{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T12:14:37Z","timestamp":1792239277172,"version":"4.4.0"},"reference-count":30,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp;amp; Cancer"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Key molecular features include histone H3 mutation (K27M) and AKT pathway dysregulation. There is currently no curative treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This is a Phase I study of vorinostat and temsirolimus in newly diagnosed (Stratum 1) and progressive (Stratum 2) DIPG (NCT02420613). The primary aims are to determine the safety, maximum tolerated dose (MTD), and toxicities. A modified 3\u00a0+\u00a03 design was used to establish the MTD, where the first three patients were assigned the first dose level regardless of stratum. Stratum 1 received radiotherapy with vorinostat, followed by up to 10 cycles of vorinostat and temsirolimus. Stratum 2 received up to 12 cycles of vorinostat and temsirolimus. Vorinostat was administered at a fixed dose of 230\u00a0mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      daily on Days 1\u20138, and temsirolimus was administered on Days 1 and 8 at 25\u00a0mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      (Dose level 1) or 35\u00a0mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      (Dose level 2).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Six patients were enrolled, three in each stratum. No dose\u2010limiting toxicity was observed, and most adverse effects were limited to Grades 1 or 2, including fatigue, myelosuppression, hyperlipidemia, hyperglycemia, elevated creatinine, nausea, vomiting, and headache. One patient experienced Grade 3 leukopenia. In the study, the MTD with acceptable toxicity was vorinostat 230\u00a0mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      and temsirolimus 35\u00a0mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overall, the combination of temsirolimus and vorinostat is well\u2010tolerated and safe, prompting the need for larger studies to investigate its efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pbc.31619","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T09:04:35Z","timestamp":1741683875000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Phase I Study of Vorinostat and Temsirolimus in Newly Diagnosed or Progressive Diffuse Intrinsic Pontine Glioma"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8119-5609","authenticated-orcid":false,"given":"Lea M.","family":"Stitzlein","sequence":"first","affiliation":[{"name":"Department of Pediatrics The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1809-1249","authenticated-orcid":false,"given":"Muhammad Usman","family":"Baig","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Loma Linda University  Loma Linda California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2077-9715","authenticated-orcid":false,"given":"Joya","family":"Chandra","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences  Houston Texas USA"},{"name":"Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"McGovern","sequence":"additional","affiliation":[{"name":"Radiation Oncology Department The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0269-3045","authenticated-orcid":false,"given":"Arnold","family":"Paulino","sequence":"additional","affiliation":[{"name":"Radiation Oncology Department The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena M.","family":"Ketonen","sequence":"additional","affiliation":[{"name":"Neuroradiology Department The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumen","family":"Khatua","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafik","family":"Zaky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"Department of Neuro\u2010Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2012.00205"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nou104"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2015.00237"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41016-020-00218-w"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-022-01324-0"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3855"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.9119"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1841"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-013-2220-z"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.19.0694"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24541"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.5463"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-017-0479-8"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24060"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11185"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-017-0033-y"},{"issue":"2","key":"e_1_2_10_18_1","first-page":"455","article-title":"Preclinical Analysis of MTOR Complex 1\/2 Inhibition in Diffuse Intrinsic Pontine Glioma","volume":"39","author":"Flannery P. C.","year":"2018","journal-title":"Oncology Reports"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2014.02.017"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.06.127"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2009.10.010"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066838"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2011.09.021"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.33.4649"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-011-9386-8"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1314"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-1215"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1385"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11109"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-3691"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"}],"container-title":["Pediatric Blood &amp; Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.31619","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pbc.31619","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.31619","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T14:23:51Z","timestamp":1773411831000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.31619"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,25]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1002\/pbc.31619"],"URL":"https:\/\/doi.org\/10.1002\/pbc.31619","archive":["Portico"],"relation":{},"ISSN":["1545-5009","1545-5017"],"issn-type":[{"value":"1545-5009","type":"print"},{"value":"1545-5017","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,25]]},"assertion":[{"value":"2024-09-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e31619"}}