ESMO Young Oncologists Masterclass II Cancer research: principle and practice

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ESMO Young Oncologists Masterclass II Cancer
research principle and practice

• From bench to bedside to bench again
• the novel paradigm of cancer research
• Cristiana Sessa
• IOSI, Bellinzona
• ECLU 2007
• Lugano, July 7th

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From bench to bedside to bench again the novel
paradigm of cancer research

• The clinical development of
• ecteinascidin-743
• a new marine natural product

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ECTEINASCIDIN -743
Ecteinascidia Turbinata

• RATIONALE
• New chemical entity
• Innovative mechanism of action
• No X-resistance with other natural drugs
• Activity in sarcomas pre-clinical models

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ET-743 MECHANISM OF ACTION
Hydrogen bonding between DNA and ET-743
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Antitumor activity in ovarian xenograft
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Antitumor activity in ovarian xenograft
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Phase II study of Yondelis in Relapsing and
Refractory Disease

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SENDO PATIENT CHARACTERISTICS
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SENDO PTS REQUIRING DOSE REDUCTION _at_ CYCLE 2
6/11
3/6
8/31
Data as of June 30 2003
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SENDO NON HEMATOLOGICAL TOXICITY BY INITIAL DOSE
_at_ CYCLE 1
Data as of June 2003
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Clinical efficacy in ovarian cancer
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Ecteinascidin-743 a marine-derived compound in
advanced, pretreated sarcoma patients.
Preliminary evidence of activity
Delaloge, JCO, 2001
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Ecteinascidin-743 (ET-743) for chemotherapy-naive
patients with advanced soft tissue sarcomas
multicenter Ph II and pharmacokinetic study
(N 36)
Carbonero, JCO, 2005
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Translational research

• From bench to bedside and back to the bench

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Sensitivity 402-91 gt 1765 gt HT1080
nM
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RT-PCR after trabectedin
Type 1
Type 8
402-91
1765
HT1080
ET
ET
ET
NT
1nM
2nM
4nM
NT
1nM
2nM
4nM
NT
1nM
2nM
4nM
Fus-chop
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RT-PCR 1765 vs 402-1
1765 Type 8
402-91 Type I
ET
ET
NT
1
2
4
nM
NT
1
2
4
nM
?
Fus-chop
Fn1
Ptx3
?
IL6
?
ctr
GAPDH
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Conclusions

• ET743 is known to have a major clinical impact in
  MLS
• MLS pathogenesis is related to a distinct
  chromosomal translocation, resulting in 9 already
  known, and 3 newly observed, fusion transcripts
• ET743 does not cause inhibition of fusion gene
  FUS-CHOP transcription but modulation of its
  transactivating properties

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Conclusions

• The persistence of FUS-CHOP transcript even in
  major pathologic responses would suggest the need
  for prolonged treatment, in order to maintain the
  modulation of gene activity over time
• Both in vitro and in vivo experimental models
  carrying different fusion proteins have been
  developed to further investigate the selective
  mode of action

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Hepatic toxicity of ET743 in rats
Liver sections from female Wistar rats which
received Yondelis (40 mg/kg i.v.) alone (A) or
24h after dexamethasone (10 mg/kg p.o.) (B)
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Grosso F. et al, Eur. J. Cancer, 1484-1490 (2006)
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From better knowledge to greater achievements
with ET743