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11th Annual CTOS Meeting November 19–21, 2005

Mutated p53 correlates with extreme sensitivity to Yondelis  in low passaged cell lines explanted from chemonaive sarcoma patients. V. Moneo, B.G. Serrelde, M. Taron, J. Fominaya, J.F. Martinez-Leal, C. Blanco-Aparicio, L. Romero, M. Sánchez-Beato,J.C Cigudosa,

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11th Annual CTOS Meeting November 19–21, 2005

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  1. Mutated p53 correlates with extreme sensitivity to Yondelis in low passaged cell lines explanted from chemonaive sarcoma patients V. Moneo, B.G. Serrelde, M. Taron, J. Fominaya, J.F. Martinez-Leal, C. Blanco-Aparicio, L. Romero, M. Sánchez-Beato,J.C Cigudosa, J.C Tercero, M.A. Piris, J. Jimeno, A. Carnero CNIO Dpt. Of Molecular Biology, Madrid, Spain PharmaMar R&D, Colmenar Viejo, Madrid, Spain 11th Annual CTOS Meeting November 19–21, 2005

  2. Proposed mechanisms of action ofET-743 ET-743 (Yondelis) Ecteinascidia turbinata • Binding to the minor groove of DNA • Interaction with transcription factors and DNA binding proteins • Interference DNA repair pathways

  3. Objective Remissions and Tumor Control in patients with Progressive STS Treated with Yondelis PFS-6 CR+PR

  4. Yondelis Long Lasting Objective Response in a patient with Anthracycline Resistant High Grade Liposarcoma Courtesy of Dr G Demetri

  5. In vitro Cytotoxicity assays • MTT assay 96h • Clonogenic assay • Q-RT-PCR: mRNA expression • Western: protein expression • full gene p-53 sequencing Generation and molecular characterization of the low passage sarcoma cell lines

  6. Sarcoma primary cell line panel ET-743 vs Doxorubicin IC50

  7. SR2103/1A SR2103/1B R R S S S S S S S S S S R R S S S S R R S S R R SR2103/A SR2103/B SR0312 SR0406 LS0904 RS0306 RS0306 CA1010 SR2205 SR0312 SR0406 SR2410 SR2910 CA1010 SR2205 LS0904 SR2410 SR2910 SW 872 SW 872 A673 A673 Apaf-1 p 21cip1 p73 p 27kip1 PTEN p16INK4a p15INK4b p85 p14ARF E-cad MSH-2 b-cat APC MLH-1 b-actin b-actin Molecular characterization sarcoma cell lines mRNA expression

  8. SR2103/A SR2103/B RS0306 CA1010 SR2205 SR2410 SR2910 SW 872 SR0312 SR0406 LS0904 A673 MUT p53 R S S S S S R S S R S R MDM2 cdk4 Cyc D1 S p27 Tubulina Molecular characterization sarcoma cell lines Protein expression A. Carnero, AARC-04

  9. Sarcoma primary cell line panel p53 mutational status Mut. p53

  10. 120 P53+/+ 110 100 90 80 70 60 50 40 30 -2 -1 0 1 2 3 4 5 6 ET-743 (log pM) P53-/- IC50 (nM) HCT116 Expt 1 Expt 2 Expt 3 P53 wt 16.63 11.30 15.89 P53 null 4.92 3.22 5.05 Impact of p53 knock-out on cytotoxicity of Yondelis

  11. Conclusions • This primary sarcoma panel has established a set of cell lines with differential extreme sensitivity to Yondelis (IC50 < 1nM).Such concentration range is reacheable in plasma well below the recommended dose. • Yondelis lacks complete cross-resistance with doxorubicin. • The extreme sensitivity to Yondelis is correlated with mp53 genotype(p<0.01). • This data might be of clinical relevance since it can provide a tool to characterize the response/resistance to Yondelis in patients. • Correlative studies in tumor samples from sarcoma patients treated with Yondelis are ongoing.

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