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THE RHYTHM OF LIFE: CHRONOTHERAPY AND CANCER CARE

BY ANDREA MONGLER
chronotherapy

Wake, sleep, repeat. Day in, day out. It’s a pattern we’re so familiar with that most of us give it little, if any, thought. The sleep-wake cycle is simply one of life’s daily rhythms. In fact, it’s one of our circadian rhythms. Put simply, circadian rhythms are physical, mental and behavioral changes that our bodies experience over a 24-hour cycle. They affect our sleep, our body temperature, our appetite, our hormones and more. And it turns out these daily rhythms may play a key role in cancer treatment.

A coordinated concert of cells

Circadian rhythms are controlled by “clock genes” in our cells. While every cell has around 20,000 genes, just a handful of these are clock genes. Despite their small number, their impact is huge. Because of clock genes, for example, you may grow tired around the same time each night and wake up around the same time each day. This circadian rhythm is your body’s way of making sure you get the sleep you need. Of course, many of us wake by alarm clocks, which interrupt our circadian rhythms.

When clock genes are disrupted, they in turn disrupt daily rhythms like the sleep-wake cycle. Anyone who’s ever had jet lag has experienced this firsthand.

Clock genes get their name because they function as miniature clocks, each with the ability to keep time on its own. In addition, these mini-clocks are synchronized with each other thanks to a central clock, technically called the suprachiasmatic nucleus (SCN) but commonly referred to as the circadian clock.

WHEN WE’RE THINKING ABOUT THE BEST TIME TO TREAT PEOPLE, WE NEED TO THINK ABOUT WHEN THEY NORMALLY GO TO SLEEP. CONSIDERING THE FACT THAT PEOPLE ARE DIFFERENT FROM EACH OTHER IN THEIR DAILY TIMING, THIS ENDS UP BEING SORT OF THE ULTIMATE PERSONALIZED MEDICINE.

ERIK HERZOG, PHD, CHRONOBIOLOGIST

Erik Herzog, PhD, a chronobiologist at Washington University, compares the SCN to the Atomic Clock in Boulder, Colorado. The Atomic Clock keeps extremely accurate time, and clocks nationwide—on our computers and smartphones, for example—are synchronized to match it. Similarly, the SCN sends out signals in the body to coordinate all of the mini-clocks in our genes. “The SCN is this tiny little population of cells in the brain that’s like a conductor for the clock genes throughout the body,” Herzog says. “The result is a coordinated concert of cells that sings together on a daily basis.”

Differences in circadian rhythms

Everyone sleeps, wakes and eats—but when we do these things can vary greatly from person to person. This is due in part to differences in our circadian rhythms. And these differences can be partly attributed to genetics—specifically to the clock genes we inherit from our parents. Just like a certain eye color or above-average height is more common in some families, different families have different types of clock genes.

Circadian rhythms also vary by age. This is why newborns sleep so much and teens tend to stay up late and sleep in. (Despite what their parents may say, they’re not just lazy.) Circadian rhythms also vary by sex, though researchers aren’t sure why. But regardless of age or sex, Herzog says most people’s clock genes synchronize to the local light-dark cycle—and their circadian rhythms respond accordingly. As a result, most people sleep at night and stay awake during the day. This is true even in places that have near-constant light in summer and near-constant dark in winter.

“Your circadian rhythms synchronize to your local schedule, which lets your body anticipate, for example, when your next meal might be coming or how to make it through the night without food and drink for eight hours,” Herzog says. Indeed, your metabolism varies predictably with time of day, not just based on when you eat or sleep.

chronotherapy
THE SUPRACHIASMATIC NUCLEUS (SCN) LIVES IN THE BRAIN AND INTERACTS WITH DAYLIGHT.
ILLUSTRATION COURTESY OF SCIENCE PHOTO

People whose circadian clocks have trouble synchronizing to the local light-dark cycle are at increased risk for certain health problems. So are people who aren’t synchronized to the light-dark schedule because they work night shifts or experience frequent jet lag. Possible health problems include sleep disorders, obesity, diabetes, depression, bipolar disorder and seasonal affective disorder. While circadian rhythms may contribute to these health problems, they may also play an important role in the treatment of many diseases and conditions.

Circadian rhythms in cancer treatment

Treating cancer is one of the biggest challenges in the field of medicine. The disease is the second-leading cause of death in the United States, and the National Cancer Institute estimates that four in 10 people in the United States will be diagnosed with cancer at some point during their lifetimes.

Through the years, researchers have continued to develop new treatments that work better and are less toxic to patients. But most physicians have given little thought to the time of day those treatments should be delivered. Researchers at Washington University School of Medicine want to change that. They’re interested in using the body’s circadian rhythms to coordinate the timing of chemotherapy, which could maximize effectiveness and minimize side effects. The idea is that because clock genes cause changes in cells throughout the day, cancer cells may be more receptive to treatment at certain times—and healthy cells may be less prone to toxic effects.

Known as chronotherapy or circadian medicine, the practice of incorporating the body’s circadian rhythms into treatment is sometimes viewed skeptically by clinicians. “Many oncologists have doubts that giving a drug at different times [of day] could really make a difference in outcomes,” says Jian Li Campian, MD, PhD, Washington University neuro-oncologist at Siteman Cancer Center’s Brain Tumor Center. “But we’re hoping that our research will open the door so that people will see circadian medicin is worth looking into for cancer treatment.”

In a randomized controlled trial, Campian and colleagues gave 27 participants, all with an aggressive form of brain cancer called high-grade glioblastoma, a chemotherapy drug called temozolomide. While all patients received the drug, they were randomly selected to take it either before 10 a.m. or after 8 p.m.

Reporting on the results of an early phase of the trial, Campian says the team found that the group who received the drug in the morning had more side effects—and more serious side effects—than the group who received the drug at night. In another phase of the trial, the researchers are studying whether the time of drug delivery affects the drug’s efficacy.

In addition, the team is studying tumor cells from people with glioblastoma. Specifically, they add something called luciferase—the enzyme that makes fireflies glow—to the cells so that the cells light up when core clock genes switch on. Then they treat the cells with temozolomide at different times in the clock genes’ cycles to see when the drug is most effective at killing the cancer cells. Essentially, this is the same idea being studied in the aforementioned clinical trial.

NEURO-ONCOLOGIST JIAN LI CAMPIAN
NEURO-ONCOLOGIST JIAN LI CAMPIAN, MD, PHD, PICTURED HERE, AND COLLEAGUES ARE WORKING TO UNDERSTAND WHETHER THE TIME OF DAY A CANCER DRUG IS GIVEN MIGHT ENHANCE ITS EFFECTIVENESS.
PHOTO BY GREGG GOLDMAN

“While we’re still analyzing the data from our trial, we can say that it’s very novel data,” says Joshua Rubin, MD, PhD, a Washington University pediatric neuro-oncologist who treats patients through Siteman Kids at St. Louis Children’s Hospital. “We’re excited to report on it and move on to another study looking at chronotherapy.”

The data are novel in part because the Washington University School of Medicine team’s study currently is the only cancer chronotherapy trial in the United States. But while chronotherapy is little known and little used in cancer treatment, it’s quite common in other branches of medicine.

Circadian medicine in other fields

In both cardiology and pulmonology, chronotherapy is standard practice. Some asthma drugs, for example, are designed to be released into the body at night, when many people suffer worse symptoms because of the circadian variation in lung function.

Similarly, the risk of heart attack is higher in the early morning, in part because the body’s levels of a blood-clotting substance peak at that time. As a result, cardiologists prescribe clot-busting drugs specifically intended to reduce the risk of early-morning heart attacks. And people with adrenal insufficiency—which means their adrenal glands don’t make enough of certain hormones— take hydrocortisone in the morning, which is when most people have a natural spike of the hormone (called cortisol in its non-medicine form).

In a review of more than 100 clinical trials, researchers at Cincinnati Children’s Hospital and the University of Pennsylvania found that 85% of drugs with half-lives of less than 15 hours had different effects when given at different times of the day. (A half-life is the time it takes for the amount of drug in the body to be reduced by half.) “These findings have exciting implications for the cancer field and beyond,” Campian says. “When it comes to cancer, if we can see a benefit just by changing the time when the patient takes a drug, we may be able to save time and money and, most important, save lives.”

Gaining support for “the ultimate personalized medicine”

While the Washington University research team looked at two general time frames—after 8 p.m. and before 10 a.m.—in their clinical trial, they note that for any one person, the most effective time to give a drug is specific to their individual circadian rhythm. “When we’re thinking about the best time to treat people, we need to think about when they normally go to sleep,” Herzog says. “Considering the fact that people are different from each other in their daily timing, this ends up being sort of the ultimate personalized medicine.”

But despite the potential of circadian medicine for individualized cancer treatment, there remains a lack of knowledge about—and interest in—the field. Campian, Herzog and Rubin note that there are a number of reasons for this. One is simply that taking circadian rhythms into account would be a significant shift in the typical approach to cancer care, which often involves accommodating patients’ lifestyles.

Herzog reiterates that because many clinicians think chronotherapy will be difficult to implement and may have only a small effect on cancer outcomes, they tend to think it’s not worth studying. His hope is that ongoing research, like the Washington University clinical trial, will help convince them otherwise.

In addition to this trial, the research team recently finished analyzing data from hundreds of people with glioblastoma who were treated with temozolomide. They looked at a variety of factors, including how long these people were treated with the drug, how well they responded and how long they survived. And because some of the patients took the drug at night and others in the morning, the researchers were able to see if outcomes differed between those dosed at night and those dosed in the morning.

While they can’t share the results yet, Campian is hopeful that the research will garner attention. “I think the more data we can provide that shows what happens when people take the drug at different times, the more interest will grow.”


Additional reading

To learn more about the trial involving Jian Li Campian, MD, PhD, and colleagues, visit: ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.e14035

Read the published review by researchers at Cincinnati Children’s Hospital and University of Pennsylvania: biorxiv.org/content/10.1101/570119v1.full

Targeting the clock machinery

time illustration

Timing the delivery of a medicine based on circadian rhythms isn’t the only form of circadian medicine. Some researchers are also interested in targeting components of the circadian clock itself.

In a study in mice, published in the journal Nature, researchers at Salk Institute for Biological Studies; University of California, Irvine; and University of Texas MD Anderson Cancer Center targeted circadian clock components called REV-ERB proteins, which repress biological functions, including cell division and cell metabolism: the things cancer cells depend on. The team used compounds that activate REV-ERBs and found that these compounds killed cancer cells (including those in the brain, colon and breast) without killing healthy brain or skin cells.

The findings suggest that drugs that activate REV-ERB proteins potentially could be used to treat several different cancer types.

Learn more about this trial: nature.com/articles/nature25170?sf179336257=1


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