Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma
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Takuya Furuta1, Hemragul Sabit1, Yu Dong1, Katsuyoshi Miyashita1, Masashi Kinoshita1, Naoyuki Uchiyama1, Yasuhiko Hayashi1, Yutaka Hayashi1, Toshinari Minamoto2, Mitsutoshi Nakada1
1Department of Neurosurgery, Division of Neuroscience, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
2Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
Mitsutoshi Nakada, email: [email protected]
Keywords: glioblastoma, GSK3β, drug repositioning, translational research, clinical study
Received: May 11, 2016 Accepted: January 25, 2017 Published: February 09, 2017
Background: Glycogen synthase kinase (GSK)-3β has emerged as an appealing therapeutic target for glioblastoma (GBM). Here, we investigated the therapeutic effect of the current approved drugs against GBM via inhibition of GSK3β activity both, in experimental setting and in a clinical study for recurrent GBM patients by repositioning existent drugs in combination with temozolomide (TMZ).
Materials and Methods: Progression-free and overall survival rates were compared between patients with low or high expression of active GSK3β in the primary tumor. GBM cells and a mouse model were examined for the effects of GSK3β-inhibitory drugs, cimetidine, lithium, olanzapine, and valproate. The safety and efficacy of the cocktail of these drugs (CLOVA cocktail) in combination with TMZ were tested in the mouse model and in a clinical study for recurrent GBM patients.
Results: Activation of GSK3β in the tumor inversely correlated with patient survival as an independent prognostic factor. CLOVA cocktail significantly inhibited cell invasion and proliferation. The patients treated with CLOVA cocktail in combination with TMZ showed increased survival compared to the control group treated with TMZ alone.
Conclusions: Repositioning of the GSK3β-inhibitory drugs improved the prognosis of refractory GBM patients with active GSK3β in tumors. Combination of CLOVA cocktail and TMZ is a promising approach for recurrent GBM.
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