Every cell in the human body operates on an intricate internal schedule, governed by circadian rhythms that synchronize our biological processes with the 24-hour cycle of day and night. Coordinated by a master clock in the brain called the suprachiasmatic nucleus, these cellular clocks control essential bodily functions including sleep-wake cycles, hormone production, immune function, and metabolism. When these internal clocks are disrupted, the consequences can be profound, potentially increasing our vulnerability to diseases including cancer.
Chi Van Dang, Bloomberg Distinguished Professor of Cancer Medicine at Johns Hopkins University and CEO and scientific director of the Ludwig Institute for Cancer Research, is at the forefront of research exploring the connection between circadian biology and cancer: how the circadian clock affects tumor biology, and how these clocks can be exploited and even manipulated for therapeutic purposes.
Dang has dedicated his career to understanding the molecular mechanisms driving cancer development and progression. He has spent decades investigating how cancer cells hijack normal cellular processes to fuel their uncontrolled growth. With support from the National Institutes of Health, his work has revealed critical insights into cancer metabolism and the genetic changes that transform healthy cells into malignant ones.
Dang's interest in circadian cancer biology began with a molecular discovery while studying the MYC oncogene, a cancer-driving gene that acts as a switch, altering metabolic pathways in cancer cells. Dang found that MYC proteins bind to the same DNA sequence to regulate gene expression as circadian clock proteins.
"This overlap sparked a key question for me: Could these two systems be interconnected?" Dang says. "It is incredibly fascinating to learn how many things are actually controlled by our circadian clocks, but we didn't realize it. Everyone is talking about fighting cancer and developing new treatments, but most people typically don't factor in our circadian rhythm. There's so much more to be discovered."
Image caption: Chi Van Dang
Image credit: Will Kirk / Johns Hopkins University
Dang says federal support has allowed him follow new leads in the fight against cancer.
"My NIH-funded work over the years has led to industry efforts in creating medicines targeting metabolism for the treatment of cancer," Dang says. "Ongoing federal research support is crucial for opening up new research avenues and hopes for new cures. Our current work on how the circadian clock and diet affect cancer immunotherapy responses should provide key insights that will improve outcomes for cancer patients."
Dang spoke with the Hub about the connection between the body's internal clock and cancer, why the timing of medical interventions could be as crucial as the treatment itself, and what health care providers, researchers, and the general public need to know about circadian biology's role in medicine.
What is the connection between circadian rhythm and cancer?
The connection between circadian rhythm and cancer is supported by extensive research across multiple domains. Large epidemiological studies following tens of thousands of people have shown that night shift work is associated with an increased risk of breast cancer, with longer exposure leading to higher risk. The International Agency for Research on Cancer has classified night shift work as "probably carcinogenic to humans." Animal studies reinforce this connection. Mice with genetically induced lung cancer developed significantly more tumors when exposed to disrupted light cycles that simulate night shift work, and mice genetically engineered to lack the BMAL1 gene, which is crucial for maintaining the body's circadian rhythm, developed more tumors and died sooner.
The other aspect to consider is the internal clock specifically of the cancer cells. Analysis of the Cancer Genome Atlas, which contains genetic data from tens of thousands of human tumors, revealed that many cancers, including liver, breast, lung, and pancreatic cancers, showed a disrupted genetic pattern associated with the loss of the clock, meaning that these cancer cells no longer had an internal clock. Interestingly, not all cancers respond the same way to circadian disruption. While most show increased tumor burden, two cancers involving stem cells—leukemia and glioblastoma—actually resulted in higher survival rates when the internal clock was disrupted, suggesting that these cancers rely on a steady circadian rhythm.
How can we use what we know about our circadian clocks and how they impact tumor growth to increase the efficacy of cancer treatments or reduce side effects?
The evidence that some therapies are more effective at certain times of day than other times is becoming increasingly solid. There are some chemotherapies that work better at specific times of day, for instance. Another example is that patients who receive radiation therapy in the afternoon experience more side effects than patients who receive it in the morning.
An area that is developing incredibly rapidly at the moment and shows great promise for treating cancer is immunotherapy. Across multiple clinical trials in recent years, it was shown very clearly that patients who receive immunotherapy in the morning do better than patients who get it in the afternoon. We're just starting to understand the underlying mechanisms.
Immunotherapy awakens lymphocytes, the body's immune cells, to fight against cancerous cells in a tumor. These professional killer cells travel in and out of the tumor while fighting it; they don't stay in the tumor. The fascinating thing that was discovered only recently is that they do this in a circadian fashion—lymphocytes enter the tumor more in the morning than later in the day. So administering a drug to activate these killer cells at a time of day where you'll have more of them going into the tumor allows them to kill better.
One focus of my research right now is going back through existing data in patient records to see if we can substantiate what has been observed in the clinic. We always have patients who respond to treatment and, unfortunately, patients who don't respond. I want to see if we can find out when these patients received treatment, and if links between timing of treatment and its effectiveness are specific to certain types of cancers.
How feasible is it to implement circadian rhythm-based cancer treatment schedules in current clinical settings?
There are some practical issues that are going to be a challenge. In a clinic, we can't fit all of the patients into a limited time window. We need to find innovative ways to work around this physical limitation. One approach would be to investigate if there are ways to deliver some of these sophisticated therapies to people in their homes. Another possibility—which still needs much more research to see how and if this can be done—could be to reset a patient's internal clock. Our circadian clocks are set by the sun. If we could figure out how to pharmacologically mimic the daily resetting of the clock, patients treated in the afternoon could potentially receive the same benefits as those treated in the morning. It would also be interesting to see if changing meal times could adjust a person's internal clock. We know that our internal clocks function better with time-restricted eating. There have also been studies that showed that animals with time restricted feeding exhibited lower cancer incidence than animals whose feeding time was not restricted. There are currently clinical studies being done to investigate whether time-restricted eating leads to better outcomes for cancer therapies in people.
Aside from cancer treatments, do circadian rhythms impact the effectiveness and side effects of other medications? Are there other classes of drugs that could benefit from circadian-informed timing?
Yes, research has shown that many drugs work better when taken at specific times of the day. For example, it has been shown time and time again that taking a low dose aspirin in the evening lowers a person's blood pressure more than if taken in the morning. Many people take aspirin to decrease the risk of heart attacks but don't know that taking it at a certain time of day increases its effectiveness. Another example is statins, medications that are broadly used for high cholesterol. It has been shown very clearly that statins are most effective when taken at night, because that's when the levels of the enzymes they block are highest.
A lot of drug metabolism is done in the liver. Within the liver, various enzymes are responsible for metabolizing these drugs, and their number and activity levels increase and decrease in a circadian rhythm. This means if you take a medication at a certain time of day when the enzymes that break it down are highly active, the drug may be metabolized more quickly. This dynamic underscores the importance of understanding the timing of drug administration in relation to circadian biology, an aspect that is often overlooked.
When it comes to aligning medication and treatment timing with the body's circadian rhythm, what roles do different stakeholders—researchers, pharmaceutical companies, health care providers, and patients—play in making this approach effective?
The first piece of the puzzle is education: There needs to be more education about circadian biology. This should start in medical school. Health care providers should be knowledgeable about the fact that circadian biology affects physiology and pathology in order to most effectively treat their patients. And then providers, in turn, need to educate patients and the community at large about circadian biology. For medications, this can be as simple as letting patients know when you prescribe a medication that it's most effective when taken at a certain time of day. It's also important to educate the public about other aspects of circadian biology that impact their health. Several studies have shown that eating at the wrong time of day disrupts a person's clock, so eating at the proper times is important for your health.
The second piece is that there should be a greater investment in research to optimize drug effectiveness by taking advantage of the circadian clock. Pharmaceutical companies should take more initiative to enhance their products by prioritizing research in this area, and when a new drug is developed, researchers should investigate its pharmacokinetics—the way the body absorbs, distributes, metabolizes, and excretes the drug—at different times of day. There is so much more to be discovered in this area that can make a real difference in clinical practice and patient outcomes.
What's next in your research?
We are currently investigating how disrupting the circadian clock in cancer cells of various types of cancer—such as breast cancer, melanoma, and colon cancer—affects tumor growth and immune system responses. Our preliminary findings suggest that the impact is tumor-type specific. For instance, removing the clock in breast cancer cells leads to faster tumor growth, so a disrupted clock gives the tumor cells an advantage. My hypothesis behind this is that the body's clock acts as an "orchestra leader" for all of the cells in our body, and at night, the metabolism winds down and the body rests, but cancer cells ignore these signals to continuously proliferate.
We are also exploring the impact of manipulating diets, specifically through time-restricted diet and fasting, as food is a cue for our internal clocks. So far, we have seen slower tumor growth and enhanced effectiveness of immunotherapy as a result of the diet manipulation. We think this may somehow be resetting the clock. Our next steps involve examining whether these dietary manipulations still yield benefits when the circadian clock is disrupted in tumor cells or even the whole organism, as well as investigating the mechanisms involved in the immune response and how exactly they are impacted by the body's clock.
