PLGG Biology and Targeted Therapy

In this episode, Dr. Chintagumpala and Dr. Abdelbaki explore the biology and therapeutic implications of pediatric low-grade glioma (PLGG), emphasizing that the MAPK pathway is the central driver of tumor behavior.

Until the first decade of this century, little was known about PLGG biology beyond neurofibromatosis type 1 (NF1) status. NF1-associated tumors tend to follow a more indolent course, whereas non-NF1 tumors were historically treated uniformly with chemotherapy. With the explosion of molecular knowledge, nearly all tumors are now biopsied for molecular profiling before initiating targeted therapy. BRAF fusions are more common in hemispheric tumors, while BRAF V600E mutations are enriched in chiasmatic-hypothalamic tumors, and V600E-mutant tumors generally have more frequent progressions and worse outcomes than fusion-driven tumors. Additional alterations—including FGFR1, FGFR2, FGFR3, MYB, and MYBL1—pose distinct challenges, with FGFR-altered tumors sometimes complicated by intratumoral hemorrhage.

The growing arsenal of oral targeted agents includes the approved combination of dabrafenib and trametinib for BRAF V600E-mutant tumors, MEK inhibitors such as selumetinib and trametinib for BRAF fusions, and newer agents like tovorafenib and mirdemetinib. While progression-free survival curves at 4–5 years may not differ dramatically from chemotherapy, these agents offer favorable quality of life and ease of administration. Certain molecular combinations carry additional prognostic weight: BRAF V600E mutations combined with CDKN2A deletion, seen in gangliogliomas, carry higher risk of progression or malignant transformation. Pleomorphic xanthoastrocytoma (PXA) also harbors BRAF V600E mutations, with CDKN2A/2B and TERT mutations influencing prognosis in anaplastic variants, where outcomes remain challenging. Long-term data on fertility and late effects of targeted agents remain limited, a critical consideration when counseling families.

In the next episode, "Navigating Treatment Burden and Family Priorities in PLGG," the panel discusses how disease and treatment burden influence family-centered decision-making and the strategic sequencing of therapies over years of care.