BI-907828, a novel potent MDM2 inhibitor, inhibits glioblastoma brain tumor stem cells in vitro and prolongs survival in orthotopic xenograft mouse models
العنوان: | BI-907828, a novel potent MDM2 inhibitor, inhibits glioblastoma brain tumor stem cells in vitro and prolongs survival in orthotopic xenograft mouse models |
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المؤلفون: | Xiaoguang, Hao, Ravinder, Bahia, Orsolya, Cseh, Danielle, Bozek, Sophia, Blake, Jörg, Rinnenthal, Ulrike, Weyer-Czernilofsky, Dorothea, Rudolph, H Artee, Luchman |
المصدر: | Neuro-Oncology. 25:913-926 |
بيانات النشر: | Oxford University Press (OUP), 2022. |
سنة النشر: | 2022 |
مصطلحات موضوعية: | Cancer Research, Oncology, Neurology (clinical) |
الوصف: | Background 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. Methods 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. Results 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 mg/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. Conclusions BI-907828 provides a promising new therapeutic option for patients with TP53 wild-type primary brain tumors. |
تدمد: | 1523-5866 1522-8517 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2daa7ac7c97de0e6acebabac00b4cb3b https://doi.org/10.1093/neuonc/noac271 |
حقوق: | CLOSED |
رقم الأكسشن: | edsair.doi.dedup.....2daa7ac7c97de0e6acebabac00b4cb3b |
قاعدة البيانات: | OpenAIRE |
تدمد: | 15235866 15228517 |
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