Nature explores the data being gathered about the surprising significance of time-of-day to effective medical treatment:
More than four decades of studies describe how accounting for the body’s cycle of daily rhythms — its circadian clock — can influence responses to medications and procedures for everything from asthma to epileptic seizures. Research suggests that the majority of today’s best-selling drugs, including heartburn medications and treatments for erectile dysfunction, work better when taken at specific times of day. “When you give a medication, you always know the dose,” says [oncologist Francis] Lévi, who also now works at Warwick Medical School in Coventry, UK, where he leads a team associated with INSERM, the French national biomedical research agency. “We have found that the timing is sometimes more important than the dose.”
Yet chronotherapy, sometimes called chronomedicine, remains at the fringes of clinical practice and drug-development programmes; the reasons for that are varied. Until about a decade ago, scientists could not explain the molecular underpinnings for these circadian effects. And clinical data have been inconsistent — although a couple of Lévi’s early trials, for example, showed clear benefits for people taking timed treatments, a later, larger trial produced more mixed results.
Chronotherapy enjoyed a publicity boost of sorts last year. Just a week after the NCI workshop, the Nobel Prize in Physiology or Medicine was awarded to a trio of scientists for elucidating the cellular mechanisms that control circadian rhythms. The circadian clock is a remarkable system. A central timekeeper in the hypothalamus orchestrates a network of peripheral clocks in nearly every organ and tissue of the body, turning on and off a bevy of genes, including some that encode the molecular targets for drugs and the enzymes that break drugs down. These clock genes are particularly important in cancer because they govern cell cycles, cell proliferation, cell death and DNA damage repair — all processes that can go haywire in cancer.
Some, but not all, cancers live by the clock as well, and researchers are trying to exploit their daily rhythms. When Joshua Rubin, a neuro-oncologist at Washington University School of Medicine in St. Louis, and his colleagues wanted to launch a chronotherapy clinical trial on a common and deadly form of brain tumour known as glioblastoma, they needed to check how the cancer behaved over time. So his team engineered cells from patient tumours to express luciferase — the protein that makes fireflies glow — every time core clock genes switched on. Then they watched. “It was so dynamic,” says Rubin. “Lights go on, lights go off. Lights go on, lights go off.” The team started treating the tumour cells with drugs at different times in the cells’ cycle and found that they were most sensitive to an oral drug, temozolomide, near the daily peak in expression of the core clock gene Bmal1. If patients could be directed to take this pill — part of the standard glioblastoma treatment — at the time of peak Bmal1 expression, the drug might be more effective, Rubin reasoned.
The trial is the first to apply chronotherapy in glioblastoma, and the only current trial in the United States that accounts for the circadian clock in cancer. A few previous US trials hinted that chronotherapy could be beneficial in treating ovarian, breast and non-small-cell lung cancers.