Collaboration between two Stanford labs has resulted in the discovery of a molecular cause for lymphedema and the first possible drug treatment for it.
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. 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.

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 the journal 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.

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.