Systems Cancer Chronotherapeutics: In Vitro Molecular Chronopharmacology of the Anticancer Drug Irinotecan

Chronotherapeutics aim at improving treatment outcomes through the delivery of medicines according to the Circadian Timing System (CTS), a complex hierarchical and dynamic network system involving all cells in the body. As a result, circadian timing modifies up to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. However, sex, circadian disruption and tumor protein expressions are independent determinants of the optimal chronotherapeutic schedule, in international studies involving large number of patients with metastatic colorectal cancer. Such clinical data have driven experimental confirmation studies in mice. Moreover, human cancer chronotherapeutics constitute a unique paradigm for cancer therapy, where "the lesser the toxicity, the better the efficacy", based on several land mark analyses of a randomized clinical trial involving 564 patients. Stochastic and deterministic mathematical models help analyze the dynamic interactions between circadian clocks, cell cycle and drug pharmacodynamics from single cell to whole organism. Biosimulation leads to the design of model-based optimal chronotherapeutic schedules, through the exploration of a wide range of parameter values, as shown for irinotecan. The systems approach to chronopharmacokineticschronopharmacodynamics modeling further reveals that optimal chronotherapeutics require circadian entrainment to be robust in healthy cells and disrupted in cancer cells. Moreover, optimal chemotherapy timing can vary by up to 8 h according to genotype and sex in mice, a finding similar to that observed in cancer patients. The liver circadian expression patterns of Rev-erba and Bmal1, two clock genes that regulate each other, were used as inputs into a mathematical model that was designed and enabled the identification of optimal circadian timing of irinotecan irrespective of genotype and sex. In practice, non invasive reliable circadian biomarkers are critical for modeling CTS dynamics as well as for increasing CTS robustness through intervention measures, and effectively personalizing circadian drug delivery schedules.