Pediatric High-Grade Glioma: Aberrant Epigenetics and Kinase Signaling Define Emerging Therapeutic Opportunities

INTRODUCTION: Supratentorial pediatric high-grade gliomas (pHGGs) are aggressive malignancies that lack effective treatment options. Deep genomic sequencing by multiple groups has revealed that the primary alterations unique to pHGGs occur in epigenetic and kinase genes. These mutations, fusions, and deletions present a therapeutic opportunity by use of small molecules targeting epigenetic modifiers and kinases that contribute to pHGG growth. METHODS: Using a targeted search of the pre-clinical literature and clinicaltrials.gov for kinase and epigenetic pathways in pHGG, we collectively describe how these mechanisms are being targeted in pre-clinical animal models and in current clinical trials, as well as propose unexplored therapeutic possibilities for future investigations. RESULTS: Relevant pHGG kinases are targetable by several FDA-approved or clinical-stage kinase inhibitors, including altered BRAF/MET/NTRK/ALK and wild-type PI3K/EGFR/PDGFR/VEGF/AXL. Epigenetic proteins implicated in pHGG are also clinically targetable and include histone erasers, writers and readers such as HDACs, demethylases LSD1/JMJD3, methyltransferase EZH2, chromatin reader bromodomains, and chromatin remodeler subunit BMI-1. Crosstalk between these pathways can occur involving kinases such as EGFR and AMPK interacting with epigenetic modifiers such as HDACs or EZH2. Single agent trial results of kinase inhibitors or epigenetic targets alone are underwhelming and hampered by poor pharmacokinetics, adaptive resistance, and broad inclusion criteria. CONCLUSIONS: The genetic and phenotypic diversity of pHGGs is now well characterized after large-scale sequencing studies on patient tissue. However, clinical treatment paradigms have not yet shifted in response to this information. Combination therapies targeting multiple kinases or epigenetic targets may hold more promise, especially if attempted in selected patient populations with hemispheric pHGG tumors and relevant targeted therapeutic biomarkers.