ArticleNeuro-oncology2026
Transcriptomics-guided high-throughput drug screening identifies potent therapies for P53 pathway altered DIPG/DMG.
Article in Neuro-oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Berzosertib enhances the sensitivity of pediatric diffuse midline glioma H3K27-altered cells to radiotherapy.Cell death & disease · 2026Article
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11 authors.
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Abstract
backgroundDiffuse midline gliomas (DMGs), particularly diffuse intrinsic pontine gliomas (DIPGs), are aggressive pediatric brain tumors with a median survival of less than 12 months. Notably, approximately 70% of these tumors harbor P53 pathway alterations, including TP53 or PPM1D mutations. Identifying precision therapies for this subset is crucial. This study aims to employ transcriptomics-guided high-throughput drug screening to identify effective treatments for DIPG/DMG with P53 pathway alterations.
methodsTranscriptomic profiling of 98 patient samples containing 31 DIPGs revealed key activated pathways. Patient-derived cell lines were subjected to high-throughput screening using a cell cycle-targeting drug library. Lead candidates were validated both in vitro and in orthotopic xenograft models, while combination therapies were assessed for their ability to overcome TP53-mutant resistance.
resultsTranscriptomic analysis revealed activation of P53 and cell cycle pathways in DIPGs. High-throughput drug screening identified SN-38, a topoisomerase I inhibitor, as selectively targeting TP53 wild-type tumor cells by inducing G2 arrest and apoptosis. TP53 knockdown abolished SN-38's efficacy, while PPM1D knockdown enhanced sensitivity, confirming a TP53-dependent mechanism. Conversely, TP53-mutated cells exhibited SN-38 resistance via ATR pathway activation. Combining SN-38 with the ATR inhibitor AZ20 restored apoptosis and suppressed TP53-mutant tumor growth in vitro and in vivo.
conclusionsGuided by transcriptomic profiling, this study utilized high-throughput drug screening to identify SN-38 as a potential therapy for TP53 wild-type DIPG/DMG, while the SN-38 and AZ20 combination was effective against TP53-mutant tumors. This approach provides a promising treatment strategy for this malignancy and establishes a novel paradigm for drug screening in DIPG/DMG.
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