Accession Number : ADA591060


Title :   Targeting Autophagy for the Treatment of TSC and LAM


Descriptive Note : Annual rept. 30 Sep 2012-29 Sep 2013


Corporate Author : BRIGHAM AND WOMENS HOSPITAL BOSTON MA


Personal Author(s) : Henske, Elizabeth


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a591060.pdf


Report Date : Oct 2013


Pagination or Media Count : 5


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


Descriptors :   *CELLS(BIOLOGY) , *CHLOROQUINE , *DISEASES , *GENES , *LUNG , *NEOPLASMS , ACTIVATION , INHIBITION , PROTEINS , SIZES(DIMENSIONS) , SOCIAL WELFARE


Subject Categories : Genetic Engineering and Molecular Biology
      Anatomy and Physiology
      Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE