TSC and LAM: Current Treatment Options and Clinical Trials

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TSC and LAM Current Treatment Options and
Clinical Trials

• Stephen Ruoss, MD
• Division of Pulmonary and Critical Care Medicine
• Stanford University School of Medicine

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Outline

• LAM disease and clinical background
• Evolution of therapies for LAM
• Future directions

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Normal lung
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CT image normal lung
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CT images LAM
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CT image TSC-LAM
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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

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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
gt 50 have respiratory symptoms lt 10 have respiratory symptoms
gt 60 have pneumothorax Pneumothorax rare
Chylothorax in 33 Chylothorax rare
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Genes Involved in LAM
Chromosome 9
Chromosome 16
TSC1 gene
TSC2 gene

• Cellular control
• Cellular size
• Cellular growth
• Intracellular trafficking
• Cell migration
• Tumor suppression

HAMARTIN
TUBERIN
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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
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Intracellular signaling pathways in LAM
insulin receptor
VEGFR3 (for VEGF-D)
PDGFR
(cell membrane)
P
P
IRS
PI3K
PDK1
estrogen receptor
Akt
TSC1
TSC2
Rheb
rictor
mTOR
raptor
mTOR
pS6
4EBP1
S6K
Lymphangiogenesis cell growth
Cell growth, movement
eIF4E
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Intracellular signaling pathways in LAM
insulin receptor
VEGFR3 (for VEGF-D)
PDGFR
(cell membrane)
P
P
IRS
PI3K
PDK1
TSC mutations
estrogen receptor
Akt
TSC1
TSC2
Rheb
rictor
mTOR
raptor
mTOR
pS6
4EBP1
S6K
Lymphangiogenesis cell growth
Cell growth, movement
eIF4E
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Intracellular signaling pathways in LAM
insulin receptor
VEGFR3 (for VEGF-D)
PDGFR
(cell membrane)
P
P
IRS
PI3K
PDK1
TSC mutations
estrogen receptor
Akt
TSC1
TSC2
Rheb
rictor
mTOR
raptor
mTOR
pS6
4EBP1
S6K
Lymphangiogenesis cell growth
Cell growth, movement
eIF4E
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Cellular drug targets for LAM
insulin receptor
VEGFR3 (for VEGF-D)
PDGFR
(cell membrane)
P
P
IRS
PI3K
PDK1
anti-VEGF-D antibodies
TSC mutations
aromatase inhibitor
estrogen receptor
Akt
rapamycin (sirolimus)
TSC1
TSC2
statins
Rheb
rictor
metformin
mTOR
raptor
mTOR
pS6
4EBP1
S6K
Lymphangiogenesis cell growth
Cell growth, movement
eIF4E
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Sirolimus studies LAM and TSC
NEJM 358(2) Jan 10, 2008

• Therapy produced
• AML volume reduction
• Suggestion of improved lung function (small
  subject numbers)

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Sirolimus studies LAM and TSC

• Therapy produced
• improved lung function
• increasing use of this therapy in LAM patients

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Disease-specific therapy LAM
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Current Therapy Developments
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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

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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.)

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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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More information access

• www.thelamfoundation.org
• Facebook page
• Lammies page