On the way to chronotherapy – Lessons from our internal clock
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Researchers of the e:Med junior research alliance DeepLTNBC, under the supervision of Dr. Adrián Granada, set sail to unlock the circadian clock of breast cancer in an effort to better understand its role in this heterogeneous type of cancer. They recently published the results of two investigations, revealing crucial insights into the dynamics of circadian rhythms in breast cancer cells and their effect on drug-response.
The body’s natural rhythm, governed by the circadian clock, regulates key processes at the molecular, cellular, and organism level. The circadian clock is known to have an impact on cancer cells but there is not enough research to fully leverage this knowledge for cancer treatment. For example, administering cancer therapy in a time-of-day dependent manner can improve its efficiency while minimizing the side effects, a treatment concept called chronotherapy. However, the underlying mechanisms by which the circadian clock affects cancer biology remain poorly understood.
Researchers of the e:Med junior research alliance DeepLTNBC, under the supervision of Dr. Adrián Granada, set sail to unlock the circadian clock of breast cancer in an effort to better understand its role in this heterogeneous type of cancer. They recently published the results of two investigations, revealing crucial insights into the dynamics of circadian rhythms in breast cancer cells and their effect on drug-response.
Like the ocean waves, the circadian rhythm has a period and an amplitude , whereby this has a rhythm of roughly 24 hours. The scientists first aimed to quantify these parameters to better understand the rhythm of breast cancer cells. “We developed a deep circadian phenotyping method to discern the circadian clock characteristics in tumor cells” explained Dr. Granada. By using high-resolution bioluminescent tracking of two core clock genes, Bmal1 and Per2, combined with quantitative time-series analysis, the team identified four circadian subtypes among 14 breast cancer cells: functional, weak, unstable, and dysfunctional clocks. Contrary to previous assumptions, certain models of aggressive cancer types, such as Triple Negative Breast Cancer (TNBC), exhibit a strong intrinsic circadian rhythm. To explore potential clinical implications, the scientists investigated whether circadian features could distinguish between drug-sensitive and drug-resistant cancer cells. While the relationship varied across treatments, a striking example emerged with cisplatin, a DNA damage response (DDR)-targeting agent, where circadian characteristics were strongly associated with sensitivity. “In our work, we introduced the chronosensitivity index to quantify the impact of circadian clock features on drug response,” added first author Dr. Carolin Ector. The drugs with a high chronosensitivity index may benefit from timing strategies that align with a patient’s biological clock. These findings provide a critical foundation for advancing chronotherapy, adding another level of control to fine-tune chemotherapy. Highlighting its significance for the broader scientific community, this study was featured on the cover page of the April 2025 volume of the Molecular Systems Biology journal.
To further explore the circadian clock’s role in drug response, the scientists combined mathematical modeling with experimental data to identify how treatment timing can maximize efficacy. In their second study, led by Dr. Nica Gutu, this integrative approach systematically uncovered the key factors influencing drug effectiveness. “Both circadian factors as amplitude, period and decay rate of the clock signal as well as non-circadian factors like drug stability, cell growth characteristics, and assay duration, shape time-of-day drug response profiles,” explained Dr. Granada. Moreover, this newly developed method can be used to improve drug screening efforts.
These two studies bring us a major step closer to integrating circadian biology into cancer research. By identifying tumor-specific rhythms and modelling drug timing effects, the researchers investigated therapies that are not just targeted to a patient’s genes—but also to their internal clock. The implications of these findings extend beyond breast cancer, offering a framework to optimize when we treat, not just how.
Further details about these works can be found at granadalab.org
e:Med Junior Research Alliance and Scientific Contact:
Dr. Adrian Granada
Charité Comprehesive Cancer Center
E-mail: adrian [at] granadalab [dot] org
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Original publications:
Carolin, E., D. Jeff, D. Landtsheer Sébastien, S. Nordentoft Malthe, S. Christoph, K. Ulrich, H. Hanspeter, K. Achim, S. Thomas, and E. Granada Adrián (2025). "Circadian clock features define novel subtypes among breast cancer cells and shape drug sensitivity." Molecular Systems Biology. https://doi.org/10.1038/s44320-025-00092-7.
Gutu, N., H. Ishikuma, C. Ector, U. Keilholz, H. Herzel, and A. E. Granada (2025). "A combined mathematical and experimental approach reveals the drivers of time-of-day drug sensitivity in human cells." Communications Biology 8(1): 491. https://doi.org/10.1038/s42003-025-07931-1