Overcoming chemotherapy resistance in low-grade gliomas: A computational approach

Low-grade gliomas are primary brain tumors that arise from glial cells and are usually treated with temozolomide (TMZ) as a chemotherapeutic option. They are often incurable, but patients have a prolonged survival. One of the shortcomings of the treatment is that patients eventually develop drug resistance. Recent findings show that persisters, cells that enter a dormancy state to resist treatment, play an important role in the development of resistance to TMZ. In this study we constructed a mathematical model of low-grade glioma response to TMZ incorporating a persister population. The model was able to describe the volumetric longitudinal dynamics, observed in routine FLAIR 3D sequences, of low-grade glioma patients acquiring TMZ resistance. We used the model to explore different TMZ administration protocols, first on virtual clones of real patients and afterwards on virtual patients preserving the relationships between parameters of real patients. In silico clinical trials showed that resistance development was deferred by protocols in which individual doses are administered after rest periods, rather than the 28-days cycle standard protocol. This led to median survival gains in virtual patients of more than 15 months when using resting periods between two and three weeks and agreed with recent experimental observations in animal models. Additionally, we tested adaptive variations of these new protocols, what showed a potential reduction in toxicity, but no survival gain. Our computational results highlight the need of further clinical trials that could obtain better results from treatment with TMZ in low grade gliomas. Low-grade gliomas are incurable brain tumors that originate from glial cells, the cells that provide physical and chemical support to neurons. Patients typically receive temozolomide (TMZ) chemotherapy as part of the standard treatment, but eventually develop resistance to the drug, what constitutes an important therapeutic challenge. We developed a mathematical model to explore novel TMZ delivery protocols that could improve survival and reduce toxicity. These are grounded in the reduction of the persister population, a recently discovered glioma cell type that reversibly changes to a quiescent state to resist insults. We measured tumor volume from longitudinal imaging studies performed in patients that showed resistance to treatment and used those measurements to validate our mathematical model. We proposed a general scheme of TMZ administration that consisted in delivering isolated doses with long resting periods, in contrast to classical cycle delivery with higher concentration of doses. Computational simulations modified schemes showed a benefit in survival with reduced toxicity. Our findings could guide biological experiments aimed at improving overall survival and quality of life for patients with low-grade gliomas.