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Transplant Drug Sirolimus Shrinks Tumors and Improves Lung Function

Study at Cincinnati Children's Shows Drug May Hold Promise for People with Tuberous Sclerosis and Lymphangioleiomyomatosis


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The drug sirolimus, normally used to help transplant patients fight organ rejection, may eventually be used as a less invasive treatment for a tumor called angiomyolipomata in patients with who would otherwise face surgery. The finding is reported by investigators from Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine in the Jan.10 edition of The New England Journal of Medicine.

One year of treatment with sirolimus significantly reduced the size of angiomyolipomata by nearly 50 percent in patients with tuberous sclerosis complex (TSC), a rare genetic multi-system disease, or lymphangioleiomyomatosis (LAM), a rare cystic lung disease, according to results of the phase I/II proof-of-concept trial. Sirolimus also improved lung function in the LAM patients. 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. Sirolimus inhibits mTOR signaling, researchers said.

"Less invasive therapies are clearly needed to treat the angiomyolipomata that people with TSC and LAM develop, and a drug that maintains or shrinks tumor size may reduce the need for procedures such as surgery," said John Bissler, MD, lead author of the study and a physician/scientist in the Division of Nephrology and Hypertension at Cincinnati Children's. "Our data suggest that mTOR inhibition with sirolimus may hold promise for treating these and other disease manifestations in patients with TSC and LAM."

In the study, tumor volume in 20 patients treated with sirolimus for 12 months had significant reductions of about 50 percent. In 18 patients evaluated 12 months after sirolimus treatment stopped average tumor volume had increased again to about 85 percent of the original size. Five of the 18 patients evaluated 12 months post treatment had a persistent tumor volume reduction of 30 percent or more. Bissler and his coauthors speculate that regression in angiomyolipoma size might stem from a form of programmed cell death called apoptosis or cell-volume reduction.

In 11 study participants with LAM, 12 months of sirolimus treat resulted in a 10 to 15 percent improvement in expiratory air flow, a standard measurement of lung function. One year after sirolimus treatment ended, the treatment effect waned somewhat, but remained substantially above the level of lung function that would have been expected over two years with no treatment. Researchers said improved pulmonary function was likely caused by a reduction of gas trapping in the lungs and a decrease in airflow obstruction. Lung function for people with LAM often declines to the point that patients require oxygen and eventually a lung transplant.

Sirolimus treatment led to several side effects, including mouth ulcers, diarrhea, upper respiratory infections and joint pain. Researchers also noted limitations in the study's open-label design, lack of a control group and small number of study participants. However, given the effects of sirolimus in the trial the researchers at Cincinnati Children's are optimistic about its potential.

Support for the phase I/II proof-of-concept study came from the patient advocacy groups, the LAM Foundation and the Tuberous Sclerosis Alliance (made possible in part by a grant from the Kettering Fund), Wyeth, the National Cancer Institute and National Institutes of Health.

Dr. Bissler and his colleagues are pursuing additional trials to further define the relative risks and benefits of mTOR inhibitors in patients with LAM and TSC. Dr. Bissler is leading another trial to see if different dosing of mTOR inhibitors improves the effectiveness of treating angiomyolipomata tumors, and is working to launch a placebo-controlled multinational trial to better understand the effects of this therapy on angiomyolipomata. Frank McCormack, MD, a physician and researcher at the UC College of Medicine, is leading multi-institutional Phase III trial of sirolimus involving 120 patients with LAM that is randomized, double-blind and placebo-controlled. David Franz, MD, a physician and researcher at Cincinnati Children's, is conducting a trial to see if mTOR-inhibitor therapy helps the specific TSC-related brain lesion subependymal giant cell astrocytoma, and is working on a second placebo-controlled, multinational trial for this treatment.

About TSC and LAM
Two genes, tuberin (TSC2) and hamartin (TSC1) normally produce proteins that act as tumor suppressors. TSC and LAM are triggered by mutations in TSC1 or TSC2, which then inappropriately activate the mTOR cellular pathway to lead to abnormal cell growth and the development of tumors and cysts. People with TSC often have skin lesions and non-cancerous tumors of the brain, lungs, kidney, eyes, liver and heart, which can lead to developmental problems, compromise organ function, or result in death. LAM is a progressive lung disease that mostly affects women during their childbearing years. LAM often occurs in conjunction with TSC. LAM is characterized by invasion of the lungs by smooth muscle cells and destruction of healthy lung tissues.

The prevalence of LAM remains unknown, although it is estimated that 250,000 women with the disease may be undiagnosed or misdiagnosed because the symptoms are similar to those of asthma, bronchitis or emphysema, according to the LAM Foundation. Although TSC is as common as Lou Gehrig's disease – it is estimated TSC impacts one of every 6,000 babies born with more than 1 million people affected worldwide – the disease is often undiagnosed because of its obscurity or the mild form of initial symptoms, according to the Tuberous Sclerosis Alliance.

About Sirolimus
Sirolimus, also known as rapamycin or Rapamune", is an immunosuppressive agent approved by the Food and Drug Administration. The small molecule drug forms a complex with a binding protein to inactivate mTOR, halting its signaling.

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Cincinnati Children's, one of the top five children's hospitals in the nation according to Child magazine, is a 475-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to providing care that is timely, efficient, effective, family-centered, equitable and safe. For its efforts to transform the way health care is provided, Cincinnati Children's received the 2006 American Hospital Association-McKesson Quest for Quality Prize". Cincinnati Children's ranks second nationally among all pediatric centers in research grants from the National Institutes of Health and is a teaching affiliate of the University of Cincinnati College of Medicine. The Cincinnati Children's vision is to be the leader in improving child health.

Contact Information

Nick Miller
(513) 803-6035
nicholas.miller@cchmc.org