Molecular Genetics and Targeted Therapies for Paediatric High-grade Glioma

Abstract

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.Intracranial and intraspinal tumours are the most common solid tumours in paediatrics (1). They are the second leading cause of cancer-associated death in children and adolescents under the age of 19 in the USA and Canada (1), with an average annual age-adjusted incidence of 6.06 per 100,000 in the USA between 2012 and 2016 (2). Brain tumours are now the leading cause of paediatric-cancer-associated death worldwide, surpassing deaths from childhood leukaemia (3). Gliomas represent the highest proportion of childhood brain tumours (4, 5) accounting for 60% of paediatric brain tumour cases (5, 6), of which approximately half are classified as high grade (6, 7).

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…In line with Schubert et al (2022) [ 391 ], CDK4/6 upregulation also plays an important role in the pathogenesis and progression of high-grade gliomas with potential actionability [ 407 , 408 , 409 ]. However, the use of CDK4/6 inhibitors alone did not show satisfactory results, suggesting the use of combinatorial intervention [ 410 ].…”

NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

“…According to the WHO classification of CNS tumors, these gliomas appear as large masses in the supratentorial compartment with frequent superficial involvement (59), which is in contrast with the tumor of the current case which was located in the interventricular foramen area. However, since the reported number of ROS-driven pLGG/pHGG cases are still very few (5,60), it is difficult to draw any major conclusions regarding location, staging, survival probability and progression of these tumor types.…”

“…ROS fusions are emerging as clinically important since they can be targeted by small inhibitors. Hence, it is becoming crucial to identify ROS-driven tumors by genetic screening so that the patients may benefit from these treatments (5,14,47,(60)(61)(62)(63). Several ROS inhibitors that have been developed are mainly tested for adult patients with NSCLC (64).…”

“…Several ROS inhibitors that have been developed are mainly tested for adult patients with NSCLC (64). Currently, three are being evaluated for children; ensartinib, entrectinib and repotrectinib (clinical open trials: Ensartinib NCT03213652 phase II, Entrectinib NCT02650401phase I/II, Repotrectinib NCT04094610 phase I/II) (29,60,(65)(66)(67)(68). Hopefully these trials will lead to ROS-inhibitors approved for clinical use for children with brain tumors and could help the current patient in case of relapse.…”

Chromatin mutations in pediatric high grade gliomas

“…In addition, there are trials underway for inhibiting EZH2 (PRC2) with tazemetostat (NCT03155620), and the polycomb protein BMI1 with PTC596 (NCT03605550) (85). Although it is not entirely clear that K27M acts through PRC2, it is clear that both the histone and IDH mutations cause widespread disruptions across the genome regardless of the specific mechanisms.…”