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 TSC1 gene TSC2 gene HAMARTIN TUBERIN Chromosome 9 Chromosome 16 TSC1 gene TSC2 gene Cellular control: Cellular size Cellular growth Intracellular trafficking Cell migration Tumor suppression HAMARTIN TUBERIN

“loss-of-function” mutations, which can alter: Genes Involved in LAM and TSC 1. TSC: germline mutations of the TSC1 or TSC2 genes altered TUBERIN and/or HAMARTIN “loss-of-function” mutations, which can alter: Cellular size Cellular growth Intracellular trafficking Cell migration Tumor suppression 2. Sporadic LAM: secondary mutations of TSC2 (only in LAM cells) altered TUBERIN

Lymphangiogenesis; cell growth Intracellular signaling pathways in LAM insulin receptor PDGFR VEGFR3 (for VEGF-D) (cell membrane) P P IRS PI3K PDK1 estrogen receptor Akt TSC1 TSC2 Rheb mTOR rictor raptor mTOR pS6 Lymphangiogenesis; cell growth S6K 4EBP1 eIF4E Cell growth, movement

Lymphangiogenesis; cell growth Intracellular signaling pathways in LAM insulin receptor PDGFR VEGFR3 (for VEGF-D) (cell membrane) P P IRS PI3K PDK1 TSC mutations estrogen receptor Akt TSC1 TSC2 Rheb mTOR rictor raptor mTOR pS6 Lymphangiogenesis; cell growth S6K 4EBP1 eIF4E Cell growth, movement

Lymphangiogenesis; cell growth Intracellular signaling pathways in LAM insulin receptor PDGFR VEGFR3 (for VEGF-D) (cell membrane) P P IRS PI3K PDK1 TSC mutations estrogen receptor Akt TSC1 TSC2 Rheb mTOR rictor raptor mTOR pS6 Lymphangiogenesis; cell growth S6K 4EBP1 eIF4E Cell growth, movement

Lymphangiogenesis; cell growth Cellular drug targets for LAM insulin receptor PDGFR VEGFR3 (for VEGF-D) (cell membrane) P P IRS PI3K PDK1 anti-VEGF-D antibodies TSC mutations aromatase inhibitor estrogen receptor Akt rapamycin (sirolimus) TSC1 TSC2 statins Rheb metformin mTOR rictor raptor mTOR pS6 Lymphangiogenesis; cell growth S6K 4EBP1 eIF4E 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