Medical Student University of Pittsburgh Brookline, MA, US
Introduction: Diffuse midline gliomas (DMG) are highly aggressive pediatric brain tumors with a dismal prognosis despite standard of care therapy. Previously, through genomic and transcriptomic profiling, we revealed that platelet-derived growth factor receptor alpha (PDGFRA) is essential for tumorigenesis and stem-like DMG cell maintenance, indicating therapeutic potential for targeting PDGFRA in DMG. Pre-clinically, we discovered that avapritinib, an FDA-approved PDGFRA inhibitor, was highly effective in patient-derived xenograft (PDX) DMG models. Further, we reported the first use of avapritinib in recurrent DMG, clinically. We observed preliminary safety, tolerability, and efficacy in patients receiving this therapy. While some patients receiving avapritinib experienced initially strong clinical responses, all patients eventually experienced disease progression.
Methods: This study explores the molecular mechanisms that DMG cells upregulate in response to avapritinib treatment, as we aim to exploit these pathways with therapeutic interventions. To identify these mechanisms, we conducted transcriptomic, metabolic, and functional assays, complemented by a combinatorial drug screening.
Results: Patient-derived DMG cell lines underwent transcriptomic analysis which revealed an upregulation of genes associated with oxidative phosphorylation (OXPHOS) and fatty acid metabolism following avapritinib treatment. These findings were further confirmed with functional studies which highlighted elevated OXPHOS in avapritinib-treated cells correlates with significant increases in mitochondrial energy transduction, increases in oxygen consumption rate which was primarily driven by the fatty acid metabolism product palmitate, and greater incorporation of palmitate-derived carbons into the tricarboxylic acid cycle. To elucidate therapies capable of targeting DMG cell dependency on fatty acid metabolism and OXPHOS, we performed a combinatorial drug screening in patient-derived DMG cell lines. Our screening revealed two metabolic drugs that have synergistic cytotoxic effects with avapritinib.
Conclusion : Our study reveals distinct metabolic reprogramming in DMG cells following avapritinib treatment and shows that targeting these metabolic vulnerabilities may increase the clinical benefit of PDGFRA inhibition in DMG.
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