Oncogenic Strategies FOR

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Oncogenic Strategies FOR p53 pathway iNactivation
in sarComaS
Roberta Maestro CRO Aviano National Cancer
Institute
ESMO, Milan 2008
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Stresses
Oxygen or Nutrients deprivation
Oncogene activation
Virus infections
DNA damage
p53
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Stresses
Oxygen or Nutrients deprivation
Oncogene activation
Virus infections
DNA damage
Uncontrolled cell proliferation
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p53 alteration frequency
Non-melanoma skin cancer 80 Lung 70
Head-and-neck 60 Colon 60
Ovary 60 Bladder 60
Stomach 45 Esophagous 40
in carcinomas
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Is p53 pathway intact in sarcoma cells?
p53 reponse is attenuated in sarcoma cells

• Sarcoma-derived cell lines tolerate relatively
  high levels of
• ectopically expressed wt p53
• Sarcoma cell lines often show resistance to DNA
• damage-induced apoptosis
• Some sarcoma-encoded fusion proteins induce a
  p53-mediated
• response when ectopically expressed in normal
  cells

Sarcoma cells are likely to carry alterations in
components of the p53 pathway other than p53
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Strategies of p53 pathway inactivation in
sarcoma cells
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From the KEGG pathway database
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p53 is normally maintained at low levels through
MDM2-mediated degradation
p53
p53
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p53
p53
p53
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MDM2 overexpression results in enhanced
degradation of p53
p53
p53
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From the KEGG pathway database
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ARF
p53
p53
p53
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Sarcomas show reduced p14ARF expression
Liposarcoma 19 (Prom. Meth) Oda et al., J
Pathol., 2005 Angiosarcoma 26 (Prom. Meth)
Wehirauch et al., Human Pat, 2002 RMS 42
(RNA) Chen et al., , Genes Chrom Cancer 2007
(CDK4/CDK6 inhibitor)
INK4A locus, chromosome 9p21
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ARF
p53
p53
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Sarcoma-encoded fusion proteins may induce
inactivation of the p53 pathway
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SYT-SSX1 negatively regulates p53
D'Arcy, P. et al. Mol Cancer Res (2008)
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SYT-SSX attenuates the p53 response
D'Arcy, P. et al. Mol Cancer Res (2008)
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SYT-SSX
p53
p53
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May we therapeutically target MDM2?
From the KEGG pathway database
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Nutilin-3 induces apoptosis in p53 wild type AML
cells in a MDM2-dependent manner
wt p53
mut p53
From Koijma et al., Blood 2005
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Nutlin-3 inhibits proliferation of MDM2-amplified
LS cells
Normal adipocites
Dediff LS MDM2 amplif.
Singer et al. Cancer Res 2007
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