Gabriele Sulli

Salk Institute for Biological Studies, California, USA

https://doi.org/10.36866/pn.113.10

The evolutionarily conserved biological clocks in organisms provide temporal organisation for the performance of specific physiological functions. In humans for example, blood pressure, body temperature, blood concentrations of melatonin, insulin, corticosteroids, and adrenaline, and many other crucial physiological nodes display nearly 24-hour (=circadian) cyclic rhythms.

But what happens when the clock is perturbed or broken? In recent years, accumulating evidence suggests that disruption of circadian rhythms precedes the advent of several neurodegenerative diseases and has been causally connected with development of obesity, diabetes, cardiovascular diseases, and even the aging process (Sulli et al., 2018). In 2007, the WHO agency IARC (International Agency for Research on Cancer) even included circadian disruption caused by shift work in the list of agents probably carcinogenic to humans (IARC Working Group, 2010).

The circadian clock is a powerful regulatory machine co-governing a complex web of physiological processes. We know that alterations of the clock can have devastating consequences for the maintenance of homeostasis. Thus, we are reaching a crucial time in biology and medicine where we will need to start addressing some fundamental chronobiology questions: Can time be a crucial parameter to consider in the quest of personalised medicine? Can we exploit the clock to improve patient treatment and
derive new therapeutic strategies? Physiological research will inevitably have a major role to play in providing answers to these questions.

Already in the 1970s and 1980s, pioneering studies were underway to assess whether the timing of treatments could be an important parameter in determining outcomes via mechanisms such as reducing toxicity in cancer chemotherapy (Haus et al., 1972; Halberg et al., 2006; Hrushesky, 1985). More specifically, studies in advanced ovarian cancer patients addressed whether a carefully scheduled timing of cyclophosphamide or a combination of adriamycin and cisplatin could improve adverse drug reactions (Halberg et al., 2006; Hrushesky, 1985).

Patients treated with cyclophosphamide at 4.00 am and adriamycin in the morning and cisplatin in the evening experienced fewer toxic effects. Thus began cancer chronotherapy (Halberg et al., 2006; Hrushesky, 1985).
Chronotherapy aims to reduce adverse drug reactions and optimise drug efficacy by timing drug administration in accordance with the body’s circadian rhythms. The principle is very simple and derives from practical observations showing that patients treated at different times but with the same drug experience differential levels of toxicity or improvements in drug efficacy. With regard to the latter, if the expression of a drug target fluctuates periodically, then said drug will be more efficient if administered when the target is expressed at its highest level.

More recently, several studies have shown that evening administration of statins (especially those with short half-life) is associated with better outcomes because peak activity of HMG-CoA reductase (statin’s target) occurs in the liver at night. Other disorders where a chronotherapeutic approach could provide benefits, beyond cancer and hyperlipidaemia, include asthma, allergic rhinitis, arthritis, peptic ulcers and hypertension, inflammatory diseases, and type 2 diabetes (Sulli et al., 2018).

Further cancer chronotherapy trials have been conducted with different therapeutic agents including cisplatin, oxaliplatin, radiotherapy, folinic acid and fluorouracil in patients with breast cancer, non-small cell lung cancer, head and neck cancer, metastatic colorectal cancer, metastatic bladder cancer, metastatic endometrial cancer, metastatic renal cell carcinoma, cervical cancer, and prostate cancer. While studies with small cohorts have been promising, larger trials have unfortunately curbed in enthusiasm for this approach. Whilst the principle is simple and intuitive, in 2016 only 0.16% of clinical trials were taking the timing of the drug administration into account (Selfridge et al., 2016). One reason for the inconsistency of large trials is that each individual enrolled in a trial will have his/her own rhythms, i.e. the timing of drug target peak expression may differ between individuals. Indeed, such timing may differ on a day-to-day basis in a given individual. A late dinner or a sleepless night can have a strong impact on the circadian clock and misalign the patient rhythms with the pre-fixed timing of the drug administration.

Is chronotherapy destined to remain a beautiful concept with no practical actuation in real life? Recent innovations suggest otherwise. Technological advancements that may aid personalised chronotherapy include wearable devices to assess rest/activity cycles and light exposure and blood tests to easily check the status of circadian rhythms (Wittenbrink et al., 2018). Moreover, progress is being made on tools to automatically release drugs in time alignment with biological rhythms and will allow performance of better chronotherapy trials. Personalised chronotherapy could be the new way forward. As drug timing affects efficacy, re-evaluation of many drug candidates that have been put aside by pharma companies may be warranted. Chronotherapy, therefore, holds a lot of promise.

Beyond chronotherapy, strengthening the link between the circadian clock and medicine may lead to additional innovations. Indeed, although still in a primordial phase of development, drugs targeting circadian clock regulators may provide new therapeutic strategies against various diseases. Recently, for instance, observations showing that pharmacological modulation of REV-ERBα and REV-ERBβ (two crucial circadian regulators) is selectively lethal in cancer cells in culture and in glioblastoma animal models and it seems to have a wide therapeutic window with limited toxic effects (Sulli et al., 2018). Such observations shedding light on a new therapeutic paradigm could put the circadian clock machinery at the centre of the next pharmacological revolution. In the future, many disorders may benefit from the development of drugs targeting circadian clocks such as metabolic and mood disorders, jet lag, and others. It’s time for a new era of medicine.

References

Halberg F, Prem K, Halberg F (2006). Cancer chronomics I. Origins of timed cancer treatment: Early marker rhythm-guided individualized chronochemotherapy. Journal of Experimental Therapeutics and Oncology 6, 55-61.

Haus E, Halberg F, Pauly JE et al. (1972). Increased tolerance of leukemic mice to arabinosyl cytosine with schedule adjusted to circadian system. Science 177(4043), 80-82.

Hrushesky WJ (1985). Circadian timing of cancer chemotherapy. Science 228(4695), 73-75.

IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2010). Painting, firefighting, and shiftwork. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 98, 9-764.

Selfridge JM, Gotoh T, Schiffhauer S et al. (2016). Chronotherapy: Intuitive, sound, founded… but not broadly applied. Drugs. 76(16),

Sulli G, Manoogian ENC, Taub PR et al. (2018). Training the circadian clock, clocking the drugs, and drugging the clock to prevent, manage, and treat chronic diseases. Trends in Pharmacological Sciences 39(9), 812-827.

Sulli G, Rommel A, Wang X et al. (2018). Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351-355.

Wittenbrink N, Ananthasubramaniam B, Münch M et al. (2018). High-accuracy determination of internal circadian time from a single blood sample. Journal of Clinical Investigation 128(9),