Long ignored, the importance of circadian rhythms—the focus of this year's Nobel Prize in Physiology or Medicine—is beginning to gain attention from researchers interested in cancer prevention, drug discovery, and therapeutic optimization.
The three scientists awarded this year's Nobel Prize in Physiology or Medicine—Michael Rosbash, PhD, and Jeffrey Hall, PhD, both of Brandeis University in Waltham, MA, and Michael Young, PhD, of Rockefeller University in New York, NY—used fruit flies to discover the molecular mechanisms controlling circadian rhythm. However, the same principles are at play in human cells and have implications for cancer prevention and treatment.
“The circadian clock is a missing link in understanding variability and heterogeneity in cancer biology,” says Chi Van Dang, MD, PhD, scientific director of the Ludwig Institute for Cancer Research in New York, NY. “This is a whole new area that needs to be explored.”
The body's internal timekeeper regulates a variety of normal cell functions, including cell division and proliferation. Throw off the rhythmicity of clock-controlled genes and cancerous growth can take hold (Cell Metab 2016;24:324–31). That explains why working the night shift seems to boost the chances of developing cancer—a finding that prompted the International Agency for Research on Cancer to classify night-shift work as a probable carcinogen in 2007.
When normal light/dark cycles are perturbed, aberrant expression of circadian clock genes such as PER2, BMAL1, or REV-ERBα occurs. This has consequences for senescence, metabolism, and DNA damage repair at the cellular level. These clock genes are therefore thought to serve as both molecular pacemakers and tumor suppressors (Nat Rev Cancer 2003;3:350–61). Many oncogenes, including MYC and RAS, have similarly been linked to circadian dysregulation.
Armed with that knowledge, researchers are exploring therapeutic strategies to boost expression of tumor-suppressing clock genes. For example, Eveline Barbieri, MD, PhD, of the Texas Children's Hospital in Houston, presented data earlier this month at the MD Anderson 2017 Symposium on Cancer Research showing that a RORα agonist can stimulate BMAL1 activity in neuroblastoma cells, leading to a dramatic reduction in tumor growth, both in cell cultures and in mouse models. “We think we have a tool now for restoring the clock,” Barbieri says.
Meanwhile, others are focused on optimizing the timing of administration of existing drug therapies to maximize benefit and minimize toxicity. The premise for chrono-modulated therapy rests on the asynchrony of both cancer and healthy cells in their activity of core clock-regulated pathways, including those involved in drug metabolism and cell division.
In fact, several studies led by Francis Lévi, MD, PhD, of the University of Warwick Medical School in Coventry, UK, have shown that there are certain times of day when chemotherapy will be most injurious to cancerous cells and least damaging to healthy ones, thus minimizing side effects and boosting survival rates (Ann Med 2014;46:191–207).
In addition to clock-related differences between tumors and healthy cells, circadian rhythm can vary from one cancer cell to the next. “This has huge implications on aspects of tumor heterogeneity,” says Thales Papagiannakopoulos, PhD, of New York University School of Medicine, NY, “which could help explain differences in responses to therapy.”
Recognizing the importance of circadian processes in cancer development and patient outcomes, the NCI recently announced funding for circadian rhythm–related research as part of its Provocative Questions Initiative. Also, in late September—less than a week before the Nobel announcement—the institute convened a 2-day workshop to assess the state of the science on the topic and discuss the development of a circadian clock atlas.
Although most cancer biologists have long ignored circadian cycles, “it's definitely gaining more traction,” Papagiannakopoulos says. –Elie Dolgin
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