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):

Report Date:

2013-10-01

Pagination or Media Count:

5.0

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

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE