Novel Targeting of Transcription and Metabolism in Glioblastoma

作者：Yuting Su, Robert Chen, Herui Wang, Hua Song, Qi Zhang, Li‐Yuan Chen, Hallie Lappin, Gabriel Vasconcelos, Adrian Lita, Dragan Maric, Aiguo Li, Orieta Celiku, Wei Zhang, Kristan Meetze, Thomas Estok, Mioara Larion, Mones Abu‐Asab, Zhengping Zhuang, Chunzhang Yang, Mark R. Gilbert, Jing Wu · 发表于：Clinical Cancer Research · 年份：2017 · DOI：10.1158/1078-0432.ccr-17-2032 · 被引用次数：70 · 研究领域：Glioma Diagnosis and Treatment、Microtubule and mitosis dynamics、Cancer-related Molecular Pathways

Abstract Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients. Experimental Design: To investigate TG02, an agent with known penetration of the blood–brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays. Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-i...