The Molecular and Genetic Pathogensis of LAM

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 DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a destructive multi-system disease of women characterized by cystic lung destruction, renal angiomyolipomas, and chylous pleural effusions. Lymphangiogenesis is prominent in pulmonary LAM nodules and serum VEGF-D is diagnostic biomarker of LAM. The majority of LAM cells carry bi-allelic inactivating mutations in the tuberous sclerosis complex (TSC) genes and circulating LAM cells with TSC2 loss of heterozygosity can be detected in the blood. The TSC protein complex inhibits the mammalian/mechanistic target of rapamycin (mTORC1) via the small GTPase Rheb (Fig.1). mTORC1 acts as a molecular sensor that regulates cell growth, metabolism, autophagy, and microRNA biogenesis. Pivotal clinical trials have demonstrated clinical benefit from treatment with sirolimus (Rapamycin) or its analogs (Rapalogs) in LAM and TSC. Collectively these data indicate that Rapamycin is an effective suppressive therapy for LAM. However, lung function decline resumes and tumors regrow when the drug is discontinued. Therefore, therapy must be used chronically - perhaps lifelong. This highlights the urgent unmet need for novel therapeutic strategies in LAM and TSC and/or mechanisms to allow Rapamycin to be dosed at the lowest effective level, to maximize benefit and minimize risk. This UO1 brings together a unique team of leaders in LAM research to address key unanswered questions with high clinical impact. First, what are the fundamental mechanisms leading to lymphangiogenesis in LAM? Second, can circulating LAM cell burden be quantitated through "next generation" sequencing and used as a biomarker of LAM? Third, will finer dissection of the genetic basis of sporadic LAM reveal generalized low-level TSC2 mosaicism? Fourth, can biomarkers including VEGF-D and microRNA be used to develop personalized strategies for sirolimus dosing? Narrative: This UO1 brings together a unique team of leaders in lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) to address key unanswered questions with high clinical impact. First, what are the fundamental mechanisms leading to lymphangiogenesis in LAM? Second, can circulating LAM cell burden be quantitated through "next generation" sequencing and used as a biomarker of LAM? Third, will finer dissection of the genetic basis of sporadic LAM reveal generalized low-level TSC2 mosaicism? Fourth, can biomarkers including VEGF-D and microRNA be used to develop personalized strategies for Sirolimus dosing?