Analysis of temozolomide resistance in low‐grade gliomas using a mechanistic mathematical model

Abstract

Understanding how tumors develop resistance to chemotherapy is a major issue in oncology. When treated with temozolomide (TMZ), an oral alkylating chemotherapy drug, most low-grade gliomas (LGG) show an initial volume decrease but this effect is rarely long lasting. In addition, it has been suggested that TMZ may drive tumor progression in a subset of patients as a result of acquired resistance. Using longitudinal tumor size measurements from 121 patients, the aim of this study was to develop a semi-mechanistic mathematical model to determine whether resistance of LGG to TMZ was more likely to result from primary and/or from chemotherapy-induced acquired resistance that may contribute to tumor progression. We applied the model to a series of patients treated upfront with TMZ (n = 109) or PCV (procarbazine, CCNU, vincristine) chemotherapy (n = 12) and used a population mixture approach to classify patients according to the mechanism of resistance most likely to explain individual tumor growth dynamics. Our modeling results predicted acquired resistance in 51% of LGG treated with TMZ. In agreement with the different biological effects of nitrosoureas, none of the patients treated with PCV were classified in the acquired resistance group. Consistent with the mutational analysis of recurrent LGG, analysis of growth dynamics using mathematical modeling suggested that in a subset of patients, TMZ might paradoxically contribute to tumor progression as a result of chemotherapy-induced resistance. Identification of patients at risk of developing acquired resistance is warranted to better define the role of TMZ in LGG.

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

“…Interestingly, we obtained PD mirror‐inverted time profiles to PK time profiles for both temporal parameters (lag time and time to peak), markedly for peak height and to a lesser extent for ETP, with peak height consistently more affected than ETP in agreement with previous findings . In some volunteers, a double peak pattern was observed with both PK and TG parameters on time profiles, suggesting multiphasic elimination including an enteroenteric cycle of rivaroxaban in these individuals, a phenomenon already described in the literature . Overall, rivaroxaban exerted a concentration‐dependent effect on all TG parameters under all TF conditions, with a greater sensitivity obtained with the intermediate TF concentration.…”

“…23,30 In some volunteers, a double peak pattern was observed with both PK and TG parameters on time profiles, suggesting multiphasic elimination including an enteroenteric cycle of rivaroxaban in these individuals, a phenomenon already described in the literature. 41 Overall, rivaroxaban In vivo, TG is down regulated by natural inhibitors, among them the protein C (PC) anticoagulant pathway. 42 Remarkably, at baseline, we found that the addition of TM in the DRIVING volunteer plasmas generated an almost 50% inhibition in ETP, validating the concentration of TM introduced into the commercial reagent.…”

A Review of Mathematical Models for Tumor Dynamics and Treatment Resistance Evolution of Solid Tumors

“…6 and 7). 10,11 Many clinical studies have applied the logistic [24][25][26] and Gompertz models 11,27 as well as simulation studies. 28,29 Finally, a combination of exponential and linear growth models (Eq.…”

“…Another commonly made assumption is that tumors are composed of drug-sensitive and drug-resistant cells. 24,34 These two cell types both proliferate, but drug treatment can only decrease the amount of drug-sensitive cells. Primary and acquired resistance can both be taken into consideration.…”

“…Primary and acquired resistance can both be taken into consideration. For illustrating the acquired resistance, the resistant cells are mostly assumed to mutate from sensitive cells because of the treatment with a first-order process 23,24,34,35 (Eqs. [12][13].…”