Glioblastoma, the most aggressive form of brain cancer, exploits the body’s circadian rhythms to accelerate its growth, according to new research from Washington University in St. Louis. The study, published in Cancer Cell, reveals that glioblastoma tumors sync their internal clocks with the host’s daily cycles, particularly in response to steroid hormones like cortisol.
Circadian Signals and Tumor Growth
Erik D. Herzog, PhD, senior author of the study, explained that glioblastoma takes cues from hormones released by the body’s central clock. The team demonstrated that blocking these circadian signals dramatically slowed tumor growth and progression. This discovery holds promise for optimizing cancer therapies by aligning treatment with the body's natural rhythms.
Maria F. Gonzalez-Aponte, PhD, the first author, noted that previous observations showed glioblastoma treatment outcomes varied with the time of day. "Whether we were looking at clinical data, patient-derived cells, or mice with model brain tumors, chemotherapy treatment always worked best around normal waking time," she said. This led the researchers to investigate how glioblastoma interacts with circadian signals to fuel its progression.
Impact of Dexamethasone Timing
A critical finding involved dexamethasone (DEX), a synthetic glucocorticoid commonly used to reduce brain swelling after surgery or radiation. The study revealed that administering DEX in the morning promotes tumor growth, while giving it in the evening suppresses growth. "Knowing that glioblastoma has daily rhythms, we immediately asked if time of day of DEX administration could explain these different findings, and it seems like it does," Gonzalez-Aponte stated.
To understand how glioblastoma syncs its rhythms with the host, researchers tested mice with flipped light and dark schedules. As the mice adjusted to their new "time zones," tumor cells also resynchronized their clocks. Using imaging methods, the team tracked changes in tumor clock genes, such as Bmal1 and Per2, observing that these genes adjusted in tandem with the host’s circadian rhythms.
Clinical Implications and Chronotherapy
The findings have significant clinical implications, especially concerning the timing of synthetic glucocorticoid administration like DEX. Herzog emphasized the importance of tailoring treatments to align with individual circadian rhythms. "To critically evaluate the potential for chronotherapy in different cancers, we must consider how daily rhythms arise and synchronize in specific tissues," he said.
Data from cancer databases further underscored the impact of circadian dynamics. Patients with glioblastomas expressing lower levels of glucocorticoid receptors tended to live 60% longer, suggesting that avoiding certain hormone treatments in the morning could improve survival.
These findings highlight the intricate relationship between circadian biology and cancer, suggesting that adjusting treatment timing—chronotherapy—could offer a new, personalized approach to managing glioblastoma. Herzog concluded, "We believe that this tractable and translatable approach will ultimately personalize patient care by determining when therapies should be given to cancer patients, depending on their individual circadian rhythms."
