Engineering of clinical glioma treatment: Prediction of pro-invasive molecular events in treated gliomas

Abstract

The diffusely infiltrative nature of malignant gliomas is the main obstacle to successful treatment approaches. Advanced simulation models of the in vivo response to therapy conditions are expected to improve malignant glioma treatment substantially. In parallel experiments, human malignant glioma cells underwent either radiation or chemotherapy treatment (chemotreatment) with temozolomide alone, or combined chemoradiation. Cells were treated according to diverse, clinically relevant, therapeutic algorithms. Quantitative ‘real-time’ polymerase chain reaction (PCR) measurements were performed for target genes, namely vascular endothelial growth factor, p53, and cyclooxygenase-2, which allow a comparative evaluation of pro-invasive molecular events in treated gliomas. The proof-of-principle study simulated variable intratumoural regional conditions. Pro-invasive molecular patterns were strongly dependent on the treatment algorithm, cellular density, and drug delivery. The highest pro-invasive potential was demonstrated for simulated peripheral regions under continued chemoradiation. This result strongly supports the clinical observations of increased aggressiveness and relatively poor response to second-line therapies in post-operatively chemoradiation-treated malignant gliomas at the time of relapse. Individualized and potentially the most effective treatment algorithms can be designed using established gene expression patterns applied on primary cell cultures obtained from individual patients. Individual drug toxicity and response to anti-cancer therapy can be predicted.