TSC and LAM: Current Treatment Options and Clinical Trials Stephen Ruoss, MDDivision of Pulmonary and Critical Care MedicineStanford University School of Medicine

Outline:LAM disease and clinical backgroundEvolution of therapies for LAMFuture directions

Normal lung

CT image: normal lung

CT images: LAM

CT image: TSC-LAM

Lymphangioleiomyomatosis (LAM)systemic diseasemultiple-organ involvementprogressive, cystic lung disease in womenassociated 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 LAMTSC-LAMEst. worldwide prevalence: ~ 35,000 (?)Est. worldwide TSC prevalence: ~ 200,000 (?)Almost exclusively femalesLAM in 30-40% of females; ~ 10% of malesOnly 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 pneumothoraxPneumothorax rareChylothorax in ~ 33%Chylothorax rare

Genes Involved in LAMTSC1 geneTSC2 geneHAMARTINTUBERINChromosome 9Chromosome 16Cellular control: Cellular size Cellular growth Intracellular trafficking Cell migration Tumor suppression

Genes Involved in LAM and TSC1. TSC: germline mutations of the TSC1 or TSC2 genesaltered TUBERINand/or HAMARTIN2. Sporadic LAM: secondary mutations of TSC2 (only in LAM cells)altered TUBERINloss-of-function mutations, which can alter: Cellular size Cellular growth Intracellular trafficking Cell migration Tumor suppression

Cell growth, movementIRSAkt4EBP1S6KRhebPI3KPPDK1PTSC2TSC1Lymphangiogenesis; cell growthmTORraptorestrogen receptormTORrictorinsulin receptorPDGFRpS6eIF4EVEGFR3 (for VEGF-D)Intracellular signaling pathways in LAM(cell membrane)

Cell growth, movementIRSAkt4EBP1S6KRhebPI3KPPDK1PTSC2TSC1Lymphangiogenesis; cell growthmTORraptorestrogen receptormTORrictorinsulin receptorPDGFRpS6eIF4EVEGFR3 (for VEGF-D)Intracellular signaling pathways in LAM(cell membrane)TSC mutations

Cell growth, movementIRSAkt4EBP1S6KRhebPI3KPPDK1PTSC2TSC1Lymphangiogenesis; cell growthmTORraptorestrogen receptormTORrictorinsulin receptorPDGFRpS6eIF4EVEGFR3 (for VEGF-D)Intracellular signaling pathways in LAM(cell membrane)TSC mutations

Cell growth, movementIRSAkt4EBP1S6KRhebPI3KPPDK1PTSC2TSC1Lymphangiogenesis; cell growthmTORraptorestrogen receptormTORrictorinsulin receptorPDGFRpS6eIF4EVEGFR3 (for VEGF-D)Cellular drug targets for LAM(cell membrane)TSC mutationsaromataseinhibitorstatinsmetforminrapamycin (sirolimus)anti-VEGF-D antibodies

Sirolimus studies: LAM and TSCTherapy produced:AML volume reductionSuggestion of improved lung function (small subject numbers)[NEJM 358(2); Jan 10, 2008]

Sirolimus studies: LAM and TSCTherapy produced:improved lung functionincreasing 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 TrialPurpose: 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 frequentlyNo changes to your usual care/medicationsTarget: 300 participants in U.S. followed for at least 2 yrs.Cincinnati only site enrolling right now; Stanford to follow

Other Current LAM TrialsSAIL: 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 cellsRole(s) of lymphatics in LAMVEGF-D as therapy target (blocking abnormal lymphatic growth, and LAM cell circulation)Cellular metabolic regulation in LAMRoles(s) of estrogen in LAMCombination therapiesOptimal clinical studies organization, coordination

More information accesswww.thelamfoundation.orgFacebook page+ Lammies page

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