{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:11:14Z","timestamp":1787901074715,"version":"build-2784847793"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The tumor suppressor TP53 (p53) is frequently mutated, and its downstream effectors inactivated in many cancers, including glioblastoma (GBM). In tumors with wild-type status, p53 function is frequently attenuated by alternate mechanisms including amplification and overexpression of its key negative regulator, MDM2. We investigated the efficacy of the MDM2 inhibitor, BI-907828, in GBM patient-derived brain tumor stem cells (BTSCs) with different amplification statuses of MDM2, in vitro and in orthotopic xenograft models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In vitro growth inhibition and on-target efficacy of BI-907828 were assessed by cell viability, co-immunoprecipitation assays, and western blotting. In vivo efficacy of BI-907828 treatments was assessed with qPCR, immunohistochemistry, and in intracranial xenograft models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>BI-907828 decreases viability and induces cell death at picomolar concentrations in both MDM2 amplified and normal copy number TP53 wild-type BTSC lines. Restoration of p53 activity, including robust p21 expression and apoptosis induction, was observed in TP53 wild-type but not in TP53 mutant BTSCs. shRNA-mediated knock-down of TP53 in wild-type BTSCs abrogated the effect of BI-907828, confirming the specificity of the inhibitor. Pharmacokinetic-pharmacodynamic studies in orthotopic tumor-bearing severe combined immunodeficiency (SCID) mice demonstrated that a single 50\u00a0mg\/kg p.o. dose of BI-907828 resulted in strong activation of p53 target genes p21 and MIC1. Long-term weekly or bi-weekly treatment with BI-907828 in orthotopic BTSC xenograft models was well-tolerated and improved survival both as a single-agent and in combination with temozolomide, with dose-dependent efficacy observed in the MDM2 amplified model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>BI-907828 provides a promising new therapeutic option for patients with TP53 wild-type primary brain tumors.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noac271","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T23:53:18Z","timestamp":1670889198000},"page":"913-926","source":"Crossref","is-referenced-by-count":31,"title":["BI-907828, a novel potent MDM2 inhibitor, inhibits glioblastoma brain tumor stem cells in vitro and prolongs survival in orthotopic xenograft mouse models"],"prefix":"10.1093","volume":"25","author":[{"given":"Xiaoguang","family":"Hao","sequence":"first","affiliation":[{"name":"Arnie Charbonneau Cancer Institute, Hotchkiss Brain Institute, Cumming School of Medicine,\u00a0University of Calgary , Calgary, Alberta , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravinder K","family":"Bahia","sequence":"additional","affiliation":[{"name":"Arnie Charbonneau Cancer Institute, Hotchkiss Brain Institute, Cumming School of Medicine,\u00a0University of Calgary , Calgary, Alberta , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsolya","family":"Cseh","sequence":"additional","affiliation":[{"name":"Arnie Charbonneau Cancer Institute, Hotchkiss Brain Institute, Cumming School of Medicine,\u00a0University of Calgary , Calgary, Alberta , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle A","family":"Bozek","sequence":"additional","affiliation":[{"name":"Arnie Charbonneau Cancer Institute, Hotchkiss Brain Institute, Cumming School of Medicine,\u00a0University of Calgary , Calgary, Alberta , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Blake","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim RCV GmbH & Co KG , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Rinnenthal","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim RCV GmbH & Co KG , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Weyer-Czernilofsky","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim RCV GmbH & Co KG , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothea","family":"Rudolph","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim RCV GmbH & Co KG , Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Artee Luchman","sequence":"additional","affiliation":[{"name":"Arnie Charbonneau Cancer Institute, Hotchkiss Brain Institute, Cumming School of Medicine,\u00a0University of Calgary , Calgary, Alberta , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"issue":"6381","key":"2023050411181245400_CIT0001","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/358015a0","article-title":"Cancer. p53, guardian of the genome","volume":"358","author":"Lane","year":"1992","journal-title":"Nature."},{"issue":"6366","key":"2023050411181245400_CIT0002","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/356215a0","article-title":"Mice deficient for p53 are developmentally normal but susceptible to spontaneous 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