Optimizing treatments for lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM), a multisystem disease predominantly affecting premenopausal women, is associated with cystic lung destruction and lymphatic and kidney tumors. LAM results from the proliferation of a neoplastic cell that has mutations in the tuberous sclerosis complex 1 or 2 genes, leading to activation of a critical regulatory protein, mammalian target of rapamycin. In this report, we discuss the molecular mechanisms regulating LAM cell growth and report the results of therapeutic trials employing new targeted agents. At present, inhibitors of mammalian target of rapamycin such as sirolimus appear to be the most promising therapeutic agents, although drug toxicity and development of resistance are potential problems. As the pathogenesis of LAM is being further recognized, other therapeutic agents such as matrix metalloproteinase inhibitors, statins, interferon, VEGF inhibitors, chloroquine analogs and cyclin-dependent kinase inhibitors, along with sirolimus or a combination of several of these agents, may offer the best hope for effective therapy.

Keywords::

• chylous effusions
• lung function decline
• lymphangioleiomyomas
• lymphangioleiomyomatosis
• sirolimus
• tuberous sclerosis complex

Acknowledgements

The authors wish to thank Dr Wendy Steagall for revising the manuscript and assisting with the preparation of the figure.

Financial & competing interests disclosure

The authors were supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung and Blood Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.