CBMT-35. METABOLIC REWIRING BY ONC201/TIC10 AND 2-DEOXYGLUCOSE HAS SYNERGISTIC ANTI-GLIOBLASTOMA ACTIVITY
In: Neuro Oncol, 2019
academicJournal
Zugriff:
BACKGROUND: Metabolic dysregulation is a common feature of cancers such as primary brain malignancies. In this work we examined whether a rewiring of the metabolome by a multi-targeting approach would induce enhanced anti-neoplastic activity in glioblastoma. METHODS: Preclinical 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 (OCR) and glycolysis (ECAR). Expression of respiratory chain complexes was analysed by Western blotting. Biological effects on tumor formation were tested in patient-derived model systems on the chorion allantoic membrane (CAM). Protein array analyses were performed to determine effects on phospho protein kinase expression. RESULTS: Treatment with ONC201/TIC10 leads to impaired mitochondrial respiration and a dose-dependent increase of glycolysis. ONC201/TIC10 combined with 2-Deoxyglucose, induces a state of energy deprivation characterized by a significant decrease in ATP levels. On the molecular level, pAMPK α1 was significantly up-regulated while a hypo-phosphorylation signature was noted including mTOR signaling, src family kinases and receptor tyrosine kinases such as EGFR and PDGFR-β. As a result, synergistic anti-proliferative and anti-migratory effects were observed among established and primary cultured glioblastoma cells. In addition, tumor formation on the CAM was significantly impaired following the combination treatment. CONCLUSIONS: Simultaneous treatment with ONC201/TIC10 and 2-Deoxyglucose causes a reprogramming of the metabolic circuitry and results in a synergistic anti-glioblastoma activity. Since both agents were tested in clinical trials with good tolerability, and they both penetrate the blood-brain barrier, further clinical evaluation of this therapeutic strategy seems promising.
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CBMT-35. METABOLIC REWIRING BY ONC201/TIC10 AND 2-DEOXYGLUCOSE HAS SYNERGISTIC ANTI-GLIOBLASTOMA ACTIVITY
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Autor/in / Beteiligte Person: | Pruss, Maximilian ; Dwucet, Annika ; Hlavac, Michal ; Kast, Richard ; Westhoff, Mike-Andrew ; Wirtz, Rainer ; Halatsch, Marc-Eric ; Siegelin, Markus ; Karpel-Massler, Georg |
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Zeitschrift: | Neuro Oncol, 2019 |
Veröffentlichung: | Oxford University Press, 2019 |
Medientyp: | academicJournal |
DOI: | 10.1093/neuonc/noz175.157 |
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