Working Out Treatment Timing

By Deborah Borfitz 

March 25, 2020 | People who have erratic schedules seem to suffer more with many diseases, including certain cancers, and women with irregular sleep-wake patterns are also at heightened risk for preterm birth, says Erik Herzog, a neuroscientist and professor at Washington University as well as president of the Society for Research on Biological Rhythms (SRBR). Working with OB-GYN researchers at Washington University, his lab found similar and reliable changes in the daily rhythms of both women and mice during pregnancy.  

Pregnancy has a normal progression whereby women shift their daily schedules to an earlier time of day during their first trimester and then gradually revert to their old pre-pregnancy schedule as their body prepares for delivery, says Herzog. Tissues in the uterus and cervix also have intrinsic circadian rhythms. 

Herzog and his colleagues are now using that information to design an intervention that will help women “regularize” their erratic daily schedules to see if that reduces their risk for preterm birth, he says. Potential risk reduction strategies that will be used in the forthcoming clinical trial, funded by the March of Dimes, include educating women about the  value of going to bed and waking up at a regular time, ensuring they get enough natural light and avoiding the use of electronic devices after sunset.  

In a literature summary published (doi: 10.1126/science.aax7621) in Science last year, researchers found that in 70% of studies where time of drug administration was a variable it was an influencer of results, says Herzog. In actual practice, the drugs commonly taken at a certain time of day are those prescribed by asthma doctors and cardiologists “who recognize that there is a daily rhythm to the disease they’re treating, and outcomes are heavily dependent on when you treat.” Routine care for several types of cancer also involves treatments at a specific time of day.  

Dosage Timing For Glioblastoma 

As a neuroscientist, Herzog’s primary research interest are circadian rhythms in the brain. He describes the brain as a clock shop with the suprachiasmatic nucleus in the hypothalamus as the master clock that synchronizes daily rhythms throughout the brain and body. For example, his lab studied daily rhythms in the olfactory bulb because it’s an easy-to-identify target known to regulate our sense of smell, he says. They found that the daily rhythms in that part of the brain increase olfactory sensitivity each night. The olfactory bulb’s clock synchronizes to local time through signals from the suprachiasmatic nucleus. 

Subsequent studies focused on the clock specific to astroglial cells, which are often considered the “glue” holding the brain together, says Herzog. “We now understand they have many more important functions, including modulating synaptic communication in the brain, making them important for learning and memory.” His lab discovered that astrocytes, all by themselves, have circadian rhythms in gene expression and ATP release. 

And that had researchers in his lab wondering about the function of astrocytes at different times of the day and, for Herzog especially, in disease. Glioblastoma multiforme (GBM), a devastating cancer, is a disease where astrocytes proliferate pathologically in the brain.  

Most recently, Herzog and his team (including Drs. Joshua Rubin and Jian Campian, two oncologists at Washington University School of Medicine) have been experimenting with dosage timing of temozolomide (TMZ) in cases of newly diagnosed GBM. TMZ has been used for the past 30 years to extend the life of patients by about two and a half months, he says, but they still have only about one year from diagnosis to death.  

In a 40-patient clinical trial now underway, Herzog and his colleagues are seeking to learn if TMZ is more effective at certain times of day, as measured by outcomes such as toxicity and progression-free survival. It builds on studies in vitro where they discovered that human glioblastoma cells have intrinsic circadian rhythms and respond differently to the drug depending on when it’s administered. “Now we’re trying to understand if that has any relevance to tumors in the host and can be used as a strategy for treating people.” 

TMZ binds to DNA, causing double-stranded breaks that tumor cells then try to repair, an ability that is known to wax and wane with the daily expression of the clock genes BMAL1 and Period 2 (Per2), Herzog explains. The goal is to get the drug to the tumor when BMAL1 is at its peak expression and Per2 is simultaneously at its daily minimum—thereby compelling the tumor to “commit suicide.” 

Challenging Research 

Drug timing studies could one day translate into highly personalized medicine where doctors routinely prescribe medicines according to the sleep schedule of individual patients, says Herzog. But it may take a while. Adding a comparator arm to trials for morning vs. evening dosing easily doubles study costs and adds to study complexity. 

“We should be skeptical, so where there are no data, we should test if [treatment timing] would have a big effect,” Herzog continues. “In some cases, the data have actually suggested that it might be hard to come up with a specific time of day for a single patient.” 

Studies also occasionally yield contradictory results. One of the largest cancer chronotherapy trials to date, led by Francis Lévi, found that timed drug delivery relative to conventional chemotherapy delivery for colorectal cancer improved survival times by 25% for men but increased the risk of an earlier death by 38% for women, says Herzog.  

For better or worse, the timing of drug treatment within hospitals already happens at a standard time, says Herzog. Moving forward, researchers need to find a way to “efficiently and effectively” add treatment timing as a variable in studies. During the GBM study, his team obtained abnormal tissue samples from patients and is now working on ways to grow tumors in a dish to rapidly screen for best time-of-day treatment response. 

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