Glioblastoma, the most aggressive form of brain cancer, has found a way to exploit one of the body’s most fundamental processes: circadian rhythms. New research from Washington University in St. Louis shows that glioblastoma tumors sync their internal clocks with the host’s daily cycles to drive growth, particularly in response to the body’s release of steroid hormones like cortisol. The findings, published in Cancer Cell, reveal a novel mechanism that could transform how this lethal cancer is treated.
“Glioblastoma takes its cues from hormones released by the same central clock in the host that establishes the body’s regular daily rhythms,” explained Erik D. Herzog, PhD, senior author of the study. The team demonstrated that blocking circadian signals dramatically slowed tumor growth and progression, a discovery that holds promise for optimizing cancer therapies.
The research builds on earlier observations that glioblastoma treatment outcomes vary 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,” said first author Maria F. Gonzalez-Aponte, PhD. These insights led the researchers to explore how glioblastoma interacts with circadian signals to fuel its progression.
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,” said Gonzalez-Aponte.
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 innovative 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.
The findings have profound clinical implications. Synthetic glucocorticoids like DEX are widely used in glioblastoma care, but these results suggest that timing their administration could significantly affect tumor growth. 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. As 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.”
