Zhou Lanlan, Zhang Leiqing, Zhang Jun, Wu Laura Jinxuan, Zhang Shengliang, George Andrew, Hahn Marina, Safran Howard P, Chen Clark C, Seyhan Attila A, Wong Eric T, El-Deiry Wafik S
Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA.
Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA.
Oncotarget. 2025 Mar 27;16:230-248. doi: 10.18632/oncotarget.28707.
Glioblastoma remains a lethal brain tumor in adults with limited therapeutic options. TIC10/ONC201, a first-in-class imipridone we discovered, achieved meaningful therapeutic effects in phase I/II trials in patients with diffuse gliomas (DG's) harboring H3K27M mutations, and currently the drug is in randomized phase III testing (ACTION trial; NCT05580562). ONC201 targets mitochondrial protease ClpP to disrupt oxidative phosphorylation and trigger the integrated stress response (ISR), TRAIL/DR5, and tumor cell death. While ONC201 and its analog ONC206 are undergoing clinical trials as single agents, there is limited information on their interactions with stand-of-care therapy. We show that ONC201 and ONC206 synergize with temozolomide (TMZ) and Radiotherapy (RT). ONC201 enhances TMZ- or RT-induced apoptosis, ISR and cytotoxicity. ClpP-silencing suppresses ONC201-induced cytotoxicity but not TMZ. Both ONC201 and ONC206 reduce expression of TMZ-resistance mediator MGMT observed in H3K27M-mutated DG cells following treatment with imipridones+TMZ. Cytokine profiling indicates distinct effects of ONC201 relative to TMZ treatment. These results suggest mechanisms underlying ONC201's anti-tumoral activity are distinct from those associated with TMZ or RT with potential for synergy between these three treatments. Triple ONC201+RT+TMZ (IRT) therapy prolonged median survival to 123 days with tail on survival curve (3-of-7 mice alive beyond 200-days) in orthotopic U251 GBM model versus ONC201 (44-days; = 0.000197), RT (63-days; = 0.0012), TMZ (78-days; = 0.0354), ONC201+RT (55-days; = 0.0004), ONC201+TMZ (80-days; = 0.0041) and RT+TMZ (103-days; > 0.05). By 231-days, the only surviving mice were in IRT group. Our results support investigation of ONC201/ONC206 in combination with RT/TMZ (IRT) in GBM or H3K27M mutated DG therapy.
胶质母细胞瘤仍然是成人中一种致命的脑肿瘤，治疗选择有限。我们发现的首个咪吡酮类药物TIC10/ONC201，在携带H3K27M突变的弥漫性胶质瘤（DG）患者的I/II期试验中取得了显著的治疗效果，目前该药物正在进行随机III期试验（ACTION试验；NCT05580562）。ONC201靶向线粒体蛋白酶ClpP，以破坏氧化磷酸化并触发整合应激反应（ISR）、TRAIL/DR5和肿瘤细胞死亡。虽然ONC201及其类似物ONC206正在作为单一药物进行临床试验，但关于它们与标准治疗的相互作用的信息有限。我们表明，ONC201和ONC206与替莫唑胺（TMZ）和放疗（RT）具有协同作用。ONC201增强TMZ或RT诱导的细胞凋亡、ISR和细胞毒性。ClpP沉默可抑制ONC201诱导的细胞毒性，但不能抑制TMZ诱导的细胞毒性。在用咪吡酮类药物+TMZ处理后，ONC201和ONC206均降低了H3K27M突变的DG细胞中观察到的TMZ抗性介质MGMT的表达。细胞因子分析表明，ONC201相对于TMZ治疗有不同的作用。这些结果表明，ONC201的抗肿瘤活性机制与TMZ或RT相关的机制不同，这三种治疗之间可能存在协同作用。在原位U251胶质母细胞瘤模型中，三联ONC201+RT+TMZ（IRT）疗法将中位生存期延长至123天，生存曲线有长尾（7只小鼠中有3只存活超过200天），而ONC201治疗组为44天（P = 0.000197），RT治疗组为63天（P = 0.0012），TMZ治疗组为78天（P = 0.0354），ONC201+RT治疗组为55天（P = 0.0004），ONC201+TMZ治疗组为80天（P = 0.0041），RT+TMZ治疗组为103天（P>0.05）。到231天时，唯一存活的小鼠在IRT组。我们的结果支持在胶质母细胞瘤或H3K27M突变的DG治疗中研究ONC201/ONC206与RT/TMZ（IRT）联合使用。
