1. 1 Hepatocellular Carcinoma Overview of Hepatocellular Carcinoma Epidemiology

2. 2 Cell Interactions During HCC Angiogenesis

3. 3 Agents that Target the EGFR Signaling Pathway

4. 4 Agents that Target Angiogenic Signaling

5. 5 Cell membrane Signaling Pathways for Angiogenesis: VEGFR and PDGFR in the Vasculature Semela D, et al. J Hepatol 2004;41:864–80 Clauss M. Semin Thromb Hemost 2000;26:561–69 RTK: VEGFR-1 VEGFR-2 VEGFR-3 PDGFR c-MYCc-JUN BcL-XL BAD ERK1/2 MEK1/2 Akt mTOR Raf PKC NF-ҚB PLC  SHC GrB2 GEF PI3K PTEN Angiogenesis HBx Ras Cediranib Bevacizumab BMS-582664 Sorafenib Sunitinib Thalidomide TSU-68 Site of action p53 x x x x x x x x x x x

6. 6 Signaling Pathways for Cell Proliferation and Survival: PI3K Cell membrane p53 c-JUN wnt Receptor MEK1/2 Survival Transcription/translation PI3 K PTEN DSH GBP GSK3   - catenin NF-ҚB c-MYC BcL-XL HBx mTOR BAD Raf PKC PLC   - catenin ERK1/2 Akt 1. Horie Y, et al. J Clin Invest 2004; 113: 1774–83; 2. Hu T-H, et al. Cancer 2003; 97:1929–40. 3. Anzola M. J Viral Hepat 2004;11:383–93 RTK: FGFR EGFR IGF-IR c-MET SHC GrB2 GEF Ras Site of action Erlotinib Gefitinib Lapatinib RAD001 Sorafenib Sunitinib x x x x x x x x x Receptor

7. 7 Signaling Pathways for Cell Proliferation and Survival: Raf/MEK/ERK Cell Membrane c-MYCc-JUN Wnt Receptor BcL-XL BAD ERK1/2 MEK1/2  - catenin GSK3  GBP DSH Akt mTO R Raf PKC NF-ҚB Ras NF-ҚB PLC  PI3K PTEN p53 Survival Transcription/Translation  - catenin 1. Feitelson MA, et al. Surg Clin N Am 2004;84:339–54 2. Thorgeirsson S, Grisham JW. Nat Genet 2002;31:339–46 3. Wiesenauer CA, et al. J Am Coll Surg 2004;198:410–21 4. Hwang YH, et al. Hepatol Res 2004;29:113–21 RTK: FGFR EGFR IGF-IR c-MET Receptor SH C GrB 2 GE F HBx x x x x Site of action Erlotinib Gefitinib Lapatinib RAD001 Sorafenib Sunitinib x x x x x x

8. 8 Sorafenib Targets both Tumor-cell Proliferation and Angiogenesis In Vitro KIT/Flt-3/ RET Angiogenesis Raf Endothelial cell or pericyte Nucleus VEGFR-2 PDGFR-β MEK Apoptosis Tumor cell Proliferation PDGF VEGF EGF Survival Wilhelm SM, et al. Cancer Res 2004;64:7099–109 Ras Nucleus Ras ERK Raf MEK Apoptosis ERK PDGF-β VEGF Paracrine stimulation Sorafenib X X X X X X X X