Abstract
Somatic alterations in the fibroblast growth factor receptor (FGFR) gene family (FGFR1/2/3) have been implicated in tumorigenesis across pediatric low-grade glioneuronal neoplasms and represent a potential therapeutic target. FGFR rearrangements and internal tandem duplication (ITD) cause constitutive receptor tyrosine kinase activation, thereby promoting tumor cell growth, differentiation, and survival through complex downstream signaling, including via the mitogen activated protein kinase (MAPK) pathway. With increasing safety and efficacy data in pediatric neuro-oncology, MEK inhibitors may be considered to target MAPK pathway activation in FGFR-altered low-grade glioneuronal tumors, although clinical evidence within this specific molecular subgroup is lacking. Herein, we describe two cases of pediatric low-grade glioneuronal tumors harboring FGFR aberrations with encouraging clinical and radiographic response to MEK inhibition. The first patient has a multiply recurrent left parietal dysembryoplastic neuroepithelial tumor (DNET) with an FGFR1 ITD, diagnosed at eight years of age after presenting with seizures. Despite two surgical resections (with identical pathology), his disease slowly progressed. Oral MEK inhibitor therapy with trametinib was initiated, which he has remained on for the past 9+ months, with stable residual tumor without continued radiographic progression. The second patient was diagnosed at three years of age with focal epilepsy, prompting imaging demonstrating an infiltrative T2/FLAIR-hyperintense right temporal mass. Subtotal resection was performed, with pathology consistent with pediatric-type diffuse low-grade glioma. Molecular profiling identified an FGFR3-TACC3 fusion, with suspected enrichment for MAPK-pathway activation by preliminary RNA-sequencing analyses. Adjuvant therapy with trametinib was started, with small reduction in residual disease burden observed radiographically three months into treatment. Both patients continue on MEK inhibitor therapy with minimal toxicity and adequate control of underlying seizures. Though further research in larger, prospective cohorts with comprehensive biology data is necessary, oral MEK inhibitors represent a feasible and rational treatment consideration for pediatric FGFR-altered low-grade glioneuronal tumors.