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
Low resectability
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－－DC vaccine
Gene therapy－－Clinical investigation

5. Median survival time： IFN 63.8m vs Control 38.8m
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 vs Control 38.8m

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

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

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
mTOR
Rapamycin
Everolimus
Protease Inhibitor
Bortezomib

11. Comparison of Oriental and SHARP Study
Endpoint
Oriental1
SHARP2
Hazard Ratio
(95% CI)
P-value OS
0.68 (+47%)
0.014
0.69 (+44%)
<0.001
( )
( )
TTSP
0.90
0.498
1.08
0.768
( )
( )
TTP
0.57 (+74%)
0.58 (+73%)
( )
( )
PFS
0.62
0.65
( )
( )
1. Cheng A et al. Lancet Oncol 2009; 10: 25-34
2. Llovet JM et al. NEJM 2008, 359: 11

12. Llovet et al NEJM 2008;359:

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

15. 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)

16. Molecular targeted therapies assessed in clinical trials in HCC
Treatment Target Clinical phase
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 VEGFR,PDGFR, FGFR II-ongoing
Bevacizumab VEGF II-closed
Evelorimus+bevacizumab mTOR, VEGF II-ongoing
Erlotinib+bevacizumab EGFR, VEGF II-ongoing
Ramucirumab VEGFR II-ongoing
Lenalidomide FGF, VEGF II-ongoing
ARQ c-Met (HGF) II-ongoing
Bortezomib Proteasome II-negative
Acyclic retinoids Differentiation III-design
Nolatrexed Thymidylate synthase III-negative
T Tubulin III-negative 16

17. 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

18. 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

19. 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

20. 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 ASO vs Controls，P<0.001 ; Stat3 ASO d2 vs d10, P<0.05

21. Thanks
Shanghai
EXPO 2010, Shanghai, China