Petővári G1, Hujber Z1, Dankó T1, Krencz I1, Tóth F1, Sebestyén A1
1First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Gliomas, glial cell derived central nerve system malignancies are a heterogeneous, aggressive tumour type with poor prognosis. The metabolic alterations, adaptations and their role in tumorigenesis and progression are well-known. Related to this mTOR pathway activation is known in many different tumours and in high-grade gliomas, as well. These prompted clinical trials for the use of PI3K/mTOR inhibitors, however, these have poor results.
In our work mTOR activity, metabolic characteristics and mTOR inhibitor sensitivity of several high-grade in vitro glioma cell lines were studied. Based on different metabolic characteristics, further metabolic inhibitors were combined with mTOR inhibitor treatments.
The expression of mTOR and other metabolic pathways activity related proteins, the metabolic profiles - based on intracellular metabolite concentration and the anti-proliferative effects of mTORC1, dual mTOR and other metabolic inhibitors (e.g. glutaminase, glycolysis and mitochondrial inhibitors) and temozolomide - were analysed in vitro.
Four studied glioma cell lines showed different mTORC1/C2 complex activities and different expression patterns of other metabolic enzymes. The basal oxygen consumptions and the intra- and extracellular concentrations of onco- (lactate, 2-HG) and TCA metabolites (malate, succinate, citrate) correlated to these metabolic differences. mTORC1/C2 and dual mTOR inhibitors had significantly higher anti-proliferative effect than rapalog treatments in vitro. Moreover, the effects of different combinations suggest an important bioenergetic role of mitochondrial functions in the proliferative capacity of these cells showing individual differences.
Our results suggest that metabolic profile analyses, and the usage of mTORI combinations or recently used other chemotherapeutics with selected metabolic pathway inhibitors – based on profile results – could further improve the personalised therapy in gliomas.
Supported by STIA-KF-17 (SA), Bolyai-590/2015 (SA) and ÚNKP-17-3 (HZ)-17-3 (KI)-17-2 (DT)
Doctoral School: Pathological Sciences
Supervisor: Anna Sebestyén
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