Transcript TSC and LAM
TSC and LAM: Current Treatment Options and Clinical Trials Stephen Ruoss, MD Division of Pulmonary and Critical Care Medicine Stanford University School of Medicine Outline: • LAM disease and clinical background • Evolution of therapies for LAM • Future directions Normal lung CT image: normal lung CT images: LAM CT image: TSC-LAM Lymphangioleiomyomatosis (LAM) • systemic disease • multiple-organ involvement • progressive, cystic lung disease in women • associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphatic vessel development. • genetically mutant cells (“LAM cells”) that circulate in affected people are involved in organ injury LAM: sporadic vs. TSC-associated Sporadic LAM TSC-LAM Est. worldwide prevalence: ~ 35,000 (?) Est. worldwide TSC prevalence: ~ 200,000 (?) Almost exclusively females LAM in 30-40% of females; ~ 10% of males Only TSC2 mutations (after birth?) TSC1 and TSC2 mutations (germline) ~ 50% have kidney angiomyolipomas ~ 70-80% have kidney angiomyolipomas > 50% have respiratory symptoms < 10% have respiratory symptoms > 60% have pneumothorax Pneumothorax rare Chylothorax in ~ 33% Chylothorax rare Genes Involved in LAM Chromosome 9 Chromosome 16 TSC1 gene HAMARTIN TSC2 gene Cellular control: • Cellular size • Cellular growth • Intracellular trafficking • Cell migration • Tumor suppression TUBERIN Genes Involved in LAM and TSC 1. TSC: germline mutations of the TSC1 or TSC2 genes altered TUBERIN and/or HAMARTIN 2. Sporadic LAM: secondary mutations of TSC2 (only in LAM cells) altered TUBERIN “loss-of-function” mutations, which can alter: • • • • • Cellular size Cellular growth Intracellular trafficking Cell migration Tumor suppression Intracellular signaling pathways in LAM insulin receptor VEGFR3 (for VEGF-D) PDGFR (cell membrane) P IRS PI3K P PDK1 estrogen receptor Akt TSC1 TSC2 Rheb mTOR mTOR Lymphangiogenesis; cell growth pS6 eIF4E S6K 4EBP1 Cell growth, movement Intracellular signaling pathways in LAM insulin receptor VEGFR3 (for VEGF-D) PDGFR (cell membrane) P IRS PI3K P PDK1 TSC mutations estrogen receptor Akt TSC1 TSC2 Rheb mTOR mTOR Lymphangiogenesis; cell growth pS6 eIF4E S6K 4EBP1 Cell growth, movement Intracellular signaling pathways in LAM insulin receptor VEGFR3 (for VEGF-D) PDGFR (cell membrane) P IRS PI3K P PDK1 TSC mutations estrogen receptor Akt TSC1 TSC2 Rheb mTOR mTOR Lymphangiogenesis; cell growth pS6 eIF4E S6K 4EBP1 Cell growth, movement Cellular drug targets for LAM insulin receptor VEGFR3 (for VEGF-D) PDGFR (cell membrane) P IRS PI3K PDK1 anti-VEGF-D antibodies TSC mutations estrogen receptor Akt TSC2 statins TSC1 aromatase inhibitor P rapamycin (sirolimus) Rheb metformin mTOR mTOR Lymphangiogenesis; cell growth pS6 eIF4E S6K 4EBP1 Cell growth, movement Sirolimus studies: LAM and TSC • [NEJM 358(2); Jan 10, 2008] Therapy produced: – AML volume reduction – Suggestion of improved lung function (small subject numbers) Sirolimus studies: LAM and TSC • Therapy produced: – improved lung function – increasing use of this therapy in LAM patients Disease-specific therapy: LAM Current Therapy Developments MIDAS Trial: Multicenter International Durability and Safety of Sirolimus in LAM Trial • Purpose: to determine if sirolimus (or everolimus) delays LAM progression • Eligibility: Diagnosis of LAM, and are either currently taking sirolimus or everolimus, or being considered for therapy in the future • Methods: – Annual visit to collect pulm. function results, quality-of-life questionnaire data, medications, clinical status data – more data will be collected if you attend your LAM clinic more frequently – No changes to your usual care/medications – Target: 300 participants in U.S. followed for at least 2 yrs. – Cincinnati only site enrolling right now; Stanford to follow Other Current LAM Trials • SAIL: Safety Study of Sirolimus and Hydroxychloroquine in Women with LAM (E. Henske, Harvard Univ.) • SOS: Safety Study of Simvastatin (V. Krymskaya, U. Penn.) • SLAM-2: Preliminary clinical study of Saracatinib in Subjects with LAM (T. Eissa, Baylor Univ.) • GWAS: LAM Genome Wide Association Study (D. Kwiatkowski, Harvard Univ.) Future directions: • Better understanding of the origins, biology, and control of LAM cells • Role(s) of lymphatics in LAM • VEGF-D as therapy target (blocking abnormal lymphatic growth, and LAM cell circulation) • Cellular metabolic regulation in LAM • Roles(s) of estrogen in LAM • Combination therapies • Optimal clinical studies organization, coordination More information access • www.thelamfoundation.org • Facebook page • + “Lammies” page