Cancer researchers develop new method that uses tumor cells’ internal clock to optimize therapies

The effectiveness of medications depends on several factors, including the time of day they are given. Why? Because our bodies don’t always work in exactly the same way. Instead, they follow the cycle set by their internal clock, otherwise known as the circadian rhythm. But because each person’s circadian rhythm is different and depends on a number of different factors, it’s difficult to tailor the medication schedule to each patient’s body clock.

Researchers at the Charité University Hospital in Berlin have developed a method to determine the optimal timing of cancer treatment based on certain breast cancer cell lines. They describe their approach in the journal Nature Communications.

An individual’s internal clock regulates the rhythm of many bodily functions and metabolic processes, such as sleep and digestion. But it’s not just organs that are more or less active depending on the time of day.

Individual cells also follow a cycle determined by a person’s biological clock, so they react differently to external influences at different times of the day. This phenomenon is extremely important for chemotherapy used to treat cancer. Previous studies have shown that chemotherapy is most effective when tumor cells are dividing. But this discovery has so far hardly been used in clinical treatment.

An interdisciplinary team at Charité Hospital, led by Dr. Adrián Enrique Granada of the Charité Comprehensive Cancer Center (CCCC), set out to fill this gap. The team began investigating the optimal time to administer the drugs, based on the individual circadian rhythms of the tumors.

Triple negative breast cancer, for example

“We cultured cells from patients with triple-negative breast cancer to observe how they respond at different times of the day to the drugs administered,” explains Carolin Ector, a researcher associated with the Granada working group. Triple-negative breast cancer is a very aggressive form of breast cancer, for which there are few effective treatments.

“We used live imaging, a method of continuous monitoring of living cells, and complex data analysis techniques to monitor and evaluate in detail the circadian rhythms, growth cycles and drug responses of these cancer cells.”

The researchers were thus able to identify the times of day when cancer cells respond best to drug treatments. For example, the chemotherapy drug 5-fluorouracil (5-FU) showed maximum effectiveness against a certain cancer cell line between 8 and 10 a.m. As the study also shows, certain cellular and genetic factors are decisive here. The scientists were even able to identify the key genes for the circadian effects of certain drugs.

“We call them ‘central clock genes’. They have a significant impact on the responsiveness of cancer cells to treatments given at different times of the day,” Granada explains.

Profiles show how cancer cell types respond to drugs

This approach can be used to create detailed profiles showing how different types of cancer cells respond to different drugs at different times. “This can help identify the most effective drug combinations,” Granada says.

“Overall, our results indicate that personalized treatment plans based on individual circadian rhythms could significantly improve the effectiveness of cancer treatment,” he concludes. In addition, unwanted side effects could also be reduced.

For these results to be quickly applied in clinical practice, they need to be validated by studies involving larger patient groups. “We also plan to investigate the molecular mechanisms underlying circadian influences on drug sensitivity in order to further optimize treatment durations and identify new therapeutic targets,” says Granada.