1. TSC and LAM: Current Treatment Options and Clinical Trials
Stephen Ruoss, MD
Division of Pulmonary and Critical Care Medicine
Stanford University School of Medicine

2. Outline: LAM disease and clinical background
Evolution of therapies for LAM
Future directions

3. Normal lung

4. CT image: normal lung

5. CT images: LAM

6. CT image: TSC-LAM

7. 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

8. 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

9. 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

10. “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

11. 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

12. 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

13. 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

14. 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

15. Sirolimus studies: LAM and TSC
[NEJM 358(2); Jan 10, 2008]
Therapy produced:
AML volume reduction
Suggestion of improved lung function (small subject numbers)

16. Sirolimus studies: LAM and TSC
Therapy produced:
improved lung function
increasing use of this therapy in LAM patients

17. Disease-specific therapy: LAM

18. Current Therapy Developments

19. 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

20. 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.)

21. 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

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