Novel Targeting of Transcription and Metabolism in Glioblastoma

Authors

• Y Su
• R Chen
• H Wang
• H Song
• Q Zhang
• L Chen
• T Estok
• G Vasconcelos
• A Lita
• D Maric
• A Li
• O Celiku
• W Zhang
• K Meetze
• C Yang
• M Larion
• M Abu-Asab
• Z Zhuang
• MR Gilbert
• J Wu

Abstract

Glioblastoma is an aggressive primary malignant brain tumor with a median survival of less than 15 months. The current standard treatment includes maximal surgical resection followed by radiation and/or chemotherapy with the alkylating agent, temozolomide but shows limited efficacy in patients with glioblastoma. Finding a promising drug targeting multiple survival mechanisms of glioblastoma is urgently needed. TG02 is a multi-kinase inhibitor, mainly inhibiting cyclin-dependent kinase 9 (CDK9), thus diminishing RNA polymerase II activation to suppress the expressions of anti-apoptotic proteins such as Mcl-1and Survivin. To investigate TG02, an agent with known penetration of the blood-brain barrier, we examined the its cytotoxic effects as monotherapy and in combination with temozolomide in glioblastoma. We demonstrated that TG02 induced cell death in eight glioblastoma cell lines with the variable genetic background but not in normal cells such as astrocytes and endothelial cells. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed the protein expressions of Mcl-1 and Survivin and induced apoptosis in glioblastoma cells. We further demonstrated that TG02 induced mitochondrial dysfunction by decreased the activity of complex I and induced Cytochrome c release to the cytoplasm. Moreover, TG02 synergizes with temozolomide to induce cell death, partially by inhibiting glycolysis and subsequently depleting energy in glioblastoma cells. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. TG02 decreasing in CDK9 phosphorylation was confirmed in the brain tumor tissue. TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy for glioblastoma. These preclinical findings, supporting the pharmacological efficacy of TG02 and temozolomide for glioblastoma, have led to the launching of a phase I/II clinical trial (NCT02942264).

Scientific Focus Area: Cancer Biology

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