{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:07:02Z","timestamp":1789614422236,"version":"build-2803163510"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["7244330"],"award-info":[{"award-number":["7244330"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["7244344"],"award-info":[{"award-number":["7244344"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes","award":["JYY2018-7"],"award-info":[{"award-number":["JYY2018-7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diffuse 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptomic 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Transcriptomic 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\u2019s 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Guided 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noaf216","type":"journal-article","created":{"date-parts":[[2025,9,14]],"date-time":"2025-09-14T11:37:49Z","timestamp":1757849869000},"page":"251-267","source":"Crossref","is-referenced-by-count":3,"title":["Transcriptomics-guided high-throughput drug screening identifies potent therapies for P53 pathway altered DIPG\/DMG"],"prefix":"10.1093","volume":"28","author":[{"given":"Zhuang","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University , Beijing 100070,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University , Beijing 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