Abstract Diffuse midline glioma (DMG) is a devastating pediatric brain tumor with a median overall survival (OS) of 11 months. Standard-of-care treatment is radiotherapy (RT), yet an increasing number of patients participate in precision medicine clinical trials. Unfortunately, DMG harbors very few druggable genomic targets. To improve therapeutic decision-making, we are performing proteogenomic analysis on 210 DMG and pediatric high-grade glioma (pHGG) tissues and cell-line samples, characterizing their genomic landscapes, proteomes and posttranslational modifications (acetylation, glycosylation, phosphorylation, cysteine oxidation). Preliminary genomic analysis of 23 DMG/pHGG samples identified driver alterations in histone H3, as well as in genes mapping to tumor suppression (TP53/PPM1D), PI3K/mTOR signaling (PIK3CA) and RTK signaling (EGFR/MET/PDGFRA). Preliminary proteomic profiling identified recurrently activated Leptin and BDNF-TrkB signaling across DMGs with potential therapeutic targets in pathways including ATM, ERK, MET, NOTCH and PI3K-Akt. Focusing on two H3.3K27M DMG cell-lines (SU-DIPG-XIII and UON-VIBE5) we identified a single, genomically-predicted, therapy for one sample; UON-VIBE5, which carries a PDGFRA-D842V activating mutation, potentially targetable using avapritinib. In addition, proteomic investigations identified increased ATM (WSD0628) and PI3K-Akt (paxalisib/GCT007) signaling, suggesting targetable vulnerabilities in both H3.3K27M DMG samples. Proliferation assays showed synergism between PDGFRA and PI3K inhibition. In vivo studies employing the RA055 patient-derived xenograft (PDX) DMG model (sharing H3.3K27M, TP53/PPM1D and PDGFRA alterations with UON-VIBE5), evaluated the preclinical utility of these therapies as a consolidation strategy post completion of RT. Avapritinib (30 mg/kg/day) and paxalisib (5 mg/kg/day) as monotherapies improved OS (57-days and 59-days, respectively, vs untreated, 51-days, P 0.01). Notably, avapritinib/paxalisib combination treatments provided additional improvement to OS (64.5-days, P 0.0001). Currently, PDX studies are testing a novel regimen combining RT/ATM inhibition (WSD0628) in the upfront setting, followed by avapritinib/paxalisib in consolidation. Ongoing work aims to harness this proteogenomic approach in our remaining samples, with the ultimate goal of revolutionizing treatment paradigms for patients with DMG.
Findlay et al. (Fri,) studied this question.