Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma

Oncotarget. 2017 Apr 4;8(14):22811-22824. doi: 10.18632/oncotarget.15206.

Abstract

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.

Keywords: GSK3β; clinical study; drug repositioning; glioblastoma; translational research.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Apoptosis / drug effects
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Drug Repositioning*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Therapy, Combination
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Temozolomide
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • Biomarkers, Tumor
  • Enzyme Inhibitors
  • Dacarbazine
  • Glycogen Synthase Kinase 3 beta
  • Temozolomide