The next breakthrough in LAM clinical trials may be their design: challenges in design and execution of future LAM clinical trials.

The past decade has resulted in stunning progress in the pathogenesis and therapy of lymphangioleiomyomatosis (LAM), culminating in the pivotal 'MILES' trial, the first-ever randomized, placebo-controlled trial in LAM, demonstrating the efficacy of sirolimus in 2011. Here, we review clinical progress since 2011, focusing on new therapeutic and observational trials. These trials include the second randomized, placebo-controlled trial, a 2-year study of doxycycline effectiveness in LAM. Other clinical studies have addressed lower-dose sirolimus and treatment of pulmonary hypertension. An improved understanding of LAM pathogenesis is essential to future therapeutic breakthroughs. Critical questions that remain to be addressed include the role of estrogen and lymphangiogenesis in LAM pathogenesis and therapy, mechanisms of cystic lung destruction, the role of autophagy and pro-survival pathways in LAM cell survival. Ultimately, achieving future 'breakthroughs' in LAM will require continued rigorous basic and preclinical investigation, innovative clinical trial design and robust biomarkers.