Download Primary Liver Cancer

Primary Liver Cancer
— Translational medicine
Jia Fan
Liver Cancer Institute, Fudan University
Department of Hepatic Surgery, Zhongshan Hospital
Death from Liver Cancer
World
4
China
2
th1990
3
rd2000
nd1990
Deaths in 2002
328,900
% in the world
55%
Parkin et al. CA Cancer J Clin 2005
Evolvement of Therapeutic Strategy
Decade of 70s
Decade of 80s
Decade of 90s
1996 —
No treatment
No treatment
No treatment
No
treatment
80% treatable
60% treatable
20% treatable
10% treatable
Anatomic liver
resection
Local resection
for small HCC
Comprehensive
treatment for
large HCC
5-y survival of HCC after curative resection 50-60%
Multimodality
Treatments
— That
why we need explore more effective treatment strategy
Llovet JM. Current Opinion in Oncology,2008
Basic research of liver cancer— Lots of
information about associated molecules and
pathways were discovered
Translational Medicine bridges the basic research
and clinical practice
Discovery Research
Clinical Development
Translational medicine
Translate from basic research to clinical
practice and preventive medicine


Dual channel modulation: B2B
Translational medicine
to bedside，bedside to bench.
B2B bench
Process of translational medicine
Dilemma in clinic
Improve
prognosis
Clues in
research
Clinical
confirmation
Practice —— Theory —— Practice
Translational medicine in HCC

Screening of molecular markers

Individualized therapy based on
molecular classification

Treatment evaluation and prognosis
analysis

New treatment and drug development
Primary Liver Cancer
— translational medicine practice
- Drug screening
- Comprehensive treatment
- Targeting Metastasis in HCC
40 years practice in liver cancer institute
Experimental Intervention using LCI-D20 Model
Liver Cancer Institute of Fudan University
• Antisense
• H-ras
• VEGF
• ECM
• BB94
• Heparin
• ICAM-1: -peptide
• Different. inducers
• CDA-II
• Retinoid acid
• Anti-angiogenesis
• TNP-470
• Suramin
• CAI
• Flk-1 mutant
• Endostatin
• IFN
• Selective chemoth
• Xeloda
• Xeloda + IFN
Capecitabin – pro-drug can be
converted to 5-FU by PD-ECGF
Volume mm3
Lung Meta %
Control
468
100 (12/12)
5-Fu
442
100 (6/6)
Furtulon
271
50 (3/6)
Xeloda
240
17 (1/6)
HCC
Lung metas
Zhou J, et al. Clinical Cancer Research, 2003; 9: 6030-6037 .
Translation — Clinical RCT Study
Multiple lung metastases
after HCC resection
Tumor regression after Xeloda – CR for 3 years
Clinical case
Interferon a1b prevent metastasis of
HCC in LCI-D20 mice model
Interferon
Recur in liver％
Lung meta％
3 x 107 / kg
13
0
1.5 x 107/kg
63
0
Control
100
100
Hepatology 2000
(nude mice model)
IFNa
postpone
recurrence
and
肝癌复发转移研究
(实验干预)
improve the survival of HCC after
curative resection
1.0
1.0
.9
.9
.8
.8
.7
Cum Survival
.7
.6
.5
.4
.6
.5
Group
.4
Group
.3
.3
IFN group
.2
IFN group-censored.2
IFN group-censored
.1
Control group
Control group
.0
IFN group
.1
Control-censored .0
0
12
24
36
48
60
Disease free survival (months)
72
Control-censored
0
12
24
36
48
60
72
Overall survival (months)
J Cancer Res Clin Oncol 2006
Confirmed by RCI in LCI→ Translated to clinical
recommended strategy
miR-26 Low expression associated with poor prognosis
of HCC, but response well to interferon treatment
Explore more personalized treatment options
Collaborated with NIH
Research:
Sorafenib induce both ER stress and autophagy, inhibiting
autophagy aggravate sorafenib lethality
Practices:
The RCT (Sorafenib plus autophagy inhibitor
CQ( Chloroquine) in advanced HCC ) is going on
Primary Liver Cancer
— translational medicine practice
- Drug screening
- Comprehensive treatment
- Targeting Metastasis in HCC
Portal vein tumor
thrombosis
 Incidence (autopsy)：
20-70%
 Microscopic PVTT：
16%±
Low resectability
 High Recurrence rate
Tumor resection plus thrombectomy — Potentially applicable
Basic research →Postoperative portal
vein heparin infusion
Thrombosis regeneration in one
week—80%
Platelet、TM involvement
 Experimental
 Platelet、low TM positive
 Heparin suppress effects of
platelet and TM
 Efficacy
Thrombosis regeneration rate in
one month: 0
肝素组
Yu Y, et al. J Cancer Res Clin Oncol, 2002
对照组
High recurrence rate→ postoperative
portal vein chemo-infusion
Prevent tumor recurrence and metastasis
 Spread via portal vein

Spread in operation

Difficult to remove completely
 Strategy: Postoperative PVI
 High local drug concentration

low side effects
 Efficacy:
 1-y survival 25%, 5-y improve 10% （N=56）
Fan J, et al. World J Gastroenterol, 2001
Treatment strategy for HCC with PVTT
－ Summing-up of experience of LCI in 12 Years
Tumor resection + thrombectomy +
Chemo port
Portal vein heparin perfusion in
one week
Portal vein chemo-PVI (2
weeks later)
Postoperative TACE (one
month later)
Mechanisms and multimodality
treatments for HCC with PVTT
2008 National Science and
Technology Progress Award
Clinical
HCC Recurrence and metastasis—
main obstacle of long-term survival
Bedside to
Bench
Basic
research
Molecular mechanism need to be
clarified
Primary Liver Cancer
— translational medicine practice
- Drug screening
- Comprehensive treatment
- Targeting Metastasis in HCC
Metastatic Models of HCC
LCI-D35
95 - no metastasis
LCI-D20
95 - 100% lung, Liver, node
Nude mice model
Lymph metas
Lung metas
Stepwise increase
HCCLYM-H
MHCC97HG
Green fluorescence
MHCC97H
MHCC97
98 – Lung 100%
01- Lung 100%
MHCC97L
01 - Lung 40%
MHCC97LG
Green fluorescence
HCCLM6
02 – Sc
Lung 100%
Lymph 60%
HCCLM3
02 – Sc
Lung 100%
Lymph 0%
HCCLYM
03
Lymph 100%
Lung 40%
03
Lymph 100%
Lung
30%
HCCLYM-L
03
Lymph 30%
Lung
30%
52 proteins are identified to be associated
with HCC Recurrence
Capn4 is an independent prognostic factor
B
Bai D, Fan J. Hepatology, 2008,49:491-503
XIAP determines the cell death in HCC
metastasis
Shi YH, Fan J Hepatology, 2008,48:497-507
Autophagy in HCC is associated with
prognosis，Beclin 1 is one of key molecules
Ding ZB, Fan J. Cancer Res, 2008, 68: 9167-75. IF=7.67
CD151 predict HCC prognosis
Ke AW, Fan J. Hepatology, 2008,49:460-70.
More clues in experimental
research are potentially to
be translated！
Evidence based medicine－
Key component of translational medicine
－ Content：RCT，Meta-analysis
－ Clinical data with statistical analysis
－ Essential for clinical usage
－ evidence for translation
－ re-confirmation of research data
Thanks!