Pediatric high‐grade glioma: moving toward subtype‐specific multimodal therapy

Abstract

Pediatric high-grade gliomas (pHGG) comprise a deadly, heterogenous category of pediatric gliomas with a clear need for more effective treatment options. Advances in high-throughput molecular techniques have enhanced molecular understanding of these tumors, but outcomes are still poor, and treatments beyond resection and radiation have not yet been clearly established as standard of care. In this review, we first discuss the history of treatment approaches to pHGG to this point. We then review four distinct categories of pHGG, including histone 3-mutant, IDH-mutant, histone 3/ IDH-wildtype, and radiation-induced pHGG. We discuss the molecular understanding of each subgroup and targeted treatment options in development. Finally, we look at the development and current status of two novel approaches to pHGG as a whole: localized convection-enhanced chemotherapy delivery and immunotherapy, including checkpoint inhibitors, vaccine therapy, and CAR-T cells. Through this review, we demonstrate the potential for rational, molecularly driven, subtype-specific therapy to be used with other novel approaches in combinations that could meaningfully improve the prognosis in pHGG.

Childhood Malignant Brain Tumors: Balancing the Bench and Bedside

“…The predominant pHGG subgroups express mutations of histones HIST1H3B ( H3.1 ) at position K27, H3.2 (rarely) and H3F3A ( H3.3 ) at positions K27 and G34 [ 90 , 92 ]. H3K27M pHGGs are characterized biologically by aberrant expression resulting from loss of trimethylation at lysine 27 on Histone 3 [ 93 , 94 ], and clinically by their midline location (pons, midbrain, thalamus, spina cord) and younger patient age [ 90 , 91 ].…”

“…The paradigm shift in understanding of the molecular heterogeneity of pHGG, together with the failure of conventional therapeutics to significantly improve outcomes for several years, has shifted focus towards developing novel agents that manipulate the epigenetic and genomic aberrations inherent in pHGG molecular subgroups, immunotherapies, and the development of alternative drug administration routes to penetrate the blood–brain barrier such as convection enhanced delivery for diffuse midline glioma H3K27 mutant/DIPG [ 92 , 101 , 102 , 103 , 104 , 105 ].…”

Advanced Magnetic Resonance Imaging in Pediatric Glioblastomas

“…Molecular-targeted therapy consists of drugs or other substances that target specific molecules involved in the growth and spread of cancer cells ( 164 ). The most common targets for molecular-targeted therapy in pediatric brain tumors, in particular, HGGs and other high-grade tumors, are the tyrosine kinase ( 165 ), tumor-specific surface proteins (monoclonal antibodies) ( 166 ), vascular endothelial growth factor ( 167 ), platelet-derived growth factor and epidermal growth factor, PI3K-mTOR pathway (mostly animal model studies) ( 168 ), ERK-RAS-RAF mitogen-activated protein kinase pathway (BRAF mutation) ( 169 ), e PI3K/AKT pathway, gene fusions ( 170 ), Sonic Hedgehog pathway ( 171 ), and epigenetic targets (DNA methylation, chromatin modeling, and histone modifications signaling) ( 172 ). Despite multiple clinical trials in pediatric brain tumors, molecular-targeted therapy, with some exceptions, has not yet made a major impact on survival or, for that matter, quality-of-life for children with brain tumors ( 164 ).…”

The ever‐expanding landscape of cancer therapeutic approaches

“…However, there are some paediatric cancers which have poor prognosis, one of which is paediatric high‐grade glioma (pHGG). This is the subject of a review by Hannah Chatwin and colleagues [15] that firstly discusses four main subtypes of pHGG and the specific treatments being developed. They then focus on two novel approaches, including mode of delivery and combination of immunotherapy, vaccine therapy and chemotherapy.…”