Hepatocellular Carcinoma Overview of Hepatocellular Carcinoma Epidemiology 1

Hepatocellular Carcinoma Overview of Hepatocellular Carcinoma Epidemiology 1

Cell Interactions During HCC Angiogenesis 2

Agents that Target the EGFR Signaling Pathway 3

Agents that Target Angiogenic Signaling 4

Signaling Pathways for Angiogenesis: VEGFR and PDGFR in the Vasculature RTK: VEGFR-1 VEGFR-2 VEGFR-3 PDGFR x Cell membrane x x SHC Gr. B 2 GEF Ras PI 3 K PLC HBx Raf PTEN Akt x PKC MEK 1/2 m. TOR BAD ERK 1/2 Bc. L-XL NF-ҚB c-MYC p 53 Angiogenesis c-JUN Site of action x x x x Cediranib Bevacizumab BMS-582664 Sorafenib Sunitinib Thalidomide TSU-68 Semela D, et al. J Hepatol 2004; 41: 864– 80 Clauss M. Semin Thromb Hemost 2000; 26: 561– 69 5

Signaling Pathways for Cell Proliferation and Survival: PI 3 K RTK: FGFR EGFR IGF-IR c-MET Receptor x x. SHC HBx PI 3 K wnt Receptor Cell membrane Gr. B 2 PTEN GEF Ras PLC DSH Raf GBP Akt PKC MEK 1/2 m. TOR BAD Bc. L-XL GSK 3 x ERK 1/2 NF-ҚB catenin NF-ҚB c-MYC c-JUN p 53 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 Survival Transcription/translation catenin x x x Site of action Erlotinib Gefitinib Lapatinib RAD 001 Sorafenib Sunitinib 6

Signaling Pathways for Cell Proliferation and Survival: Raf/MEK/ERK RTK: FGFR EGFR IGF-IR c-MET Cell Membrane Receptor x x. SH GE F Gr. B 2 Wnt Receptor Ras C PI 3 K PLC HBx PTEN BAD DSH x Akt m. TO R Raf PKC GBP MEK 1/2 x GSK 3 ERK 1/2 NF-ҚB catenin Bc. L-XL NF-ҚB c-MYC c-JUN p 53 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 Survival Transcription/Translation catenin x x x Site of action Erlotinib Gefitinib Lapatinib RAD 001 Sorafenib Sunitinib 7

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