Biological and Molecular Targeted Therapy for HHC

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--IFNa?Ta1?IL-2
• Adoptive immunotherapy--CIK?CTL
• Radioimmunotherapy--I131 Metuximab
• Tumor vaccines--DC vaccine
• Gene therapy--Clinical investigation

5
IFNaprevents 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 1437-1447
7
Prevention of Postresective Recurrence in HCC by
LAK/IL-2
8
Combination Treatment of p53 TACE in HCC



Plt0.05 Plt0.01
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 Oriental and SHARP Study
Endpoint Oriental1 Oriental1 SHARP2 SHARP2
Endpoint Hazard Ratio (95 CI) P-value Hazard Ratio (95 CI) P-value
OS 0.68 (47) 0.014 0.69 (44) lt0.001
OS (0.50-0.93) 0.014 (0.55-0.87) lt0.001
TTSP 0.90 0.498 1.08 0.768
TTSP (0.67-1.22) 0.498 (0.88-1.31) 0.768
TTP 0.57 (74) lt0.001 0.58 (73) lt0.001
TTP (0.42-0.79) lt0.001 (0.45-0.74) lt0.001
PFS 0.62 lt0.001 0.65 lt0.001
PFS (0.46-0.82) lt0.001 (0.52-0.79) lt0.001
1. Cheng A et al. Lancet Oncol 2009 10 25-34
2. Llovet JM et al. NEJM 2008, 359 378-390.
12
Llovet et al NEJM 2008359378-390
13
Cheng AL, et al. Lancet Oncol, 2009 10 25-34
14
(No Transcript)
15
Development of HCC Therapy with Sorafenib

• DoxorubicinSorafenib
• Sorafenib5-FU /UFT /Xeloda
• SorafenibErlotinib (SEARCH)
• TACESorafenib (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-68
  VEGFR,PDGFR, FGFR II-ongoing
• Bevacizumab VEGF
  II-closed
• Evelorimusbevacizumab mTOR, VEGF
  II-ongoing
• Erlotinibbevacizumab 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

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,P0.005 Stat3 ASO vs BRC
oligon.,P0.002
20
Stat3 ASO Improves Survival of Nude Mice Bearing
Human HCCLM3 Cells
Day 2 Administration

• NS49.04.9 d
• BRC52.76.7 d
• Stat3 ASO 10114.6 d

Survival
Day 10 Administration

• NS46.24.3d
• BRC50.26.2d
• Stat3 ASO 82.311.1d

Time (day)
Stat3 ASO vs Controls,Plt0.001 Stat3 ASO d2 vs
d10, Plt0.05
21
Thanks
EXPO 2010, Shanghai, China