Collaboration between two Stanford labs has resulted in the discovery of a molecular cause for lymphedema and the first possible drug treatment for it.
May 10, 2017 - By Tracie White
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.
“The cool thing about this story — which you almost never see — is that a clinical trial testing the therapy has already started before the basic research was even published,” Nicolls said. “This is the first pharmaceutical company-sponsored trial for a medical treatment of lymphedema, a condition that affects millions.”
Nicolls and Tian are co-founders of Eiccose LLC. Eiccose is now part of Eiger BioPharmaceuticals, which gets the drug from Nippon Kayaku in Japan. Eiger is sponsoring the clinical trial. Nicolls and Rockson are both scientific advisers to the company.
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.
At the time, Rockson had begun to suspect that lymphedema was an inflammatory disease. This led to his team’s discovery that the anti-inflammatory drug ketoprofen successfully helped to relieve lymphedema symptoms, although it wasn’t a perfect drug; side effects were a concern, and it remained unclear how the drug worked at the molecular level.
Meanwhile, the Nicolls lab had discovered that LTB4 was part of the cycle of inflammation and injury that keeps pulmonary hypertension progressing. When researchers blocked LTB4 in rats with the disease, their symptoms lessened and blood vessels became less clogged, lowering blood pressure in the lungs.
“When we became aware of Mark’s work, we began to realize that we were both possibly dealing with the activation of steps downstream of the 5-LO [5-lipoxygenase] pathway,” Rockson said. “This became intriguing and formed the basis of our relationship.”
The two teams joined forces to figure out the mechanism that triggered lymphedema, hopefully revealing a target for drug treatment in humans. After determining that ketoprofen was primarily working on the 5-LO pathway, the researchers began blocking the various endpoint pathways after 5-LO activation in mouse models of lymphedema, Rockson said.
“It turned out that, in fact, we were both dealing with the same branch, which is LTB4,” Rockson said.
When all of the sudden one of your limbs begins to swell, you want to understand what the heck is going on.
“So now it became clear we really were dealing with a very similar biological process in two different diseases,” he said. “Because of Mark’s work in pulmonary hypertension, we knew that we had an ideal form of therapy that we could try in lymphedema as well.”
The Nicolls lab had used the drug bestatin, which blocks the enzyme that generates LTB4, to reverse pulmonary hypertension disease processes. When researchers tested bestatin in the mouse lymphedema model, it worked to reverse symptoms of that disease.
“I’m still in awe,” Rockson said. “There are few situations where you take a problem at the bedside, and go into the lab, and then take discoveries back to the bedside. It’s amazingly gratifying.”
Campbell, who is now participating in the double-blinded, placebo-controlled bestatin trial at Stanford, remains hopeful.
“When all of the sudden one of your limbs begins to swell, you want to understand what the heck is going on,” she said. “It’s a tough condition that few people seem to care about, even though millions and millions suffer with it. We’re hoping for something that gives some relief.”
Other Stanford authors are research associate Jeanna Kim; former medical students Adrian Begaye, MD, and Abdullah Feroze, MD; Roham Zamanian, MD, associate professor of medicine and director of the Adult Pulmonary Hypertension Service; Gundeep Dhillon, MD, associate professor of medicine and medical director of the Stanford Lung Transplant Program; and research assistants Eric Shuffle and Allen Tu. Shuffle and Tu are affiliated with both Stanford and the VA Palo Alto.
Researchers at the Georgia Institute of Technology, Virginia Commonwealth University, the University of Michigan Health Systems and the University of Illinois at Chicago are also co-authors.
Eiger BioPharmaceuticals has licensed intellectual property developed by Tian, Rockson, Jiang, Kim and Nicolls involving the targeting of LTB4 for the treatment of lymphedema.
Stanford’s Department of Medicine supported the work.
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