Combination Chemotherapy of Multidrug-resistant Early-stage Colon Cancer: Determining Optimal Dose Schedules by High-performance Computer Simulation

Abstract

The goal of this project was to utilize mechanistic simulation to demonstrate a methodology that could determine drug combination dose schedules and dose intensities that would be most effective in eliminating multidrug-resistant cancer cells in early-stage colon cancer. An agent-based model of cell dynamics in human colon crypts was calibrated using measurements of human biopsy specimens. Mutant cancer cells were simulated as cells that were resistant to each of two drugs when the drugs were used separately. The drugs, 5-flurouracil and sulindac, have different mechanisms of action. An artificial neural network was used to generate nearly 200,000 two-drug dose schedules. A high-performance computer simulated each dose schedule as a in silico clinical trial and evaluated each dose schedule for its efficiency to cure (eliminate) multidrug-resistant cancer cells and its toxicity to the host, as indicated by continued crypt function. Among the dose schedules that were generated, 2,430 dose schedules were found to cure all multidrug-resistant mutants in each of the 50 simulated trials and retained colon crypt function. One dose schedule was optimal; it eliminated multidrug-resistant cancer cells with the minimum toxicity and had a time schedule that would be practical for implementation in the clinic. These results demonstrate a procedure to identify which combination drug dose schedules could be most effective in eliminating drug-resistant cancer cells. This was accomplished using a calibrated agent–based model of a human tissue, and a high-performance computer simulation of clinical trials. Significance: The results of computer-simulated clinical trials suggest a practical dose schedule for two drugs, 5-fluorouracil and sulindac, that could eliminate multidrug resistant early-stage colon cancer cells with minimum toxicity to the host.