Abstract
BackgroundThe treatment of glioblastoma multiforme (GBM) is an unmet clinical need. The 5-year survival rate of patients with GBM is less than 3%. Temozolomide (TMZ) remains the standard first-line treatment regimen for gliomas despite the fact that more than 90% of recurrent gliomas do not respond to TMZ after repeated exposure. We have also independently shown that many of the Asian-derived glioma cell lines and primary cells derived from Singaporean high-grade glioma patients are indeed resistant to TMZ. This issue highlights the need to develop new effective anti-cancer treatment strategies. In a recent study, wild-type epidermal growth factor receptor (wtEGFR) has been shown to phosphorylate a truncated EGFR (known as EGFRvIII), leading to the phosphorylation of STAT proteins and progression in gliomagenesis. Despite the fact that combination of EGFR targeting drugs and rapamycin has been used before, the effect of mono-treatment of Nimotuzumab, rapamycin and combination therapy in human glioma expressing different types of EGFR is not well-studied. Herein, we evaluated the efficacy of dual blockage using monoclonal antibody against EGFR (Nimotuzumab) and an mTOR inhibitor (rapamycin) in Caucasian patient-derived human glioma cell lines, Asian patient-derived human glioma cell lines, primary glioma cells derived from the Mayo GBM xenografts, and primary short-term glioma culture derived from high-grade glioma patients.MethodsThe combination effect of Nimotuzumab and rapamycin was examined in a series of primary human glioma cell lines and glioma cell lines. The cell viability was compared to TMZ treatment alone. Endogenous expressions of EGFR in various GBM cells were determined by western blotting.ResultsThe results showed that combination of Nimotuzumab with rapamycin significantly enhanced the therapeutic efficacy of human glioma cells compared to single treatment. More importantly, many of the Asian patient-derived glioma cell lines and primary cells derived from Singaporean high-grade gliomas, which showed resistance to TMZ, were susceptible to the combined treatments.ConclusionsIn conclusion, our results strongly suggest that combination usage of Nimotuzumab and rapamycin exert higher cytotoxic activities than TMZ. Our data suggest that this combination may provide an alternative treatment for TMZ-resistant gliomas regardless of the EGFR status.
Highlights
The treatment of glioblastoma multiforme (GBM) is an unmet clinical need
We evaluated the efficacy of dual blockage using monoclonal antibody against EGFR (Nimotuzumab) and an mammalian target of rapamycin (mTOR) inhibitor in Caucasian patient-derived human glioma cell lines, Asian patient-derived human glioma cell lines, primary glioma cells derived from the Mayo GBM xenografts, and primary short-term glioma culture derived from high-grade glioma patients
The combination of Nimotuzumab with Sirolimus increased glioma cell cytotoxicity when compared to single drug treatment As TMZ is routinely used as a first-line therapy for GBMs, we sought to first determine the concentration required to achieve 50% inhibition of cell proliferation, i.e., IC50 of TMZ, Nimotuzumab and rapamycin in immortalized human astrocytes which are the most common cell types that give rise to glioma
Summary
The treatment of glioblastoma multiforme (GBM) is an unmet clinical need. The 5-year survival rate of patients with GBM is less than 3%. We have independently shown that many of the Asian-derived glioma cell lines and primary cells derived from Singaporean high-grade glioma patients are resistant to TMZ. This issue highlights the need to develop new effective anti-cancer treatment strategies. Despite the fact that combination of EGFR targeting drugs and rapamycin has been used before, the effect of mono-treatment of Nimotuzumab, rapamycin and combination therapy in human glioma expressing different types of EGFR is not well-studied. In a report by Heimberger and colleagues, 42.6% of GBM patients failed to express EGFR, 25.9% had an overexpression of wtEGFR and 31.5% expressed a specific EGFR mutant (EGFRvIII, known as EGFR type III, de, ΔEGFR) [2]. Given the high frequency of EGFR dysregulation, inhibiting EGFR signaling pathway appears to be a promising and rational therapeutic strategy for attenuating GBM growth
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