Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Cell Rep. 2021 Apr 13;35(2):108994. doi: 10.1016/j.celrep.2021.108994.
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.
弥漫性内在脑桥胶质瘤（DIPG）是一种侵袭性和无法治愈的儿童脑肿瘤，需要新的治疗方法。CBL0137 是一种从吖啶衍生而来的抗癌化合物，靶向 facilitiates chromatin transcription（FACT），这是一种参与转录、复制和 DNA 修复的染色质重塑复合物。我们表明，CBL0137 通过恢复肿瘤抑制因子 TP53 和 Rb 的活性，对一系列患者来源的 DIPG 培养物显示出显著的细胞毒性活性。此外，在 DIPG 的原位模型中，CBL0137 的治疗显著延长了动物的存活时间。发现 FACT 亚基 SPT16 与 H3.3K27M 直接相互作用，CBL0137 的治疗恢复了组蛋白 H3 的乙酰化和三甲基化。CBL0137 与组蛋白去乙酰化酶抑制剂 panobinostat 的联合治疗导致 Rb/E2F1 途径的抑制和细胞凋亡的诱导。CBL0137 和 panobinostat 的联合治疗显著延长了携带 DIPG 异体移植物的小鼠的存活时间，这表明了一种治疗 DIPG 的潜在治疗策略。
