A Circadian Clock Transcription Model for the Personalization of Cancer Chronotherapy

Circadian timing of anticancer medications has improved treatment tolerability and efficacy several-fold, yet with inter-subject variability. Using three C57BL/6-based mouse strains of both sexes, we identified three chronotoxicity classes, with distinct circadian toxicity patterns of irinotecan, a topoisomerase I inhibitor active against colorectal cancer. Liver and colon circadian 24-h expression patterns of clock genes Rev-erbα and Bmal1 best discriminated these chronotoxicity classes, among 27 transcriptional 24-h time series, according to Sparse Linear Discriminant Analysis. An 8-hour phase advance was found both for Rev-erbα and Bmal1 mRNA expressions and for irinotecan chronotoxicity in clock-altered Per2m/m mice. The application of a Maximum-A-Posteriori Bayesian inference method identified a linear model based on Rev-erbα and Bmal1 circadian expressions that accurately predicted for optimal irinotecan timing. The assessment of the Rev-erbα and Bmal1 regulatory transcription loop in the molecular clock could critically improve the tolerability of chemotherapy through a mathematical model-based determination of host specific optimal timing. Major findings: The optimal circadian timing of an anticancer drug was predicted despite its variation by up to 8-h along the 24 h among six mouse categories. This prediction relied on a mathematical model using liver circadian expression of clock genes Rev-erbα and Bmal1 as input data and treatment tolerability as output parameter.