Towards personalised therapy for lymphangioleiomyomatosis: lessons from cancer

Abstract

Lymphangioleiomyomatosis (LAM) is a rare cystic, destructive lung disease occurring almost exclusively in females. Bi-allelic inactivating tuberous sclerosis complex (TSC) gene mutations occur in LAM cells, resulting in activation of the mTORC1 pathway. Pivotal clinical trials have demonstrated that inhibition of mTORC1 with sirolimus can induce a partial response of TSC-associated tumours and decrease the rate of lung function decline in females with LAM. Many parallels have been identified between LAM pathogenesis and neoplasia. Here, we highlight three key nodes through which advances in cancer therapy can streamline future innovation in clinical LAM research with parallels to breast and prostate cancer. These include: 1) hormonally targeted therapies to achieve true disease-free complete remissions; 2) the use of vascular endothelial growth factor-D and other plasma biomarkers to streamline early-phase clinical trials; and 3) the utilisation of histological and molecular features of biopsy material to enable patient stratification and personalised therapies. @ERSpublications This review discusses key lessons from cancer that the LAM community can build on towards personalised therapy in LAM http://ow.ly/slJLR

Treatment of lymphangioleiomyomatosis: building evidence in orphan diseases

“…LAM cells (harbouring loss of heterozygosity of the TSC2 locus) can be found in a variety of body fluids including the blood and lymphatic system [27][28][29]. LAM cells further induce angiogenesis and lymphangiogenesis, and exhibit metabolic switch toward aerobic glycolysis [30]. Therefore, LAM is currently considered as a lowgrade metastatic neoplasm [31], a concept that may foster innovation in LAM research [30].…”

“…LAM cells further induce angiogenesis and lymphangiogenesis, and exhibit metabolic switch toward aerobic glycolysis [30]. Therefore, LAM is currently considered as a lowgrade metastatic neoplasm [31], a concept that may foster innovation in LAM research [30]. This further supports the development of alternative approaches to the current use of mTOR inhibitors that mostly target cell proliferation, with a lesser or no effect on cell adhesion, migration, motility, survival, resistance to anoikis, and release of pathogenic mediators including proteases.…”

Effects of Combining Rapamycin and Resveratrol on Apoptosis and Growth of TSC2-Deficient Xenograft Tumors

“…inhibition of autophagy maintains the LAM cells in a stagnant metabolic state, preventing cell growth and proliferation that would have otherwise been stimulated by mTORC1 activity (21,35). In addition, LAM cells seem to be dependent on even the low levels of autophagy because further inhibition of autophagy induces cell death (21).…”

TheEuropean Respiratory Review: meeting expectations of respiratory physicians through diversity and quality

“…In addition to publishing state-of-the-art reviews (updates), focused review articles, reports of high-quality scientific meetings, supporting documents of ERS task forces, sponsored review articles, editorials, letters to the editor and correspondence, the ERR now publishes thematic review series and Clinical year in review articles. The publication of cutting edge mini-reviews [5][6][7][8][9], case-based reviews [10] and images in respiratory medicine [11] has also been initiated, and spontaneous submissions are particularly welcome.…”

“…Although not explicitly identified as part of a series, three outstanding short articles have further reviewed the common features between cancer and conditions generally considered as non-neoplastic (pulmonary arterial hypertension, lymphangioleiomyomatosis and idiopathic pulmonary fibrosis, [8,9,14], with many learning points for both clinicians and scientists.…”