Everolimus for the treatment of lymphangioleiomyomatosis

mTOR is dysregulated in a range of tumour types and can be targeted with mTOR inhibitor treatments such as everolimus and sirolimus. Tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyamatosis (LAM) result from mutations in TSC1 or TSC2 that disrupt mTOR signalling (Carsillo et al., 2000, Glasgow et al., 2010). The associated aberrant cell growth, survival and movement results in the formation of slow growing tumours in various tissues and pulmonary cyst formation with loss of pulmonary function. The pivotal role of mTOR signalling in the pathogenesis of TSC/LAM mean mTOR inhibitors have great potential as treatments.

Previous trials have shown that sirolimus and everolimus are effective treatments for angiomyolipomas, slow-growing kidney tumours, in TSC and LAM patients (Bissler et al., 2008, Bissler et al., 2013). It was noted that the angiomyolipoma patients with LAM receiving sirolimus showed improved pulmonary function (Bissler et al., 2008). This effect was confirmed in the larger MILES phase III trial (McCormack et al., 2011). Now a new report from Goldberg et al., (2015) suggests that everolimus could also be an efficient treatment for LAM pulmonary symptoms.

The cystic degeneration of lung tissue in LAM patients eventually results in chronic respiratory failure and can limit survival to 10-20 years after diagnosis. The decline in pulmonary function can be monitored by assessing the decrease in force vital capacity (FVC) and forced expiratory volume in one second (FEV1). It is also associated with an increase in serum VEGF-D levels.

Goldberg et al. assessed everolimus in 24 female patients, with 20 completing the initial 26-week dose escalation trial (2.5mg, 5mg and 10mg daily) and 17 entering the optional extension period of up to 62 weeks. Dose reduction occurred as required in patients with adverse events. The range of adverse events correlated with those reported in previous everolimus trials with severe events only associated with the higher dosage. The authors state that the chosen dosages were based on previous oncology safety trials, and potentially lower doses of everolimus, with fewer adverse events, would be effective.

Everolimus treatment in these patients resulted in FVC stability and improved FEV1; the increased effect on FEV1 compared to FVC is suggestive of reduced airflow obstruction. The patients also showed reduced levels of serum VEGF-D, however there was no correlation between the reduction in VEGF-D and increased lung function. These results provide the initial evidence for everolimus as an effective LAM treatment comparable to other mTOR inhibitors. Everolimus has a shorter half-life and a greater bioavailability than sirolimus, potentially offering a more effective treatment which can more rapidly clear the body if required.

Recently this blog discussed an ongoing phase II clinical trial of everolimus in BHD patients with renal cell carcinoma (RCC). Dysregulated mTOR signalling has also been indicated in pulmonary BHD pathologies with increased mTOR activity reported in patient cystic lung samples (Furuya et al., 2012, Nishii et al., 2013). Therefore, mTOR inhibitor treatments might be useful in treating multiple BHD symptoms. However, unlike LAM, BHD is not a progressive degenerative pulmonary disease and cyst formation rarely has a significant impact on pulmonary function. It is debatable therefore whether the adverse effects associated with long-term mTOR inhibitor treatment would be acceptable to the majority of BHD patients without significant advances in health. Future research and trials will help to clarify the role of mTOR inhibitor treatments in these rare diseases.


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  • Carsillo T, Astrinidis A, Henske EP (2000). Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. May 23;97(11):6085-90. PMID: 10823953.
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  • Glasgow CG, Steagall WK, Taveira-Dasilva A, Pacheco-Rodriguez G, Cai X, El-Chemaly S, Moses M, Darling T, Moss J (2010). Lymphangioleiomyomatosis (LAM): molecular insights lead to targeted therapies. Respir Med. Jul;104 Suppl 1:S45-58. PMID: 20630348.
  • Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, Cheng Y, Khindri S, Kovarik JM, Ma S, McCormack FX, & Henske EP (2015). Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. The European respiratory journal, 46 (3), 783-94 PMID: 26113676.
  • McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. Apr 28;364(17):1595-606. PMID: 21410393.
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