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Targeting cellular metabolism using rapamycin and/or doxycycline enhances anti-tumour effects in human glioma cells
Gábor Petővári1, Zoltán Hujber1, Ildikó Krencz1
111st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, 1085 Hungary.
Background:
Glioma is the most common highly aggressive, primary adult brain tumour. Clinical data show that therapeutic approaches cannot reach the expectations in patients, thus gliomas are mainly incurable diseases. Tumour cells can adapt rapidly to alterations during therapeutic treatments related to their metabolic rewiring and profound heterogeneity in tissue environment. Renewed interests aim to develop effective treatments targeting angiogenesis, kinase activity and/or cellular metabolism. mTOR (mammalian target of rapamycin), whose hyper-activation is characteristic for many tumours, promotes metabolic alterations, macromolecule biosynthesis, cellular growth and survival. Unfortunately, mTOR inhibitors with their lower toxicity have not resulted in appreciable survival benefit. Analysing mTOR inhibitor sensitivity, other metabolism targeting treatments and their combinations could help to find potential agents and biomarkers for therapeutic development in glioma patients.
Methods:
In vitro proliferation assays, protein expression and metabolite concentration analyses were used to study the effects of mTOR inhibitors, other metabolic treatments and their combinations in glioma cell lines. Furthermore, mTOR activity and cellular metabolism related protein expression patterns were also investigated by immunohistochemistry in human biopsies. Temozolomide and/or rapamycin treatments altered the expressions of enzymes related to lipid synthesis, glycolysis and mitochondrial functions as consequences of metabolic adaptation; therefore, other anti-metabolic drugs (chloroquine, etomoxir, doxycycline) were combined in vitro.
Results:
Our results suggest that co-targeting metabolic pathways had tumour cell dependent additive/synergistic effects related to mTOR and metabolic protein expression patterns cell line dependently. Drug combinations, especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas. Additionally, our immunohistochemistry results suggest that metabolic and mTOR activity alterations are not related to the recent glioma classification, and these protein expression profiles show individual differences in patients' materials.
Conclusions:
Based on these, combinations of different new/old drugs targeting cellular metabolism could be promising to inhibit high adaptation capacity of tumour cells depending on their metabolic shifts. Relating to this, such a development of current therapy needs to find special biomarkers to characterise metabolic heterogeneity of gliomas.
Insights
Combining metabolic treatments shows promise for treating aggressive gliomas by targeting tumor cell adaptation. Further research into biomarkers is needed to personalize therapy for glioma patients.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glioma is a highly aggressive primary adult brain tumor with limited therapeutic options.
- Tumor cells exhibit metabolic rewiring and heterogeneity, contributing to treatment resistance.
- Hyperactivation of mTOR (mammalian target of rapamycin) promotes tumor growth and metabolic alterations, but mTOR inhibitors alone have shown limited survival benefits.
Purpose of the Study:
- To investigate the effects of combining mTOR inhibitors with other metabolic treatments in glioma.
- To identify potential therapeutic agents and biomarkers for glioma treatment by analyzing drug sensitivity and metabolic pathways.
- To understand the role of mTOR activity and cellular metabolism in glioma heterogeneity.
Main Methods:
- In vitro proliferation assays, protein expression, and metabolite concentration analyses were performed on glioma cell lines.
- Immunohistochemistry was used to assess mTOR activity and metabolic protein expression in human glioma biopsies.
- Glioma cells were treated with temozolomide, rapamycin, and combinations with other anti-metabolic drugs like chloroquine, etomoxir, and doxycycline.
Main Results:
- Co-targeting metabolic pathways demonstrated additive or synergistic anti-tumor effects, dependent on cell line and associated mTOR/metabolic protein expression.
- The combination of rapamycin and doxycycline showed a promising anti-tumor effect in gliomas.
- Metabolic and mTOR activity alterations were independent of the current glioma classification and exhibited patient-specific expression profiles.
Conclusions:
- Combinations of drugs targeting cellular metabolism offer a promising strategy to overcome the adaptive resistance of glioma cells.
- Identifying specific biomarkers is crucial for characterizing glioma metabolic heterogeneity and developing personalized therapies.
- Targeting metabolic shifts presents a potential avenue for improving current glioma treatment strategies.
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