Table 1.

Subtypes of pediatric high-grade gliomas, relevant mutations and features, and pediatric clinical trials designed to target these mutations. Diffuse intrinsic pontine glioma (DIPG), histone H3 K27M variant (H3-K27M), TP53, ACVR1, activin receptor-like kinase-2 (ALK2), ATRX-DAXX, platelet-derived growth factor receptor A (PDGFRA), pan-histone deacetylase (HDAC), FGFR1, MAPK, BRAF, MEK, NTRK, TRK, mTOR, IDH1, MYCN, TERT, SETD2, WEE1, NCT.

Pediatric High-Grade Gliomas: Mutations, Features, and Novel Clinical Therapies
Anatomical Classification	Defining Mutations	Features	Other Mutations	Targeted Therapies and Pediatric Clinical Trials
Midline location	H3-K27M	Includes DIPG Predominantly astrocytic differentiation	TP53 (60%) ACVR1/ALK2 (20–30%) ATRX-DAXX (30%) PDGFRA amplification	H3.3-K27M peptide vaccine ○ NCT02960230 * HDAC inhibitors (Vorinostat, Panobinostat) ○ NCT02420613 ○ NCT01189266 ○ NCT02717455 ○ NCT03566199 PDGFR inhibitors (Crenolanib, Dasatinib) ○ NCT01393912 ○ NCT01644773 ○ NCT00996723
	FGFR1	MAPK activation Usually found in thalamic gliomas		FGFR inhibitor (Erdafitinib) ○ NCT03210714
	BRAF V600E	Rarely co-exists with H3-K27M More common in low grade glioma		BRAF/MEK inhibitors (Dabrafinib, Vemurafanib, Trametinib, Selumetinib, Binimetinib) ○ NCT02684058 ○ NCT01748149 ○ NCT03220035 ○ NCT03363217 ○ NCT01677741 ○ NCT01089101 ○ NCT03213691 ○ NCT02285439
Hemispheric location	H3-G34R/V	15% Histologically homogenous appearance	ATRX/DAXX (100%) TP53 (90%) NTRK fusion	TRK inhibitors (Larotectinib, Entrectinib) ○ NCT03213704 ○ NCT02637687 ○ NCT03215511 ○ NCT02650401
	IDH1 mutant	Small population Better survival than wild type		mTOR inhibitor (Everolimus) ○ NCT01734512
	H3/IDH wild type		MYCN amplification TP53 PDGFRA TERT
	SETD2 (15%)	Mutually exclusive with H3-G34R/V		WEE1 inhibitor (Adavosertib)

* All NCT entries indicate trial number listed in clinicaltrials.gov.