TARGETING A TRANSLOCATION

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TARGETING A TRANSLOCATION?
Milan, May 13, 2008
2 ESMO SYMPOSIUM ON SARCOMA AND GIST
Maurizio DIncalci Department of
Oncology Istituto Mario Negri, Milan, Italy
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STRATEGIES TO INHIBIT TRANSCRIPTION FACTORS
OLIGO - NUCLEOTIDES
SMALL MOLECULES
Active in vitro
Drug design
Natural products
?
Active in vivo
?
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Oligonucleotide-based therapeutics
Antisense oligonucleotides
siRNAs
microRNAs
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Antisense oligonucleotides and siRNAs
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• Some natural products appear to have the ability
  to interfere with transcription regulation.
• The marine natural product Trabectedin appears
  to be the prototype of this new class of
  anticancer drugs as shown by in vitro and
  cellular experiments

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TRABECTEDIN, YONDELIS (ET-743) Background

• TETRAHYDROISOQUINOLINE
• MARINE COMPOUND WITH ANTITUMOR ACTIVITY
• ISOLATED BY THE CARIBBEAN TUNICATE
  ECTEINASCIDIA TURBINATA

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YONDELISTM (ET-743) CHEMICAL STRUCTURE
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INHIBITION OF THE DNA SPECIFIC BINDING BY ET-743
SRF E2F1 NF-Y TBP C-MYC C-MY
B - SP1 -
Bonfanti et al., Anticancer Drug Des., 14
179-186 (1999)
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Minuzzo et al., PNAS, 97 (12) 6780-6784 (2000)
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Minuzzo et al., Mol. Pharmacol., 68 1496-1503
(2005)
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Minuzzo et al., Mol. Pharmacol., 68 1496-1503
(2005)
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FUS-CHOP t(1216)(q13 p11) 95
EWS-CHOP t(1222)(q13 q12)
CHOP
FUS
1 2 3 4
1 2 3 4 5 6 7 8 9
10 11 12 13 14 15
Type 1
Type 2
Type 3
Type 4
Type 5
Type 6
Type 7
Type 8
Type 9
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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
402-91 Type I
1765 Type 8
ET
ET
NT
1
2
4
nM
NT
1
2
4
nM
?
Fus-chop
Fn1
Ptx3
?
IL6
?
GAPDH
ctr
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Sensitivity 402-91 gt 1765 gt HT1080
nM
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RT-PCR ANALYSIS OF GENES INVOLVED IN ADIPOGENESIS
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TRABECTEDIN-INDUCED DIFFERENTIATION ASSESSED BY
OIL RED O STAINING
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OPERATING THEATRE
PATHOLOGICAL CLASSIFICATION
MOUSE TRANSPLANTATION
SHORT TERM CULTURES
MOLECULAR INVESTIGATION FISH, RT-PCR, DNA
sequencing
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CONCLUSIONS
Trabectedin interferes with transcription
regulation in a promoter-dependent fashion, thus
it can modulate the aberrant expression/function
of transcription factors in some sarcomas (e.g.
MLS) Although the precise molecular mechanisms
are not fully elucidated yet, it appears that
Trabectedin modulation of gene expression may
induce differentation of MLS. We are
developing novel experimental models to
investigate the molecular basis for Trabectedin
selectivity and to develop the most rational
dosage-schedules and combinations.
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ISTITUTO MARIO NEGRI, MILAN, ITALY Maurizio
DIncalci Eugenio Erba Matteo Simone Michele
Tavecchio Massimo Broggini Giovanna Damia Roberta
Frapolli ISTITUTO NAZIONALE DEI TUMORI, MILAN,
ITALY Silvana Pilotti Elena Tamborini Stefania
Lagonigro Paola Casieri Tiziana Negri Angela
Greco Jessica Galleani Paolo G.
Casali Alessandro Gronchi Federica Grosso
UNIVERSITY OF MILAN, ITALY Roberto
Mantovani Claudia Forni