On optimal temozolomide scheduling for slowly growing gliomas

Abstract

BackgroundTemozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma, and is commonly used in low-grade gliomas. In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes.MethodsAgent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR wt or EGFR vIII in primary progenitors from p16/p19 ko mice and grown in vitro and in vivo in orthotopic allografts, and human glioblastoma U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study.ResultsSlow growth ‘virtual’ murine gliomas benefited from increasing TMZ dose separation in silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly-growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically-driven changes in tumor phenotype, which could explain the reduction in glioma growth speed. In-silico trials provided support for methods of implementation in human patients.ConclusionsIn-silico simulations, and in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in gliomas.IMPORTANCE OF THE STUDYIn-vivo evidence is provided of improvements in survival, resistance, and toxicity from TMZ schemes with long rest periods between doses in slowly-growing GBM mouse models. The results match hypotheses generated in silico using a mathematical model incorporating the main biological features and fed with real patient data. An epigenetically-driven change in tumor phenotype was also revealed experimentally, which could explain the reduction in glioma growth speed under the ‘long cycle’ scheme. To determine the extent to which our results hold for human patients, large sets of simulations were performed on virtual patients. These in-silico trials suggest different ways to bring the benefits observed in experimental models into clinical practice.