Primary Liver Cancer — Translational medicine

1. Primary Liver Cancer — Translational medicine Jia Fan Liver Cancer Institute, Fudan University Department of Hepatic Surgery, Zhongshan Hospital

2. Death from Liver Cancer World 4th19903rd2000 China 2nd1990 Deaths in 2002 328,900 % in the world 55% Parkin et al. CA Cancer J Clin 2005

3. Evolvement of Therapeutic Strategy Decade of 70s Decade of 80s Decade of 90s 1996 — No treatment No treatment No treatment 80% treatable 60% treatable No treatment 20% treatable 10% treatable Anatomic liver resection Local resection for small HCC Comprehensive treatment for large HCC Multimodality Treatments 5-y survival of HCC after curative resection50-60%—That why we need explore more effective treatment strategy

4. Basic research of liver cancer—Lots of information about associated molecules and pathways were discovered Llovet JM. Current Opinion in Oncology,2008

5. 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 B2B bench tobedside，bedside to bench.

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

7. Translational medicine in HCC • Screening of molecular markers • Individualized therapy based on molecular classification • Treatment evaluation and prognosis analysis • New treatment and drug development

8. Primary Liver Cancer — translational medicine practice - Drug screening - Comprehensive treatment - Targeting Metastasis in HCC 40 years practice in liver cancer institute

9. 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

10. 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

11. Multiple lung metastases after HCC resection Tumor regression after Xeloda – CR for 3 years Clinical case

12. Interferon a1b prevent metastasis of HCC in LCI-D20 mice model InterferonRecur in liver％ Lung meta％ 3 x 107 / kg 13 0 1.5 x 107/kg 63 0 Control 100 100 (nude mice model) Hepatology 2000

13. 肝癌复发转移研究 (实验干预) IFNapostpone recurrence and improve the survival of HCC after curative resection J Cancer Res Clin Oncol 2006 Confirmed by RCI in LCI→ Translated to clinical recommended strategy

14. miR-26 Low expression associated with poor prognosis of HCC, but response well to interferon treatment Explore more personalized treatment options Collaborated with NIH

15. 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

16. Primary Liver Cancer — translational medicine practice - Drug screening - Comprehensive treatment - Targeting Metastasis in HCC

17. Portal vein tumor thrombosis • Incidence (autopsy)： 20-70% • Microscopic PVTT： 16%±Low resectability • High Recurrence rate

18. Tumor resection plus thrombectomy — Potentially applicable

19. Basic research →Postoperative portal vein heparin infusion Platelet、TM involvement Thrombosis regeneration in one week—80% • Experimental • Platelet、low TM positive • Heparin suppress effects of platelet and TM • Efficacy • Thrombosis regeneration rate in one month: 0 对照组 肝素组 Yu Y, et al. J Cancer Res Clin Oncol, 2002

20. Prevent tumor recurrence and metastasis High recurrence rate→ postoperative portal vein chemo-infusion • 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

21. 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)

22. Mechanisms and multimodality treatments for HCC with PVTT 2008 National Science and Technology Progress Award

23. HCC Recurrence and metastasis— main obstacle of long-term survival Clinical Bedside to Bench Molecular mechanism need to be clarified Basic research

24. Primary Liver Cancer — translational medicine practice - Drug screening - Comprehensive treatment - Targeting Metastasis in HCC

25. Metastatic Models of HCC LCI-D35 95 - no metastasis Nude mice model LCI-D20 95 - 100% lung, Liver, node Lymph metas Lung metas Stepwise increase HCCLYM-H MHCC97HG 03 Lymph 100% Lung 30% HCCLM6 HCCLYM Green fluorescence 02 – Sc Lung 100% Lymph 60% 03 Lymph 100% Lung 40% MHCC97H HCCLYM-L MHCC97 01- Lung 100% 03 Lymph 30% Lung 30% HCCLM3 MHCC97L 98 – Lung 100% 01 - Lung 40% 02 – Sc Lung 100% Lymph 0% MHCC97LG Green fluorescence

26. 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

27. XIAP determines the cell death in HCC metastasis Shi YH, Fan J Hepatology,2008,48:497-507

28. 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

29. CD151 predict HCC prognosis Ke AW, Fan J. Hepatology,2008,49:460-70.

30. More clues in experimental research are potentially to be translated！

31. 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

32. Thanks!