Clinical features and prevalence of LAM.
LAM is an unusual lung disease in which benign-appearing smooth muscle cells proliferate extensively in the lungs, leading to cystic, emphysema-like lung destruction. For reasons that are not yet completely understood, LAM affects almost exclusively women. LAM progresses most rapidly in premenopausal women, and can lead to shortness of breath, lung collapse, oxygen dependency, and lung failure. LAM occurs in a sporadic form (sporadic LAM) and in women with TSC (TSC-LAM). Among women with sporadic LAM, about a third have renal angiomyolipomas. Histologically, angiomyolipomas and LAM appear identical between sporadic LAM and TSC.
Role of the Henske Lab in LAM research.
The Henske group is best known for discovering that sporadic LAM is caused by somatic TSC2 mutations. We also discovered (using genetic approaches) that when LAM recurs after lung transplantation, the source of the recurrent LAM is the patient’s original LAM cells. Based on these genetic data, we proposed the hypothesis that LAM cells metastasize to the lung, despite the fact that they are histologically benign, or the “benign metastasis” model. Recently, it has been proposed that LAM should be reclassified as a low-grade neoplasm.
Examples of bench-to-bedside LAM research arising from Henske Lab discoveries.
As one example of bench-to-bedside translation in LAM, our discovery of TSC2 mutations as a cause of sporadic LAM led to a multicenter clinical trial demonstrating the efficacy of sirolimus in LAM. Another example is the Sirolimus and Autophagy Inhibition in LAM (SAIL) trial, which tested the safety of hydroxychloroquine and sirolimus and LAM, based on data from the Henske Lab.