When is the best time of day for cancer treatment?
Can the time of day at which a cancer therapy is administered optimize its effectiveness? e:Med researchers led by Dr. Adrián Granada, Charité Universitätsmedizin Berlin, show that the internal clock of cancer cells is a gap in their system that can be used therapeutically to maximize the effect of chemotherapy. The scientists used breast cancer cells to identify time windows in which the administration of drugs was particularly effective. This novel approach is a further building block in personalized cancer therapy, as it can improve treatment outcomes while minimizing side effects. The work has now been published in the journal Nature Communications.
Microscope image of a triple-negative breast cancer cell line, Granada Lab @Charité | Granada Lab
Manuela Zingl GB Corporate Communications
Charité - Universitätsmedizin Berlin
How well medication works also depends on what time of day it is taken. The reason for this is that our bodies do not always work in the same way, but according to our internal clock, also known as the circadian rhythm. However, as this is different for everyone and depends on many factors, it is difficult to tailor medication intake to the individual. Researchers at Charité - Universitätsmedizin Berlin have now developed a method that can be used to determine the optimal time for cancer treatment using the example of certain breast cancer cell lines. They describe their approach in the journal Nature Communications*.
The internal clock controls the rhythm of many bodily functions and metabolic processes: Sleep and digestion, for example. However, it is not only the organs that are more or less active at different times of the day. The individual cells also follow the rhythm of the internal clock and react differently to external influences at different times. This is of great importance for cancer chemotherapy. It is known from previous studies that the effect of chemotherapy is most effective when the tumor cells are dividing. However, this knowledge has hardly been used in clinical treatment to date.
This is why an interdisciplinary team at Charité, led by Dr. Adrián Enrique Granada from the Charité Comprehensive Cancer Center, set out to close this gap. The team set out to find the optimal time for drug administration - based on the individual circadian rhythms of the tumors.
Example of triple-negative breast cancer
"We cultivated cells from patients with triple-negative breast cancer to observe how they react to the drugs administered at different times of the day," explains Carolin Ector, research associate in Adrián Granada's team. Triple-negative breast cancer is a particularly aggressive form of breast cancer for which there are few treatment options. "Using live imaging, a technique for continuous observation of living cells, and complex data analysis techniques, we were able to precisely monitor and evaluate the circadian rhythms, growth cycles and drug responses of these cancer cells."
In this way, the researchers have identified certain times of day when cancer cells are most susceptible to drug treatments. For example, they found that the chemotherapeutic agent 5-fluorouracil worked best on a certain cancer cell line between 8 and 10 o'clock in the morning. The study also shows that certain cellular and genetic factors are decisive for this. The scientists were even able to find out which genes are decisive for the circadian effect of certain drugs. "We call these genes 'core clock genes'. They significantly influence the sensitivity of cancer cells to treatments at different times of the day," says Adrián Granada.
Profiles show reactions of cancer cell types to drugs
This approach can be used to create detailed profiles that show how different cancer cell types react to different drugs at different times. "This can help to identify the most effective drug combinations," comments Adrián Granada. "Overall, our results suggest that personalized treatment plans based on individual circadian rhythms could significantly improve the effectiveness of cancer therapies," concludes the scientist. Undesirable side effects could also be reduced.
In order for these findings to soon find their way into clinical practice, the results are to be tested in studies with a larger group of patients. "In addition, we plan to investigate the molecular mechanisms behind the circadian influences on drug sensitivity in order to further optimize the timing of treatment and identify new therapeutic targets," elaborates Adrián 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 heads the "Granada Lab", a working group specializing in systems oncology. Carolin Ector, first author of the publication, is a research associate at the CCCC and at Humboldt Universität Berlin.
The team worked closely with the Laboratory for Chronobiology at the Charité under the direction of Prof. Dr. Achim Kramer to collect complex time series data on the internal clock. The data analysis was carried out in cooperation with Prof. Dr. Hans-Peter Herzel from the Institute for Theoretical Biology at Humboldt University and the working group of Prof. Dr. Thomas Sauter from the University of Luxembourg. The study was funded by the Federal Ministry of Education and Research and the German Research Foundation, among others.
*Ector C et al. Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping. Nat Commun 15, 7205 (2024), doi: 10.1038/s41467-024-51611-3
More about this news:
For a deeper dive into the topic, you can read the interview with Dr. Granada from insideprecisionmedicine.com here
Alliance and contact person:
Dr. Adrián Granada, Charité - Universitätsmedizin Berlin