Science & Tech
DANG Chi Van generally declines to discuss the science that made him famous.
A leading authority on cancer metabolism, he routinely is asked to speak about how tumours 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.
As scientific director of the Ludwig Institute for Cancer Research, a non-profit 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.
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-optimised 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 tumour development and the responses of patients to therapy.
“It’s capturing people’s interest,” Dang says.
Dang 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 centre, he jumped.
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 tumour development and growth.
The circadian clock is a complex biological circuit that controls daily rhythms of sleep, eating, body temperature and more.
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 tumours to grow and spread.
Earlier this year, 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 tumours in mice.
By reawakening circadian clocks in cancer cells, the drugs seemed to block biological functions that tumours 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 tumour progression.
Dang also has recently studied a class of anti-tumour 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 10am or 6pm both caused tumour regression, but only the 6pm treatment caused low platelet counts. Perhaps, he says, patients in those early trials were given the drugs at the wrong time.—
It’s just always been on the fringe. There weren’t that many card-carrying cancer biologists like me getting into it. — Dang Chi Van, scientific director of the Ludwig Institute for Cancer Research