Primary Liver Cancer Translational medicine Jia Fan Liver

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 th 1990 3 rd 2000 nd 1990 Deaths in 2002 % in the world 328, 900 55% Parkin et al. CA Cancer J Clin 2005

Evolvement of Therapeutic Strategy Decade of 70 s Decade of 80 s Decade of 90 s 1996 — 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 n n Dual channel modulation: B 2 B Translational medicine to bedside，bedside to bench. B 2 B bench

Process of translational medicine Dilemma in clinic Improve prognosis Clues in research Clinical confirmation Practice —— Theory —— Practice

Translational medicine in HCC n Screening of molecular markers n Individualized therapy based on molecular classification　 n Treatment evaluation and prognosis analysis n 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-D 20 Model Liver Cancer Institute of Fudan University • Antisense • H-ras • VEGF • ECM • BB 94 • Heparin • ICAM-1: -peptide • Different. inducers • CDA-II • Retinoid acid • Anti-angiogenesis • TNP-470 • Suramin • CAI • Flk-1 mutant • Endostatin • IFN • Selective chemoth • Xeloda + IFN

Capecitabin – pro-drug can be converted to 5 -FU by PD-ECGF Volume mm 3 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 a 1 b prevent metastasis of HCC in LCI-D 20 mice model Interferon Recur in liver％ Lung meta％ 3 x 107 / kg 13 0 1. 5 x 107/kg 63 0 Control 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 J Cancer Res Clin Oncol 2006 Confirmed by RCI in LCI→ Translated to clinical recommended strategy

mi. R-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 l Incidence (autopsy)： 20 -70% l Microscopic PVTT： 16%± Low resectability l 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 p Experimental n Platelet、low TM positive n Heparin suppress effects of platelet and TM p Efficacy n. 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 n Spread via portal vein n Spread in operation n Difficult to remove completely p Strategy: Postoperative PVI n High local drug concentration n low side effects p Efficacy: n 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 2008 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-D 35 95 - no metastasis LCI-D 20 95 - 100% lung, Liver, node Nude mice model Lymph metas Lung metas Stepwise increase MHCC 97 HG Green fluorescence MHCC 97 H MHCC 97 01 - Lung 100% 98 – Lung 100% MHCC 97 L 01 - Lung 40% MHCC 97 LG Green fluorescence HCCLYM-H HCCLM 6 02 – Sc Lung 100% Lymph 60% HCCLM 3 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 Capn 4 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

CD 151 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!