Metabolic dependencies and neural progenitor dysregulation: driving forces in paediatric high-grade glioma
Yan Hay Grace Lee1,2, Maria Tsoli1,2, Yan Chuan Shi3,4
1Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia, Sydney, NSW, Australia.
Insights
Paediatric high-grade gliomas (pHGGs) are aggressive childhood brain tumours. Understanding their molecular subtypes, epigenetic changes, and metabolic vulnerabilities is key to developing targeted therapies for these lethal diseases.
Area of Science:
- Pediatric oncology
- Neuro-oncology
- Cancer epigenetics
Background:
- Paediatric high-grade gliomas (pHGGs) are the deadliest pediatric brain tumors.
- The 2021 WHO Classification defines distinct molecular subtypes of pHGGs, differing from adult glioblastoma.
- Limited treatment options and profound epigenetic dysregulation characterize pHGGs.
Purpose of the Study:
- To review the molecular classification of pHGGs based on the 2021 WHO framework.
- To examine the role of the tumor microenvironment and glioma stem cells in pHGG progression and treatment resistance.
- To explore metabolic reprogramming and its interplay with epigenetic regulation in pHGGs.
Main Methods:
- Literature review synthesizing current research on pHGG molecular subtypes, tumor microenvironment, and glioma stem cells.
- Analysis of metabolic alterations, including glucose and lipid metabolism, and their link to epigenetic modifications.
- Discussion of preclinical models and emerging immunotherapies like CAR T-cell therapy and oncolytic viruses.
Main Results:
- pHGGs comprise distinct molecular subtypes (H3K27-altered, H3G34-mutant, infant-type, IDH-mutant) with unique biological features.
- Glioma stem cells exhibit plasticity and drive tumor initiation, maintenance, and therapeutic resistance.
- Metabolic reprogramming and epigenetic crosstalk (e.g., α-ketoglutarate, 2-hydroxyglutarate) are critical in pHGG pathogenesis.
Conclusions:
- Targeting subtype-specific metabolic and epigenetic vulnerabilities is crucial for effective pHGG treatment.
- Further research into preclinical models and immunotherapies holds promise for advancing pHGG therapy.
- A deeper understanding of pHGG biology is essential for developing novel, tailored therapeutic strategies.
Abstract:
Paediatric high-grade gliomas (pHGGs) are the most lethal brain tumours in children, characterised by profound epigenetic dysregulation and limited treatment options. The 2021 WHO Classification has established a molecular framework that distinguishes pHGGs as biologically distinct from adult glioblastoma, recognising four major subtypes: H3K27-altered diffuse midline glioma, H3G34-mutant diffuse hemispheric glioma, infant-type hemispheric glioma, and the rare IDH-mutant gliomas. Each subtype exhibits unique epigenetic landscapes, metabolic dependencies, and therapeutic vulnerabilities, necessitating subtype-specific treatment strategies. This review explores the molecular classification of pHGGs and examines the critical role of the tumour microenvironment in disease progression. We focus on glioma stem cells as central drivers of tumour initiation, maintenance, and therapeutic resistance, highlighting their remarkable cellular plasticity and ability to dynamically transition between different states. Particular attention is given to metabolic reprogramming in pHGGs, including alterations in glucose and lipid metabolism, and the exceptional metabolic flexibility of glioma stem cells that enables adaptation to microenvironmental pressures. Importantly, we discuss the intimate crosstalk between metabolism and epigenetic regulation, whereby metabolites serve as essential cofactors for chromatin-modifying enzymes-exemplified by α-ketoglutarate maintaining low H3K27me3 in H3K27M tumours and 2-hydroxyglutarate driving hypermethylation in IDH-mutant gliomas. We review preclinical models that have advanced pHGG research and discuss emerging immunotherapeutic approaches, including CAR T-cell therapies and oncolytic viruses. By synthesising current understanding of pHGG biology, this review aims to identify promising therapeutic avenues that exploit the unique metabolic and epigenetic vulnerabilities of each molecular subtype.
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