Investigating patient and tumor circadian rhythms to optimize anticancer chemotherapies
Most physiological functions of the organism display biological rhythms at different time scale or periods [1, 2]. 24h-rhythms have been observed in the rest-activity, body temprature, sleep, food intake or hormanl secretion of most mammals including the man [3, 4]. Those temporal variations are called "circadian" rhythms from latin, "circa", aound, and "dies", a day. Circadian rhythms.

Those rhythms are endogeneous and are induced by the circadian timing system (CTS) whose period is approximately 24h and is entrained by the environement such as light-dark cycles to exactly 24h  [5].

More than 30 years of research in the field of circadian rhythms have recently been acknowledged by the 2017 Nobel prize of medicine awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their discoveries of molecular mechanisms controlling the circadian rhythm [6].

The Circadian Timing System

The circadian timing system (CTS) is composed of a central pacemaker, the suprachiasmatic nuclei (SCN), located in the hypothalamus that sends physiological signals to the peripheral organs to synchronize cells. Indeed, each cell is endowed with a molecular clock composed of approximately 15 genes which are organized in several feedback loops. The SCN are themselves under the control of environmental cues such as light, physical activity or socio-professional interactions.

The temporal organization of the body induces circadian rhythms in the efficacy and toxicities of numerous drugs [9]. The disruption of the circadian timing system is often associated to an increased incidence of chronic diseases or to a poorer patient's prognosis and quality of life, in particular for cancer. In particular, the International Agency for Cancer Research of the World Health Organization (Lyon, France) published a monography concluding that : "Shift work or night work which induce circadian disruption is probably cancérogène for men (Group 2A)". Overall, recent investigations have demonstrated that chronobiology plays a critical role in the main causes of human mortality, including cancer.

The existence of biological rhythms highlights the need for time-dependent approahces in Biology and in Medicine for better understanding, preventing and treating diseases. Our laboratory propose a global vision of the circadian timing system and studies its role in carcinogenesis and in the response to anticancer chemotherapies. the transfer of experimental resultas towardsthe clinic is operated though the Clinical Unit of Cancer Chronotherapy within the Oncology department of the Hôpital Paul Brousse (Villejuif, France). Clinical investigations rely on e-Health strategies integrating longitudinal physiological measurements recorded thanks to portable non invasive devices that the patients wear in their everyday life.


Multi-scale circadian measurements

Recent technologies allow for the recording of biomarkers of the CTS at multiple scales: in Per2::luc Hepa1-6 cell culture, imposed temperature cycles (A) and Per2 bioluminescence measured by Lumicycle (B); in individual B6D2F1 male mice entrained in LD12:12, body temperature recorded by telemetry (C); and, in Per2::luc animals, bioluminescence recorded in RT-Bio (D); in individual young male healthy volunteers, skin temperature recorded though new thoracic wearable sensors (E, In Casa project), and individual Per2 mRNA level in peripheral blood mononuclear cells (F, dots are data from Teboul et al., 2005; dotted line is the best-fit cosinor model). Longitudinal measurement over several days of molecular biomarkers is currently not available in the clinics, and multiscale systems approaches aim at predicting from preclinical results and clinical investigations the patient-specific dynamical information needed for treatment personalization. Time is expressed in days. Zero represents midnight (clock hours) on the first day of experiment.


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