In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 2066-2066
Abstract:
2066 Background: The human epidermal growth factor receptor (EGFR) is an ideal therapeutic target for inhibiting glioblastoma (GBM) growth as the signaling pathway is highly dysregulated in GBM. However, trials so far with EGFR inhibitors have not shown clinically meaningful improvement in response rates and survival. One of the postulated mechanisms of resistance is the constitutive activation of the downstream, PI3K/AKT/mTOR pathway, independent of the upstream EGFR activation status. Hence, the dual blockage of the pathways with an anti-EGFR agent and mTOR inhibitor is postulated to have synergistic anti-tumour effects. We aim to investigate the anti-tumour effect of combined nimotuzumab (anti-EGFR monoclonal antibody) and sirolimus (mTOR inhibitor) in a GBM preclinical model. Methods: Primary human GBM cells were derived from surgical GBM specimens. The endogenous expressions of glial-fibrillary acidic proteins and EGFR were determined by IHC staining and Western Blot analysis. Cell viability assays were then carried out in these GBM cells and immortalized human normal astrocytes (iHNA) using a range of concentrations of nimotuzumab alone, sirolimus alone or combined treatment. Results: GBM cells treated with nimotuzumab showed a dose- dependent cell kill and the optimal concentration was determined to be 2 µg/ml. Treatment of the GBM cells with sirolimus showed that the drug was capable of inducing cell death at varying levels and the optimal level was determined to be 0.1 mM. Combined treatment with nimotuzumab (2µg/ml) and rapamycin (0.1 mM) showed a dose dependent cell kill in GBM cells which was not observed in iNHA cells. The combined treatment resulted in only 10% of residual gliomas at 24 h post treatment. Single treatment with rapamycin has no cytotoxic effect whereas treatment with nimotuzumab alone exerts a cytotoxicity effect of 33%. Taken together, we observed an additive effect of cell kill when rapamycin is used together with nimotuzumab in human glioma cells. Conclusions: In this study, combined treatment of nimotuzumab and sirolimus resulted in a greater cytocidal effects in GBM cells than either agent alone. We will further examine this combination regimen in a subsequent phase I clinical trial.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.2066
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
