How to Select Targets for Sarcoma

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How to Select Targets for Sarcoma

• Margaret von Mehren, MD
• Fox Chase Cancer Center
• Philadelphia, PA

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Goal of Therapy

• Cure the patient
• Control the disease palliate or prevent symptoms

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Traditional Therapies
Sarcoma
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Traditional Therapies
Sarcoma
XRT
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Traditional Therapies
TNT
Sarcoma
TNT
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Traditional Therapies
TNT
TNT
Sarcoma
Sarcoma
XRT
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Traditional Therapies

• Not tumor type specific
• Not tumor specific
• Limited therapeutic efficacy

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GIST

• Prior to the 21st century, recurrent disease was
  uniformly fatal

DeMatteo RP et al Human Pathology, 2002
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Elevated levels of MDR proteins
Plaat BEC et al JCO, 2000
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Identification of KIT Mutations in GIST
Hirota S, et al. Science, 1998
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TKI therapy in GIST

• Imatinib
• Sunitinib
• Investigational agents
• Sorafenib
• Nilotinib
• Motesanib
• Dasatinib

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Gastric GIST have a better prognosis than Small
Bowel GIST
Miettinen M and Lasota J. Arch Pathol Lab Med,
2006
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Gene Expression based on Anatomic Site
Antonescu et al. Clin Cancer Res, 2004
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Different Mutations require varying doses of
therapy
Debiec-Rychter et al. Eur J Cancer, 2006.
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RTOG 0132 Phase II Study of Neoadjuvant
Imitanib for Primary or Recurrent Operable GIST
R E G I S T E R
Surgery
Biopsy
8 weeks imatinib
S C R E E N
PET Imaging
CD117 positive
Primary or recurrent operable GIST
Glut-4 Analysis
KIT, PDGFR Mutation analyses
Gene Profiling
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Resistance
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Resistance
Surgical specimen photo courtesy of JC Watson
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Comparison of Cytogenetic Complexity in GIST and
Other Tumors
Leiomyo-sarcoma
GIST
NSCLC
Ovarian
OC and NSCLC karyotypes provided by J. Testa

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The Lessons from GIST

• Target must be biologically relevant
• KIT/PDGFR are the oncogenic drivers of most GIST
• Treatment need not be cytotoxic for benefit
• Therapy must have limited toxicity because of
  chronic use
• Cancer cells evolve survival mechanisms to bypass
  the inhibited target

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Is having the Target Sufficient ?

• MPNST and Synovial Cell Sarcoma
• Express EGFR
• Gene amplification
• Model systems suggesting potential role in
  oncogenesis in MPNST
• Clinical trial using oral TKI against EGFR
  revealed a median PFS of 2 months

KH Albritton et al, ASCO Abs 9518, 2006 JY Blay
et al, ASCO Abs 9517, 2006
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Ecteinascidia turbinata
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Trabectedin
Subunits AB are responsible for binding to the
minor groove of DNA
Highly reactive carbinolamine bond responsible
for alkylation
Subunit C is available for interaction with other
macromolecules
Used with permission from Pharma Mar USA, Inc.
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Trabectedin

• Inhibits transcription of heat shock?inducible
  genes
• Interacts with the transcription-coupled
  nucleotide excision repair system
• Leads to the formation of DNA strand breaks, late
  S and G2 phase cell cycle arrest, and p-53
  independent apoptosis

Minuzzo M et al, PNAS 2000 Takebayashi Y et al.
Nat Med 2001 Erba E et al Eur J Cancer 2001
Martinez EJ, Corey EJ, Owa T Chem Biol 2001.
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Trabectedin

• Trabectedin has resulted in tumor responses
  particularly in liposarcomas
• Myxoid-round cell liposarcomas commonly has a
  translocation resulting in the FUS-CHOP or rarer
  EWS-CHOP fusion proteins

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Be Open to Surprises
Grosso F et al, ASCO 2007, ABS 10000
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How do we know the target is relevant?

• Knowing the pathophysiology of a tumor
• Understanding what and how the drug targets
• Identifying the ideal patient population for each
  therapy

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What targets are out there?
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Future Challenges

• Synthesizing data from genomic and proteomic
  studies
• Evaluating the biologic implications of findings
• Determining the drugability of a target
• Designing trials to efficiently test targeted
  agents
• Predicting resistance mechanisms

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The Future

• Combination therapies
• Therapies targeting several pathways or one
  pathway at different sites
• Combining with standard chemotherapies
• Metastatic sarcomas becoming chronic diseases