline alteration in the NF1 gene, which normally helps regulate RAS/MAPK signaling. The alteration may be inherited or arise as a new genetic change. Children with NF1 have an increased risk of gliomas, particularly those involving the optic pathways.

MEK inhibitors—including selumetinib, trametinib, and binimetinib—have been studied in NF1-associated and sporadic pLGG. Selumetinib has shown activity in children with NF1-associated and sporadic disease, including tumors that cannot be safely removed.

A molecular diagnosis does not automatically mean a child needs targeted therapy. Decisions for NF1-associated gliomas are individualized with an expert medical team.

Some pLGGs contain alterations involving FGFR1, FGFR2, or FGFR3. These changes can activate signaling that promotes tumor growth, including the MAPK and PI3K/mTOR pathways.

FGFR inhibitors such as erdafitinib, pemigatinib, and futibatinib have been developed, but they are not broadly FDA-approved for pLGG based solely on an FGFR alteration. Their role in pediatric glioma remains an area of clinical research. Whether an alteration may be targetable depends on its exact type and the child’s clinical circumstances.

Some pediatric gliomas contain fusions involving NTRK1, NTRK2, or NTRK3. Although uncommon in pLGG, these fusions are important because they can activate TRK proteins that drive tumor growth—and selective TRK inhibitors are available.

Larotrectinib selectively inhibits TRK, while entrectinib targets TRK as well as ROS1 and ALK. Both have demonstrated activity in tumors harboring NTRK fusions. Tumor-agnostic approvals illustrate why comprehensive molecular testing can matter: a rare finding may reveal an opportunity that is not apparent from the tumor’s appearance under a microscope.

ALK and ROS1 alterations are uncommon in pLGG but have been identified across pediatric brain tumors. Targeted inhibitors have shown activity in cancers driven by these alterations, but their use in pLGG depends on the exact finding, the clinical circumstances, and the availability of an appropriate clinical trial or treatment pathway.

Because these alterations are rare, collaborative research and clinical trials are particularly important for determining which children are most likely to benefit.

Not every pLGG is driven exclusively by MAPK. PI3K/mTOR is another signaling network involved in cell growth, metabolism, and survival. The MAPK and mTOR pathways can interact, and some pLGGs show activation of both.

Drugs that inhibit mTOR, including everolimus, have been studied in pediatric low-grade gliomas and related tumors. The central research challenge is determining which tumors truly depend on this pathway and which children are most likely to benefit.

A subset of pediatric-type diffuse low-grade gliomas contains alterations involving MYB or MYBL1. Unlike BRAF, these proteins are transcription factors rather than conventional druggable kinases, making them especially challenging therapeutic targets.

Researchers are working to understand how these alterations drive tumor formation, what other proteins and pathways the tumors depend on, whether those dependencies can be targeted, and why these tumors can behave differently from other pLGGs.