Lymphangioleiomyomatosis (LAM): molecular insights lead to targeted therapies

Respir Med. 2010 Jul;104 Suppl 1(Suppl 1):S45-58. doi: 10.1016/j.rmed.2010.03.017.


LAM is a rare lung disease, found primarily in women of childbearing age, characterized by cystic lung destruction and abdominal tumors (e.g., renal angiomyolipoma, lymphangioleiomyoma). The disease results from proliferation of a neoplastic cell, termed the LAM cell, which has mutations in either of the tuberous sclerosis complex (TSC) 1 or TSC2 genes. Molecular phenotyping of LAM patients resulted in the identification of therapeutic targets for drug trials. Loss of TSC gene function leads to activation of mammalian target of rapamycin (mTOR), and thereby, effects on cell size and number. The involvement of mTOR in LAM pathogenesis is the basis for initiation of therapeutic trials of mTOR inhibitors (e.g., sirolimus). Occurrence of LAM essentially entirely in women is consistent with the hypothesis that anti-estrogen agents might prevent disease progression (e.g., gonadotropin-releasing hormone analogues). Levels of urinary matrix metalloproteinases (MMPs) were elevated in LAM patients, and MMPs were found in LAM lung nodules. In part because of these observations, effects of doxycycline, an anti-MMP, and anti-angiogenic agent, are under investigation. The metastatic properties of LAM cells offer additional potential for targets. Thus, insights into the molecular and biological properties of LAM cells and molecular phenotyping of patients with LAM have led to clinical trials of targeted therapies. Funded by the Intramural Research Program, NIH/NHLBI.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Cyclin-Dependent Kinase Inhibitor p21 / therapeutic use*
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Lymphangioleiomyomatosis* / drug therapy
  • Lymphangioleiomyomatosis* / genetics
  • Lymphangioleiomyomatosis* / pathology
  • Phenotype
  • Prognosis
  • Rare Diseases* / drug therapy
  • Rare Diseases* / genetics
  • Rare Diseases* / pathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics


  • Cyclin-Dependent Kinase Inhibitor p21
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases