Targeting Autophagy for the Treatment of TSC and LAM
Abstract
Lymphangioleiomyomatosis (LAM), a disease that primarily affects women, is characterized by cystic lung destruction. LAM results from the proliferation of LAM cells that harbor mutations in the TSC1 or TSC2 genes, leading to activation of the mammalian target of rapamycin complex 1 (mTORC1). Recently, sirolimus (rapamycin) has been shown to stabilize lung function decline and decrease angiomyolipoma tumor size. Discontinuation of therapy results in progression of lung function decline and tumor growth, suggesting that continuous use is required to maintain its beneficial effects. Autophagy (self eating) is a mechanism by which tumor cells recycle proteins and organelles. Blocking TORC1, a known autophagy inhibitor, with rapamycin increases autophagy and promotes survival of TSC2-deficient cells. The Sirolimus and Autophagy Inhibition in LAM (SAIL) trial is a phase I clinical trial to test the safety and tolerability of a combination of hydroxychloroquine and sirolimus in women with LAM. We will measure the effect of therapy using the following secondary endpoints: 1. Forced expiratory volume in 1 sec (FEV1), 2. Forced vital capacity (FVC), 3. 6-minute walk test (6MWT), 4. Angiomyolipoma size, 5. Quality of life and 6. VEGF-D serum levels
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA591060
Entities
People
- Elizabeth P Henske
Organizations
- Brigham and Women's Hospital