Receptor tyrosine kinase (RTK) targeting in pediatric high-grade glioma and diffuse midline glioma: Pre-clinical models and precision medicine

Abstract

Pediatric high-grade glioma (pHGG), including both diffuse midline glioma (DMG) and non-midline tumors, continues to be one of the deadliest oncologic diagnoses (both henceforth referred to as “pHGG”). Targeted therapy options aimed at key oncogenic receptor tyrosine kinase (RTK) drivers using small-molecule RTK inhibitors has been extensively studied, but the absence of proper in vivo modeling that recapitulate pHGG biology has historically been a research challenge. Thankfully, there have been many recent advances in animal modeling, including Cre-inducible transgenic models, as well as intra-uterine electroporation (IUE) models, which closely recapitulate the salient features of human pHGG tumors. Over 20% of pHGG have been found in sequencing studies to have alterations in platelet derived growth factor-alpha (PDGFRA), making growth factor modeling and inhibition via targeted tyrosine kinases a rich vein of interest. With commonly found alterations in other growth factors, including FGFR, EGFR, VEGFR as well as RET, MET, and ALK, it is necessary to model those receptors, as well. Here we review the recent advances in murine modeling and precision targeting of the most important RTKs in their clinical context. We additionally provide a review of current work in the field with several small molecule RTK inhibitors used in pre-clinical or clinical settings for treatment of pHGG.

Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations

“…Three drugs emerged as OncoTreat-predicted inhibitors of OPC states, respectively, including trametinib (highly selective inhibitor of the mitogen-activated protein kinase enzymes MEK1 and MEK2 68 ), mocetinostat (an HDAC inhibitor with highest affinity to HDAC1, but also targeting HDAC2, 3 and 11 69 ), and dinaciclib (a potent small molecule cyclin-dependent kinase inhibitor targeting CDK2, CDK5, CDK1 and CDK9 70 ). Two additional drugs emerged as OncoTarget-predicted inhibitors of OPC and OC states, respectively, including etoposide (a TOP2 inhibitor, targeting both TOP2 isoforms: TOP2A and TOP2B 71 ), and avapritinib (a CNS-penetrant PDGFRA inhibitor 72 ). Similarly, two drugs emerged as OncoTreat-predicted inhibitors of AC states, including venetoclax (a highly selective BCL2 inhibitor 73 ) and ruxolitinib (an ATP-competitive JAK1/2 inhibitor 73 ) and an additional two were predicted by OncoTarget, including larotrectinib (a highly selective TRK inhibitor 74 ) and napabucasin (a STAT3 inhibitor 75 ).…”

Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients

“…5,6 Erdafitinib is expected to have sufficient blood-brain barrier penetration. 17 Current literature reports on seven paediatric patients treated with FGFR inhibitors to date, five with Debio1347 4…”

“…Moreover, certain high‐risk tumour types such as EPN have been shown to exhibit FGFR activation 5,6 . Erdafitinib is expected to have sufficient blood–brain barrier penetration 17 . Current literature reports on seven paediatric patients treated with FGFR inhibitors to date, five with Debio1347 4 and two with erdafitinib as part of the RAGNAR study 3 .…”

New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor α) based on computational study for high−grade glioma therapy

“…Moreover, preclinical studies have shown that Imatinib can prevent the PI3K/mTOR signaling pathway or MAPK signaling pathway by docking with PDGFRA. It can effectively inhibit tumor growth, exert anti-tumor activity, and be proven effective in pediatric HGG with PDGF pathway alterations ( Schwark et al, 2022 ). In line with this, a small RCT study found that patients with glioblastoma responded frequently to the combination of hydroxyurea and imatinib ( Joensuu et al, 2005 ; Mantica et al, 2018 ).…”

“…This study selected Imatinib as the reference drug. However, Imatinib has significant therapeutic limitations, with developmental toxicity and the risk of intratumoral hemorrhage as side effects ( Schwark et al, 2022 ). The screening of more desirable inhibitors of PDGFRA is therefore essential for the treatment of HGG.…”