Is the Fixed Periodic Treatment Effective for the Tumor System without Complete Information?

Abstract

Objective

The treatment plans designed with the guidance of the mathematical model and adaptive strategy can trap tumor subpopulations in a periodic and controllable loop. But this process requires detailed information about the tumor system, which is difficult to obtain. Therefore, we wondered whether the fixed periodic treatment plans designed with the typical values of population parameters could be applied to a similar tumor system without complete information.

Methods

A binary tumor system constructed by an EGFR-mutant and a KRAS-mutant cell line was used to explore the applicability of the fixed periodic treatment plans. The dynamics of this system were described by combining the Lotka-Volterra model with the framework of the nonlinear mixed-effects model. The typical values of population parameters were used to design the plans, and the robust plans were screened through parameter variation. These screened plans were examined their applicability in animal experiments and simulations.

Results

In animal experiments where system parameters vary from −30% to 30%, the “osimertinib administration, withdrawal, FK866 administration and withdrawal” plan can trap subpopulations of the system in periodic cycles. In simulation, when there was an unknown resistant subpopulation, the screened fixed periodic treatment plans can still delay the evolution of resistance. The median outcomes of screened plans were better than conventional sequential treatment in most cases. There was no significant difference between the outcomes of the screened plan with median stability and the optimal therapy. The evolutionary trajectories of these two plans were similar.

Conclusion

According to the results, these fixed periodic plans should be tried in treatment even the information of the tumor system was incomplete.

Keywords:

• adaptive strategy
• osimertinib resistance
• tumor evolution
• fixed periodic treatment plans

Acknowledgments

This research was supported by funding from the Graduate Research Innovation Program of Jiangsu Province (KYCX20_0631) and the “Double First-Class” University Project (CPU2018GY19). Part of the experimental instruments was provided by the public platform of the State Key Laboratory of Natural Medicines.

Abbreviations

DEGs, differentially expressed genes; PPI, protein–protein interaction; GDSC, Genomics of Drug Sensitivity in Cancer; O-W-F-W, osimertinib administration, withdrawal, FK866 administration, withdrawal; O-F-W, osimertinib administration, FK866 administration, withdrawal.

Ethics Approval

All animal care and experimental protocols (Approval No:2020081407) were approved by the animal ethics committee of the Pharmaceutical Animal Experiment Center of China Pharmaceutical University.

Disclosure

The authors report no conflicts of interest in this work.