Project 1: Lymphangioleiomyomatosis (LAM) is an uncommon neoplasm affecting women that is associated with cystic lung destruction and progressive respiratory failure. Mutations in tuberous sclerosis genes result in activation of mTOR signaling, loss of homeostatic growth control, and inappropriate lymphangiogenic growth factor expression. From an unknown source, metastasis of LAM cells to the lung and destructive lung remodeling result in recurrent pneumothoraces, chylous-effusions and lung function impairment. The Multicenter International LAM Efficacy of Sirolimus (MILES) Trial demonstrated that mTOR inhibition with sirolimus was an effective therapy which stabilized decline in FEV1. However, lung function decline resumed when the drug was held at the one year point in MILES, suggesting that the therapy is suppressive rather than remission-inducing, and may need to be lifelong. We therefore need to know whether long-term therapy with sirolimus is safe and effective. To accomplish this goal, we will enroll 75 LAM patients on sirolimus for clinical reasons in a longitudinal observational study, and following lung function tests, biomarker and adverse events over periods of up to 4 years. Another observation from MILES was that the patients who enrolled had surprisingly severe lung function impairment, including (on average) an FEV1 and diffusing capacity for carbon monoxide of ~50% of predicted, and a need for supplemental oxygen in the majority of patients. It is unclear, therefore, if the results of MILES can be generalized to patients with early disease. In the face of this uncertainty, and because of fear of toxicities, patients and their physicians generally opt to defer therapy until lung function is abnormal;a stage at which extensive lung damage has already occurred. To determine if prophylactic treatment of early, often asymptomatic patients can arrest lung function decline, we will screen a population of premenopausal patients with LAM and normal lung function (postbronchodilator FEV1 of >70% predicted) for patients who are declining at a rate of 3 fold normal (-90cc/yr) or greater, or 2 fold normal (-60cc/yr) or greater in combination with an elevated VEGF-D (which predicts rapid disease progression). This rapid declining cohort will then be placed on low dose sirolimus therapy and followed every three months with pulmonary function tests, biomarker studies and safety monitoring for two years. Collectively, these two trials will help us to refine the approach to treatment of patients with LAM, and determine if low dose long term suppressive therapy with sirolimus can prevent progression to later stages.

Public Health Relevance

We recently showed that an FDA approved drug, sirolimus, can slow down disease progression in people with advanced forms of lymphangioleiomyomatosis, a cystic lung disease of women, but we don't know if sirolimus treatment will stabilize lung function beyond the first year of treatment, or how safe it is to stay on sirolimus. We also don't know if people with milder forms of LAM will benefit from treatment. This study will answer these questions, and refine our approach to treatment of lymphangioleiomyomatosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
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Eu, Jerry Pc
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Cincinnati Children's Hospital Medical Center
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