Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma

Maximilian Pruss,Mine Tanriover,Markus David Siegelin,Richard Eric Kast,Klaus-Michael Debatin,Annika Dwucet,Georg Karpel-Massler,Mike-Andrew Westhoff,Marc-Eric Halatsch,Christian Rainer Wirtz,Michal Hlavac

doi:10.1038/s41416-020-0759-0

Abstract

BackgroundDysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma.MethodsPreclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM).ResultsONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM.ConclusionTreatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood–brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.

Highlights

Dysregulation of the metabolome is a hallmark of primary brain malignancies
1234567890();,: In this study, we show that treatment with the imipridone ONC201/TIC10 suppresses mitochondrial respiration while it upregulates the glycolytic rate of glioblastoma cells
Treatment with ONC201/TIC10 suppresses OXPHOS in glioblastoma cells We previously described that imipridones such as ONC201/TIC10 may affect the cellular energy metabolism of glioblastoma cells.[29]

Summary

BACKGROUND

Glioblastoma represents a highly therapy resistant primary cancer of the brain Patients diagnosed with this devastating disease generally, have to face an overall survival of only 1–2 years after diagnosis.[1,2] While much progress has been made to characterise and identify molecular subgroups with resulting stratification according to MGMT or IDH status and to refine treatment modalities, such as maximising resection, introducing temozolomide or alternating electric fields, the therapeutic reality remains grim. Pharmacological inhibition of glycolysis might prove to be a worthy adjunct to imipridones and increase their therapeutic efficacy

METHODS

RESULTS

III IV V Actin

DISCUSSION