Lymphangioleiomyomatosis - potential clues into the treatment and diagnosis

Studies published in the Jan. 10 edition of the New England Journal of Medicine (NEJM) are providing clues into the treatment and diagnosis of LAM, or lymphangioleiomyomatosis, a progressive and deadly lung disease that affects women in their childbearing years.

There currently are no treatments for LAM and scientists estimate as many as 250,000 women may be going misdiagnosed or undiagnosed.

Researchers from Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine reported on a study testing the drug sirolimus in patients with LAM or tuberous sclerosis complex (TSC) with angiomyolipomas, benign kidney tumors common to both diseases. Approved to help transplant patients fight organ rejection, sirolimus treatment resulted in a 50 percent reduction in tumor growth; a significant improvement in lung function was observed in LAM patients. In addition, a letter published in the same issue of NEJM reports on preliminary data to support the use of a serum marker test to confirm a diagnosis of LAM. The disease has traditionally required a lung biopsy or CT scan for confirmation of diagnosis, contributing to diagnosis complications.

“These studies represent significant advances for LAM patients,” said Leslie Sullivan-Stacey, J.D., President and CEO of The LAM Foundation, a supporter of both studies. “The LAM Foundation has been the driving force behind major breakthroughs in LAM research over just the last decade, and we now have scientific evidence to support further study of treatments and diagnostic tools. The sirolimus study already is serving as the basis for other studies in TSC and LAM, including the first-ever LAM treatment trial, now enrolling patients.”

In addition to these U.S. studies, a second letter to the editor from researchers in the United Kingdom reports on a Phase II study of sirolimus in patients with TSC and sporadic LAM. An editorial authored by Drs. Elahna Paul and Elizabeth Thiele of Massachusetts General Hospital in Boston, expresses enthusiasm and caution in the interpretation of the sirolimus research.

The Phase I/II open-label study enrolled 25 patients with either LAM or TSC and angiomyolipomas. Sirolimus was administered to 20 patients for 12 months; 18 patients were followed 12 months after treatment was stopped. Researchers observed a 50 percent reduction in the primary endpoint – angiomyolipoma volume at 12 months.

Secondary endpoints included average tumor size at 24 months and spirometric measurements of lung function. Angiomyolipoma volume increased to 85 percent of baseline at 24 months. In 11 patients with LAM, 12 months of sirolimus treat resulted in a 10 to 15 percent improvement in lung function. Researchers said improved pulmonary function was likely caused by a reduction of gas trapping in the lungs and a decrease in airflow obstruction.

Disease manifestations in the lungs, skin, brain and kidneys were also observed as these organs are affected by both diseases. The study was a non-randomized, open label proof of concept trial to lay the groundwork for larger trials to address questions about the safety and effect of sirolimus in LAM and TSC patients.

“Our patients suffer tremendously from their disease,” said John Bissler, M.D., lead author of the study and Physician-Scientist at Cincinnati Children's Hospital Medical Center and the Cell and Cancer Biology Program at the University of Cincinnati College of Medicine. “We currently treat their severe renal and pulmonary disease with surgery and organ transplantation. We hope that our results and additional research with sirolimus and other drugs will lead to specific targeted therapies that minimize the need for such surgeries.”

”We're encouraged to see progress with diseases for which there were no new therapies on the horizon,” said Frank McCormack, M.D., study co-author, Division Director of Pulmonary, Critical Care & Sleep Medicine at the UC College of Medicine, and Scientific Director for The LAM Foundation. “We can now design larger trials powered to observe treatment effects on the lungs and kidneys.”

Both TSC and LAM are associated with gene mutations that result in inappropriate activation of mTOR (mammalian target of rapamycin), an enzyme that helps control the growth and proliferation of all cells. Researchers suspect that sirolimus works by inhibiting mTOR signaling. Several new studies are currently underway, including a Phase III double-blind, randomized trial to examine the effect of sirolimus on lung function in patients with LAM.

Side effects observed in the proof of concept study included mouth ulcers, diarrhea, upper respiratory infections and joint pain. Support was provided by The LAM Foundation, the Tuberous Sclerosis Alliance (with funding from the Kettering Fund), Wyeth, the National Cancer Institute and the National Institutes of Health.

In a Jan. 10 letter to the editor published in NEJM, University of Cincinnati College of Medicine investigators reported the serum VEGF-D may be a clinically useful diagnostic test for LAM. Vascular endothelial growth factor (VEGF) is a major angiogenic growth factor produced by malignant cells. Previous research reported elevated levels of VEGF-D, but not VEGF-A or VEGF-C in patients with LAM.

Investigators found VEGF-D levels were elevated up to 30-fold in LAM patients, but were normal in patients with lymphangiomatosis, PLCH, and emphysema, suggesting the serum may distinguish LAM from S-other cystic and chylous lung diseases.

Following validation in a larger, longitudinal study, the test could be used to test for LAM in women who present with characteristic symptoms of LAM, such as a collapsed lung (pneumothorax) and/or lung cysts. Women who have tuberous sclerosis complex (TSC) may also be tested, as 40-50 percent of women with LAM develop TSC kidney tumors.

“Beyond its use as a potential clinical diagnostic for LAM, VEGF-D may prove useful as a potential biomarker for the development of LAM treatments,” said Lisa Young, M.D., Pulmonary, Critical Care & Sleep Medicine at the UC College of Medicine, and study co-author. “It may prove useful in testing outcome measures similar to the way we used kidney tumor volume as a measurement in the sirolimus study.”

Researchers say that if validated as a biomarker, the serum test may improve the ability to conduct trials more quickly. Furthermore, identification of a biomarker for LAM may have treatment implications for other diseases with similar pathways that affect millions of Americans, including breast cancer, diabetes, obesity and even autism.