ABSTRACT: Lymphangioleiomyomatosis (LAM), a multisystem disease affecting almost exclusively women, is characterized by cystic lung destruction and presents with dyspnea, recurrent pneumothoraxes, chylous effusions, lymphangioleiomyomas, and angiomyolipomas. It is caused by the proliferation of a cancer-like LAM cell that possesses a mutation in either the tuberous sclerosis complex (TSC)1 or TSC2 genes. This article reviews current therapies and new potential treatments that are currently undergoing investigation. The major development in the treatment of LAM is the discovery of two mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, as effective drugs. However, inhibition of mTOR increases autophagy, which may lead to enhanced LAM cell survival. Use of autophagy inhibitors, for example, hydroxychloroquine, in combination with sirolimus is now the subject of an ongoing drug trial (SAIL trial). Another consequence of mTOR inhibition by sirolimus is an increase in Rho activity, resulting in reduced programmed cell death. From these data, the concept evolved that a combination of sirolimus with disruption of Rho activity with statins (e.g. simvastatin) may increase TSC-null cell death and reduce LAM cell survival. A combined trial of sirolimus with simvastatin is under investigation (SOS trial). Since LAM occurs primarily in women and TSC-null cell survival and tumor growth is promoted by estrogens, the inhibition of aromatase to block estrogen synthesis is currently undergoing study (TRAIL trial). Other targets, for example, estrogen receptors, mitogen-activated protein kinase inhibitors, vascular endothelial growth factor-D signaling pathway, and Src kinase, are also being studied in experimental model systems. As in the case of cancer, combination therapy may become the treatment of choice for LAM.
