Tracey Campbell has lived for seven years with lymphedema, a chronic condition that causes unsightly swelling in her left leg.
The disease, which stems from a damaged lymphatic system, can lead to infections, disfigurement, debilitating pain and disability. There is no cure. The only available treatment is to wear compression garments or use massage to suppress the swelling,
which can occur throughout the body in some cases. Campbell — who had two quarts of excess water in her left leg by the time she was diagnosed — has for years worn restrictive garments 24 hours a day and has spent an hour each night massaging the lymph fluid out of her leg.
Lymphedema is uncomfortable, exhausting and dangerous if left uncontrolled. As many as 10 million Americans and hundreds of millions of people worldwide suffer from the condition, many from the after-effects of cancer therapy treatments.
“There’s this extra layer of emotional burden,” said Campbell, who added that she has to be constantly vigilant to protect against infection. “All you want to be is normal.”
Now there’s new hope for a possible pharmaceutical treatment for patients like Campbell. A study led by scientists at the Stanford University School of Medicine has uncovered for the first time the molecular mechanism responsible for triggering lymphedema, as well as a drug with the potential for inhibiting that process.
The study was published May 10 in Science Translational Medicine.
“We figured out that the biology behind what has been historically deemed the irreversible process of lymphedema is, in fact, reversible if you can turn the molecular machinery around,” said Stanley Rockson, MD, professor of cardiovascular medicine and the Allan and Tina Neill Professor of Lymphatic Research and Medicine at Stanford. Rockson shares senior authorship of the study with Mark Nicolls, MD, professor of pulmonary and critical care medicine. Stanford research scientists Wen “Amy” Tian, PhD, and Xinguo Jiang, MD, PhD, share lead authorship of the study and are also affiliated with the Veterans Affairs Palo Alto Health Care System.
‘Fundamental new discovery’
“This is a fundamental new discovery,” said Nicolls, who is also a researcher at the VA Palo Alto.
The researchers found that the buildup of lymph fluid is actually an inflammatory response within the tissue of the skin, not merely a “plumbing” problem within the lymphatic system, as previously thought.
Working in the lab, scientists discovered that a naturally occurring inflammatory substance known as leukotriene B4, or LTB4, is elevated in both animal models of lymphedema and in humans with the disease, and that at elevated levels it causes tissue inflammation and impaired lymphatic function.
Further research in mice showed that by using pharmacological agents to target LTB4, scientists were able to induce lymphatic repair and reversal of the disease processes.
“There is currently no drug treatment for lymphedema,” Tian said. Based on results of the study, the drug bestatin, which is not approved for use in the United States but which has been used for decades in Japan to treat cancer, was found to work well as an LTB4 inhibitor, with no side effects, she said.
Based on the research, bestatin (also known as ubenimex), is being tested in a clinical trial that started in May 2016 — known as ULTRA — as a treatment for secondary lymphedema, which occurs because of damage to the lymphatic system from surgery, radiation therapy, trauma or infection. Primary lymphedema, on the other hand, is hereditary. The results of the research pertain to both types.
Rockson is principal investigator for this multisite phase-2 clinical trial.
Two labs, two diseases
The study, which got underway about four years ago, began somewhat uniquely as a collaboration between two labs that were studying two completely different diseases. At the time, the Nicolls lab, where Tian works, was studying pulmonary hypertension. The Rockson lab was conducting lymphedema research.
The two teams met through SPARK, a Stanford program designed to help scientists translate biomedical research into treatments for patients.
“I was in a privileged position of seeing two faculty conducting important research and recognizing the possible link in causality,” said Kevin Grimes, MD, associate professor of chemical and systems biology and co-founder of SPARK. “It occurred to me that both diseases affected vascular tissues and had strong inflammatory components.”
“He blind-dated us,” Nicolls said. “When Amy Tian and I looked at the data from Stan’s research, Amy said, ‘It looks like it could be the same molecular process.’”
“It was an arranged marriage between us and Stan which worked out great,” Tian said.