Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis

University of Cincinnati, Cincinnati, OH, USA.
New England Journal of Medicine (Impact Factor: 55.87). 03/2011; 364(17):1595-606. DOI: 10.1056/NEJMoa1100391
Source: PubMed


Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.
We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)).
During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.
In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

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    • "Individuals with TSC have a genetic mutation of TSC 1 or TSC 2 which inherently leads to over activation of signalling via the mTOR complex, a regulator of cell growth. Individuals with sporadic LAM can acquire mutations of TSC 2 [7], [12]. Sirolimus has been found to reduce the size of renal angiomyolipomas and decrease the serum levels of VEGF-D [10]. "
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    ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung condition affecting approximately 3.4-7.5/million women, with an average lag time between symptom onset and diagnosis of upwards of 4 years. The aim of this work was to identify altered proteins in LAM serum which may be potential biomarkers of disease. Serum from LAM patient volunteers and healthy control volunteers were pooled and analysis carried out using quantitative 4-plex iTRAQ technology. Differentially expressed proteins were validated using ELISAs and pathway analysis was carried out using Ingenuity Pathway Analysis. Fourteen proteins were differentially expressed in LAM serum compared to control serum (p<0.05). Further screening validated the observed differences in extracellular matrix remodelling proteins including fibronectin (30% decrease in LAM, p = 0.03), von Willebrand Factor (40% reduction in LAM, p = 0.03) and Kallikrein III (25% increase in LAM, p = 0.03). Pathway networks elucidated the relationships between the ECM and cell trafficking in LAM. This study was the first to highlight an imbalance in networks important for remodelling in LAM, providing a set of novel potential biomarkers. These understandings may lead to a new effective treatment for LAM in the future.
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    • "Considering these facts and the instances of LAM observed in postmenopausal women, we believe that excess estrogen and progesterone deficiency are not the primary causes of the disease, but may be one of the triggers for pulmonary LAM progression. Recent therapeutic trials with sirolimus, an inhibitor of mTOR, have shown stabilized lung function associated with a reduction in symptoms and improvement in the quality of life [20]. However, the indications for sirolimus treatment for LAM in postmenopausal women currently remain unknown. "
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    • "We have demonstrated that chronic, long-term administration of rapamycin results in inhibition of not only mTORC1, but also mTORC2, in vitro in cancer cell lines as well as in vivo in mice (Sarbassov et al., 2006; Lamming et al., 2012). Long-term rapamycin treatment results in glucose intolerance in humans, rats, and C57BL/6 mice as well as genetically heterogeneous HET3 mice (Houde et al., 2010; Gyurus et al., 2011; McCormack et al., 2011; Lamming et al., 2013). We found that this effect is mediated in part by decreased hepatic insulin sensitivity, an effect that can be reproduced by depletion of RICTOR, an essential protein component of mTORC2, in the whole body (Lamming et al., 2012) or specifically in the liver (Hagiwara et al., 2012; Lamming et al., 2012; Yuan et al., 2012). "
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