Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

Abstract

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.

Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

“…As an exception, the WHO 2016 classification incorporated the entity of histone H3 K27 M diffuse midline glioma, which mainly occurs in pediatric patients and regardless of the histological grade, has a poor prognosis. Our molecular knowledge of pediatric gliomas has been refined over the last few years, and some molecular markers, such as H3 G34R/V, BRAF, NF1 mutations, and PDGFRα amplifications, are now becoming relevant for the decision of clinical interventions (Koschmann et al, 2016;Miklja et al, 2019;Haase et al, 2020).…”

“…The blood-brain barrier hampers the delivery of therapeutic compounds to the tumor site. Despite these limitations, intense research has opened up opportunities to explore tailored therapies for different glioma subtypes with particular molecular lesions that are currently under clinical trials (Haase et al, 2020).…”

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

“…Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Resistance to standard therapies is a frequent occurrence in pHGGs [ 1 , 2 , 3 ]. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act as key biological drivers of pHGGs.…”

“…These mutations lead to distinct epigenetic reprogramming, telomere maintenance mechanisms, and oncogenesis scenarios, resulting in distinct subgroups of patients characterized by differences in tumor localization, clinical outcome, as well as concurrent epigenetic and genetic alterations [ 4 ]. However, contrasting with our understanding of the molecular biology of pHGGs, there has been little improvement in the treatment of pHGGs, for which genotoxic chemotherapy and ionizing radiation (IR) remain mainstays of therapy [ 1 , 2 , 3 , 5 ]. In sus-tentorial locations, radiotherapy follows surgical resection, which tends to be extensive, and is associated at least with DNA alkylating agents like temozolomide (TMZ) [ 6 ].…”

“…In sus-tentorial locations, radiotherapy follows surgical resection, which tends to be extensive, and is associated at least with DNA alkylating agents like temozolomide (TMZ) [ 6 ]. In thalamic pHGGs and DIPG, targeted therapies are nowadays proposed concomitantly to irradiation and prolonged until progression [ 1 , 2 , 3 , 5 , 7 ]. Preventing resistance to chemoradiation through the targeting of the underlying pathways is crucial to improve the efficiency of the current treatments.…”