by Vera Krymskaya, PhD, MBA, Professor of Medicine, Perelman School of Medicine, University of Pennsylvania

The LAM community including LAM researchers, clinicians and patients has made incredible progress over the last 20 years. Frank McCormack and I were honored to write an invited review article “Lymphangioleiomyomatosis: A Monogenic Model of Malignancy” for the prestigious The Annual Review of Medicine, which covers significant developments in various fields of medicine since 1950. (http://www.annualreviews.org/doi/abs/10.1146/annurev-med-050715-104245M)

This review represents a remarkable milestone that denotes a tour de force effort put forth by the LAM community in bringing to the forefront this previously unknown disease. This review highlights the journey made by the LAM community, including researchers, health-care providers, advocates and patients, in transforming LAM from an obscure disease to a well-recognized, well-resourced disease with exciting therapeutic options on the horizon.

Until recently, the treatment options available to the LAM patient included watchful waiting, unproven hormonal therapies, and, in advanced cases, lung transplantation. However, remarkable progress in our understanding of LAM – driven by patient advocacy, abundant clues from nature [restriction to females, recurrence in transplanted lungs, occurrence in patients with tuberous sclerosis complex (TSC), etc.], and intense scientific interest in the pathway – has yielded an effective therapy in under 20 years since efforts began in earnest. In the process, study of this rare monogenic neoplasm and the parent disease, TSC, has yielded astonishing insights into cellular metabolism that are informing our approach to more common cancers.

LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell – metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism.

From the study of LAM and TSC, we have learned that mTOR is a master regulator that integrates cellular inputs of nutrient availability. We have learned that oxygen and energy status link LAM and TSC to outputs of protein translation; generation of macromolecular precursors, such as purines and pyrimidines; processes of cell metabolism, such as glycolysis and the accumulation of cellular biomass and macromolecules (including lipids, proteins, and polynucleotides); and cell survival, migration, and invasiveness. We have discovered that mTOR exerts these actions from its perch on the lysosomal surface, where it is ideally positioned to sample the status of nutrient availability, and through effects on transcription in the nucleus and mitochondrion. The translation of scientific discoveries in mTOR signaling from genetic dissection to astute observations in the eyes of flies to effective therapies for TSC and LAM occurred with astounding speed and ranks among the triumphs of twenty-first-century medicine. Perhaps even more remarkable, that it was driven by patient advocacy is a testament to the awesome power of that motivating force.