Could Harnessing the Body’s Circadian Rhythm Strengthen Cancer Treatment?

Illustration by Charlie Layton

Circadian rhythm is a series of processes that occur cyclically during a 24-hour period and are controlled by biological clocks. These clocks are present in nearly every cell in our body, instructing them how to behave. White blood cells, for example, possess these internal clocks that command them to migrate to lymph nodes at a certain time and back to the blood at another time. This is a perpetual daily oscillation occurring throughout the life of the organism.

These cellular clocks can be entrained or influenced by exposure to light or other stimuli which can reset or disrupt the cellular circadian rhythm. Disruptions to this normal rhythm, from shift work or other stimuli, have been shown to increase the risk for certain diseases including obesity, diabetes and cancer.

A 2022 study published in the journal Nature showed that breast cancer is more likely to metastasize at night. This effect appears to be influenced by the circadian nature of several steroid hormones. Another study in Nature demonstrated that the time of day a tumor is injected into a mouse dictates how rapidly that tumor grows and the overall immune response to the tumor.

These thought-provoking results suggest that cancer evolves ways to take advantage of the body’s natural circadian rhythm. They also beg the question: Can we leverage the circadian rhythm to improve
cancer treatment outcomes?

This area of research, known as circadian medicine, works to harness the body’s natural rhythm to enhance treatment efficacy and/or reduce its toxicity. Chronomodulation of cytotoxic chemotherapy–
synchronizing it with the body’s circadian rhythm–was investigated by Dr. Francis Lévi of France in the late 1990s. He found that chronomodulation of three conventional chemotherapies (oxaliplatin, fluorouracil and folinic acid) improved outcomes and reduced side effects for patients with metastatic colorectal cancer. This approach failed to gain significant traction as scientific trends moved in other directions, including a focus on targeted therapy.

Cancer therapy has shifted in the intervening decades—in part, to drugs that stimulate the immune system, known generally as immunotherapy. Immune checkpoint inhibitors—including ipilimumab (Yervoy), pembrolizumab (Keytruda) and nivolumab (Opdivo)—have improved survival for many different types of cancer, including melanoma.

Given that white blood cells, the target of these immune checkpoint drugs, have an oscillatory circadian rhythm, my colleagues and I hypothesized that chronomodulation of immune checkpoint inhibitors may improve their efficacy. In our initial study, we focused on patients with metastatic melanoma (stage IV) who were treated at Winship Cancer Institute of Emory University, starting in 2012. In this retrospective analysis, we found that patients who received a larger percentage of their immunotherapy cycles earlier in the day had improved clinical outcomes, including longer survival. Similar results also have been seen in non-small cell lung cancer and metastatic kidney cancer.

These compelling results still need to be validated in a gold-standard randomized clinical trial. Funding for this next step has been challenging to secure, but progress is being made.

Currently, circadian medicine is still in its infancy. Our understanding of how anti-cancer drugs and other medications interact with the circadian rhythm is inadequate. Given the pace of research, however, we anticipate many exciting discoveries in the coming decades.