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Biological and Molecular Targeted Therapy for HHC

Biological and Molecular Targeted Therapy for HHC. Sheng-Long Ye, MD, PhD Liver Cancer Institute Zhongshan Hospital Fudan University Shanghai, China. Problem in HCC. Severe cirrhosis Intrahepatic spread and distant metastasis Low resectability High postoperative recurrence.

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Biological and Molecular Targeted Therapy for HHC

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  1. Biological and Molecular Targeted Therapy for HHC Sheng-Long Ye, MD, PhD Liver Cancer Institute Zhongshan Hospital Fudan University Shanghai, China

  2. Problem in HCC Severe cirrhosis Intrahepatic spread and distant metastasis Lowresectability High postoperative recurrence

  3. Non-Surgical Treatment Regional therapy – TACE Ablation therapy – PEI, RFA, MWCT, Laser, HIFU, Cryoablation Radiotherapy Chemotherapy Biological & Molecular targeted therapy Traditional Chinese medicine

  4. Biotherapy for HCC Cytokines－－IFNα、Tα1、IL-2 Adoptive immunotherapy－－CIK、CTL Radioimmunotherapy－－I131 Metuximab Tumor vaccines－－DCvaccine Gene therapy－－Clinical investigation

  5. IFNαprevents recurrence and prolongs survival in postresective HCC patients Randomized control clinical trial of 236 HCC cases with 6-year follow-up Median survival time： IFN 63.8m vsControl 38.8m

  6. Survival and miR-26a Expression in HCC N Engl J Med 2009; 361: 1437-1447

  7. Prevention of Postresective Recurrence in HCC by LAK/IL-2 Recurrence% 61 .5 37.8 34 .6 32 .5 31 .1 28 .8 26 .9 17.7 15 .4 3.8

  8. Combination Treatment of p53 & TACE in HCC ** * ** *P<0.05 **P<0.01

  9. Strategy for Molecular Targeted therapy Growth factor & receptor inhibitors Angiogenesis inhibitors Signal transduction pathway inhibitors Monoclonal antibodies Cell-cycle modulation & gene therapy

  10. Targeted Therapy for HCC Targets & Drugs EGFR: TKI: Erlotinib, Lapatinib Gefitinib Ab: Cetuximab VEGF TKI: Sorafenib Sunitinib Ab: Bevacizumab RAF TKI: Sorafenib mTOR Rapamycin Everolimus Protease Inhibitor Bortezomib

  11. Comparison of OrientalandSHARPStudy 1. Cheng A et al. Lancet Oncol 2009; 10: 25-34 2. Llovet JM et al. NEJM 2008, 359: 378-390.

  12. Llovet et alNEJM2008;359:378-390

  13. Cheng AL, et al. Lancet Oncol, 2009; 10: 25-34

  14. Development of HCC Therapy with Sorafenib Doxorubicin+Sorafenib Sorafenib+5-FU /UFT /Xeloda Sorafenib+Erlotinib(SEARCH) TACE+Sorafenib (SPACE) Radical cure（Resection, RFA, PEI）+Sorafenib (STORM) Long-term follow-up (GIDEON)

  15. Sorafenib RAF, VEGF, PDGFR III- positive Brivanib FGF, VEGF III-design Sunitinib PDGFR, VEGFR, KIT III-design Erlotinib EGFR II-closed Cetuximab EGFR II-ongoing Lapatinib EGFR, Her2/nu II-ongoing Linifanib VEGF, PDGF II-ongoing TSU-68 VEGFR,PDGFR, FGFR II-ongoing Bevacizumab VEGF II-closed Evelorimus+bevacizumab mTOR, VEGF II-ongoing Erlotinib+bevacizumab EGFR, VEGF II-ongoing Ramucirumab VEGFR-2 II-ongoing Lenalidomide FGF, VEGF II-ongoing ARQ-197 c-Met (HGF) II-ongoing Bortezomib Proteasome II-negative Acyclic retinoids Differentiation III-design Nolatrexed Thymidylate synthase III-negative T138067 Tubulin III-negative Molecular targeted therapies assessed in clinical trials in HCC Treatment Target Clinical phase

  16. Molecular Approaches to Targeting Metastasis in HCC Potential targets for organ-specific metastasis Viral-gene therapy targeting AFP-expression HCC Antisense gene therapy targeting HCC metastasis

  17. Stat3 ASO Inhibits Proliferation of Human HCC Cells Lipo.Control（24h） 250nM BRC （24h） Stat3 ASO（24h） Concentration dependence of Stat3 ASO Inhibition in HCCLM3 Cells Stat3 ASO inhibits proliferation in HCCLM3 cells with concentration dependence； Inhibition of proliferation in HCC cells reaches highest at 48h Inhibitory Effects of Stat3 ASO with Different Time in HCCLM3 Cells

  18. Antisense stat3 Oligodexynucleotides Inhibits Metastatic Potential in Human HCCLM3 HCC cells Stat3 ASO vs LIPO，P=0.005; Stat3 ASO vs BRC oligon.，P=0.002

  19. Stat3 ASO Improves Survival of Nude Mice Bearing Human HCCLM3 Cells Day 2 Administration • NS：49.0±4.9 d； • BRC：52.7±6.7 d； • Stat3 ASO ：101±14.6 d Survival Day 10 Administration • NS：46.2±4.3d； • BRC：50.2±6.2d； • Stat3 ASO ：82.3±11.1d Time (day) Stat3 ASOvs Controls，P<0.001 ; Stat3 ASO d2 vs d10, P<0.05

  20. Thanks EXPO 2010, Shanghai, China

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