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• W4282946032 abstract "Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults with a median survival of just over a year and a two-year survival of about 30%. Only 10% of people survive five years of this grade IV cancer. Standard of care therapy comprises maximal safe surgical resection followed by adjuvant alkylating agent temozolomide (TMZ) and radiotherapy conferring a median survival time of 14.6 months compared with 12.1 months for GBM patients treated with radiotherapy alone. First-in-class small-molecule imipridone ONC201 has shown efficacy in glioblastoma models in vitro, in vivo, and ex vivo. It is also orally active and is administered once every week, a favorable dosing schedule for patients. We hypothesized that ONC201 may synergize with radiotherapy and Temozolomide in GBM in vitro and in vivo. We previously reported that ONC201 synergizes with radiotherapy and/or TMZ to inhibit cell viability and colony formation and induce ER stress and apoptosis in GBM cells. To pursue this promising combinational therapy in vivo, we established GBM mouse orthotopic models through intracranial injection of luciferase expressing GBM cells U-251-LUC with a KOPF model 940 small animal stereotaxic frame and a Stoelting Quintessential Stereotaxic Injector. Tumor formation was confirmed with bioluminescence imaging. Randomized treatment group mice have received weekly treatment of ONC201 (100 mg/kg p.o.) and/or radiotherapy (2 Gy local irradiation) and/or TMZ (20 mg/kg i.p.) for four weeks. We observed the triple combination of ONC201 and radiotherapy and TMZ significantly reduced tumor burden and prolonged survival compared to dual combinations in GBM mouse orthotopic model U-251-LUC. We are currently exploring the synergistic mechanisms of triple combination including TRAIL signaling pathway, ISR, dopamine receptors and mitochondrial ClpXP, and potential pharmacodynamic biomarkers from in vivo samples. Our study suggests that the investigational triple combination therapy of ONC201 and radiotherapy and TMZ is going to be an important option for patients with GBM. Citation Format: Lanlan Zhou, Jinxuan Laura Wu, Howard P. Safran, Wafik S. El-Deiry. Synergistic antitumor effect of ONC201, radiotherapy and temozolomide in glioblastoma mouse orthotopic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5448." @default.
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• W4282946032 date "2022-06-15" @default.
• W4282946032 modified "2023-10-07" @default.
• W4282946032 title "Abstract 5448: Synergistic antitumor effect of ONC201, radiotherapy and temozolomide in glioblastoma mouse orthotopic models" @default.
• W4282946032 doi "https://doi.org/10.1158/1538-7445.am2022-5448" @default.
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