Chronotherapy Could Make Cancer Treatments More Effective, Here’s How

Chronotherapy Could Make Cancer Treatments More Effective, Here

Chi Van Dang generally declines to discuss the science that made him famous. A leading authority on cancer metabolism, he routinely is asked to speak about how tumors reprogram biochemical pathways to help them slurp up nutrients and how disrupting these noxious adaptations could be a powerful approach to treating cancer. Instead of doing so, Dang uses his soapbox at every research meeting, lecture and blue-ribbon panel to advocate for something else: a simple yet radical tweak to how oncologists administer cancer drugs.

The approach, known as chronotherapy, involves timing delivery of drugs to minimize side effects while maximizing effectiveness. The idea is to synchronize therapy with the body’s natural 24-hour rhythms — the circadian clock — and striking when cancer cells are most vulnerable or when healthy cells are least sensitive to toxicity (or, ideally, both).

Dang didn’t set out to become an ambassador for this field. But as scientific director of the Ludwig Institute for Cancer Research, a nonprofit that funds cancer labs worldwide, and chair of the board of scientific advisers at the National Cancer Institute, he finds himself in a powerful position to reshape the research agenda — and he believes chronotherapy’s time has come.

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It is not an entirely new concept. Some trials in the 1980s and 1990s showed dramatic reductions in toxicities and extended survival times among cancer patients who were treated in a clock-optimized fashion. But mostly “it’s just always been on the fringe,” says Dang. “There weren’t that many card-carrying cancer biologists like me getting into it.”

Until now.

Researchers are finding new ways to administer old drugs and they are devising clever tactics for rewiring aberrant clocks. They are transforming a strategy long dismissed as complementary or alternative medicine into rigorous science. Last year, the NCI — the largest funder of cancer research in the world — put out a call for grant applications from scientists seeking to understand how circadian processes affect tumor development and the responses of patients to therapy.

“It’s capturing people’s interest,” Dang says.

A slender and bespectacled 63-year-old with the confident and unhurried voice of a seasoned physician, Dang cites his father — Chieu Van Dang, Vietnam’s first neurosurgeon and a former dean of the University of Saigon School of Medicine — as a role model. His father’s death from liver cancer in 2004 remains an inspiration to develop better treatments.

Family also was a driving factor behind a career move that prompted Dang’s embrace of circadian biology. He had spent nearly 25 years at Johns Hopkins University, rising to vice dean for research of the medical school; he figured he’d never leave. But in 2011, after his older brother Bob died of cancer, Dang said he thought, “I need to do more.”

So when the University of Pennsylvania approached him that year with an offer to become director of its cancer center, he jumped.

Penn also is home to one of the nation’s largest groups of chronobiology researchers, and Dang found himself chatting and collaborating with clock researchers across the campus. It prompted an epiphany: If cancer is a disease of runaway cell growth and if circadian rhythms keep cell cycles in check, then disrupting the internal clock must be, as Dang puts it, a “missing link” of tumor development and growth.

The circadian clock is a complex biological circuit that controls daily rhythms of sleep, eating, body temperature and more. There is a master clock that sits in the brain, secondary clocks in other organs and clocks in each cell, controlled by a network of genes and proteins that oscillate their activity levels in periodic cycles.

When these clocks are in sync, the body operates properly. But when clock genes are mutated or thrown off by jet lag, these systems can get out of whack, which can create conditions for tumors to grow and spread.

Early hints that disrupted clocks could lead to cancer came in 2001, when two teams of epidemiologists concluded that women who regularly worked night shifts had increased chances of developing breast cancer. Later studies established links between graveyard shifts and cancers of the colon, prostate and endometrium — which prompted the World Health Organization’s International Agency for Research on Cancer in 2007 to designate night-shift work involving circadian disruption as a probable carcinogen.

Researchers now generally believe that nocturnal light, which decreases the body’s natural production of the clock-regulating hormone melatonin, explains such a link. This suggests that melatonin pills or modulating ambient lighting could help mitigate risk among shift workers.

But, says Steven Hill, a circadian cancer researcher at Tulane University, “there are no published studies or active interventional studies” to back that up.

In part, that’s because prevention trials of this kind would be hugely expensive and lengthy — and also because many researchers are instead focused on treatment strategies for people who already have a cancer diagnosis. Earlier this year, for example, a team at the Salk Institute for Biological Studies in La Jolla, California, described two novel drugs that target key clock components and kill several types of cancer cells in a laboratory dish while also slowing the growth of brain tumors in mice.

By reawakening circadian clocks in cancer cells, the drugs seemed to block biological functions that tumors rely upon.

Dang’s own research has focused mainly on showing how a notorious cancer gene named MYC suppresses genes at the core of the mammalian clock. This suppression pushes cells into aberrant, perpetual activity that drives tumor progression. Last year, researchers at Texas Children’s Cancer Center reported that a drug that indirectly stimulates one of these clock genes, BMAL1, could help blunt the growth of neuroblastoma, a cancer of nerve tissue, in cell cultures and mice.

Dang also has recently studied a class of anti-tumor drugs that failed in clinical testing 10 to 20 years ago. They all caused such low platelet counts that they never progressed past early trials.

Now, in mouse experiments, Dang’s team has found that timing is key. Drugs given at 10 a.m. or 6 p.m. both caused tumor regression, but only the 6 p.m. treatment caused low platelet counts. Perhaps, he says, patients in those early trials were given the drugs at the wrong time.

Another drug that doctors may be administering suboptimally is streptozocin, used to treat a rare form of pancreatic cancer. A 2017 mouse study showed that timing streptozocin administration minimized drug toxicity. And although research results in mice often don’t translate to people, the scientists behind this finding hope to test this schedule in patients.

Other data suggest that resetting clocks in tumors could mitigate cancer side effects such as low blood-cell counts and perhaps cachexia, a devastating loss of body weight and strength that often afflicts people in the final stages of cancer.

At the moment, only one chronotherapy clinical trial is running in the United States. It’s happening at the Washington University School of Medicine in St. Louis, where neuro-oncologist Jian Campian and colleagues over the past two years have treated 30 brain cancer patients with the chemotherapy drug temozolomide at 8 a.m. or 8 p.m.

So far, Campian said, it looks as if the drug’s side effects are far worse when people take it in the morning, though it’s too early to say anything conclusive.

A sticking point for timed treatment is that people differ. We all have “chronotypes” that determine whether we are morning or evening people, and that will probably affect responses to cancer drugs, notes Campian’s collaborator Erik Herzog. Ideally, treatment timings would be finely tuned to patients — “the ultimate personalized medicine,” Herzog says.

But precisely and noninvasively measuring people’s clocks, or the clock of their tumors, is no small task. “We still need to identify better biomarkers to personalize chronotherapy,” says Francis Lévi, a chronotherapy researcher at the University of Warwick in Britain.

For now, most human data comes from anecdotal reports such as those of Joe Kuna, who was diagnosed with metastatic colon cancer in 2014 and given two to five years to live. Four years on, the 61-year-old has survived a tennis-ball-size tumor in his colon and 15 lesions in his liver. Kuna, who runs a bowling alley in Johnsburg, Illinois, opted to undergo chronotherapy at the nearby Block Center for Integrative Cancer Treatment in Skokie.

For almost two years, Kuna would arrive at the center every other Tuesday, usually between 1 p.m. and 3:30 p.m., for his dose of oxaliplatin. Oncologist Keith Block, medical director of the clinic, said oxaliplatin seems to work best in the afternoon.

Kuna would sit in a cubicle and eat his tuna fish sandwich while the intravenous medication dripped into his veins through a port.

Another drug in Kuna’s chemotherapeutic cocktail, fluorouracil, is considered more of a nighttime agent — so Kuna took home a pump that was programmed to kick in at 10 p.m.

“I truly believe it’s why I’m still here,” Kuna said of this treatment and the diet and supplement regimen he followed. Although a scan in January revealed two new cancerous spots in his liver, Kuna is confident that, with surgery and more chronotherapy, he could be cancer-free once more. Doctors removed the new tumors on April 26.

Still, there’s no proof that Kuna’s treatment made a difference. The other patients he befriended at the Block Center are not alive today.

Most chronotherapy strategies are based on a limited understanding of clock biology — which frustrates Dang, who has yet to test any of his ideas surrounding drug timing in patients.

“We really want to provide the mechanistic basis of why you treat at a certain time of day, and not just rely on trial and error,” he said.

But perhaps, just as a small career move reshaped his own research, “it could be,” he said, “that simple adjustments make a big difference for patients.”


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