How effective the drugs are depends on several factors, including the time of day they are given. Why? Because our bodies don’t always work exactly the same. Instead, they follow the cycle set by their internal clock, otherwise known as the circadian rhythm. But since each person’s circadian rhythm is different and depends on many different factors, it is difficult to tailor medication schedules to an individual patient’s body clock. Researchers at Charité – Universitätsmedizin Berlin have now developed a method to determine the optimal cancer treatment time based on certain breast cancer cell lines. They describe their approach to the magazine Nature communications.
A person’s internal clock regulates the rhythm of many different bodily functions and metabolic processes, such as sleep and digestion. But organs aren’t the only things that are more or less active depending on the time of day. Individual cells also follow a cycle set by a person’s body clock, so they respond differently to external influences at different times of the day. This is extremely important for chemotherapy given to treat cancer. Previous studies have shown that chemotherapy is most effective when tumor cells are dividing. But this finding has hardly been used in clinical treatment to date.
An interdisciplinary team at Charité led by Dr. Adrián Enrique Granada from the Charité Comprehensive Cancer Center (CCCC) set out to fill this gap. The team began looking for the optimal time to deliver drugs, based on the tumors’ individual circadian rhythms.
Triple negative breast cancer as an 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 in the Granada working group. Triple-negative breast cancer is an extremely aggressive form of breast cancer, with few effective treatments available. “We used live imaging, a continuous live cell monitoring method, and sophisticated data analysis techniques to monitor and evaluate in detail the circadian rhythms, growth cycles, and drug responses of these cancer cells.”
In this way, the researchers identified certain times of the day when cancer cells are most responsive to drug-based treatments. For example, the chemotherapy drug 5-fluorouracil (5-FU) was shown to be maximally effective against a particular cancer cell line between eight and ten am. As the study also shows, the critical aspects here are certain cellular and genetic factors. Scientists have yet to determine which genes are key to the circadian effects of certain drugs.
We call them ‘core clock genes’. They have a significant impact on how well cancer cells respond to treatments given at different times of the day.”
Dr. Adrián Enrique Granada, Charité Comprehensive Cancer Center
Profiles show how cancer cell types respond to drugs
This approach can be used to create detailed profiles that show how different types of cancer cells respond to different drugs at different times. “This can help identify the most effective drug combinations,” says Granada. “Overall, our findings suggest that personalized treatment plans based on individual circadian rhythms could significantly improve the efficacy of cancer treatment,” he concludes. In addition, unwanted side effects could also be reduced.
To soon contribute these findings to clinical practice, the results should be validated in studies involving larger groups of patients. “We also plan to study the molecular mechanisms behind circadian effects on drug sensitivity to further optimize treatment times and identify new therapeutic targets,” says Granada.
About the study
The study was conducted at the Charité Comprehensive Cancer Center (CCCC) under the leadership of Dr. Adrián Enrique Granada (last author). He is in charge of the Granada laboratory there, which focuses on systems oncology. Carolin Ector, the first author of the publication, is a research associate at CCCC and a graduate student at Humboldt-Universität zu Berlin.
The team worked closely with the Department of Chronobiology at Charité, led by Professor Achim Kramer, to collect complex time-series data on the cell’s biological clocks. The data analysis was created in collaboration with Prof. Hanspeter Herzel from the Institute of Theoretical Biology at the Humboldt-Universität zu Berlin and the working group led by Prof. Thomas Sauter at the University of Luxembourg. Funding sources for the study included the German Federal Ministry of Education and Research (BMBF) and the German Research Foundation (DFG).
Source:
Journal Reference:
Ector, C., et al. (2024). Anticancer drug day effects revealed by deep high-throughput phenotyping. Nature communications. doi.org/10.1038/s41467-024-51611-3.
