Circadian biology in brain cancer diagnosis and treatment

Glioblastoma (GBM), the most common and lethal primary brain cancer, has a median survival of 15 months. Despite repeated efforts over 20 years to introduce life-extending therapies, little has changed in the standard of care. Recent studies have revealed that GBM cells express daily rhythms in gene expression and sensitivity to chemotherapy. In this review, we highlight the role of circadian biology in GBM growth, and its potential applications to GBM diagnosis and treatment. The hallmarks of cancer often show daily variation. We emphasize opportunities to advance our understanding of glioblastoma pathophysiology by considering how brain tumors integrate into the host circadian system and respond to daily rhythms in neuronal, paracrine, or hormonal signals to promote growth. Circadian treatment strategies include disrupting daily rhythms in GBM cells, blocking their synchronization to the host, or finding best times of day for biopsy, surgery, radiation, or chemotherapy. We discuss an ongoing temozolomide chronotherapy trial in the context of recent evidence against chronotherapy and suggest ways to critically assess time-of-day effects in GBM. With over 500 active clinical trials for GBM, it is time to evaluate, and control for, circadian rhythms in care for brain cancer patients.