Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma.

Autor:	Rallis KS; Barts Cancer Institute, Queen Mary University of London, London, U.K.; k.s.rallis@smd16.qmul.ac.uk.; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K., George AM; Liverpool School of Medicine, University of Liverpool, Liverpool, U.K.; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K., Wozniak AM; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K., Bigogno CM; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K., Chow B; UCL Cancer Institute, University College London, London, U.K.; GKT School of Medicine, King's College London, London, U.K., Hanrahan JG; Cambridge University Hospitals NHS Foundation Trust, Cambridge, U.K., Sideris M; Women's Health Research Unit, Queen Mary University of London, London, U.K.
Jazyk:	angličtina
Zdroj:	Cancer genomics & proteomics [Cancer Genomics Proteomics] 2022 Jul-Aug; Vol. 19 (4), pp. 390-414.
DOI:	10.21873/cgp.20328
Abstrakt:	Brain tumours are the leading cause of paediatric cancer-associated death worldwide. High-grade glioma (HGG) represents a main cause of paediatric brain tumours and is associated with poor prognosis despite surgical and chemoradiotherapeutic advances. The molecular genetics of paediatric HGG (pHGG) are distinct from those in adults, and therefore, adult clinical trial data cannot be extrapolated to children. Compared to adult HGG, pHGG is characterised by more frequent mutations in PDGFRA, TP53 and recurrent K27M and G34R/V mutations on histone H3. Ongoing trials are investigating novel targeted therapies in pHGG. Promising results have been achieved with BRAF/MEK and PI3K/mTOR inhibitors. Combination of PI3K/mTOR, EGFR, CDK4/6, and HDAC inhibitors are potentially viable options. Inhibitors targeting the UPS proteosome, ADAM10/17, IDO, and XPO1 are more novel and are being investigated in early-phase trials. Despite preclinical and clinical trials holding promise for the discovery of effective pHGG treatments, several issues persist. Inadequate blood-brain barrier penetration, unfavourable pharmacokinetics, dose-limiting toxicities, long-term adverse effects in the developing child, and short-lived duration of response due to relapse and resistance highlight the need for further improvement. Future pHGG management will largely depend on selecting combination therapies which work synergistically based on a sound knowledge of the underlying molecular target pathways. A systematic investigation of multimodal therapy with chemoradiotherapy, surgery, target agents and immunotherapy is paramount. This review provides a comprehensive overview of pHGG focusing on molecular genetics and novel targeted therapies. The diagnostics, genetic discrepancies with adults and their clinical implications, as well as conventional treatment approaches are discussed. (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
Databáze:	MEDLINE
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