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Hepatocellular Carcinoma

Overview of Hepatocellular Carcinoma

Epidemiology

2

Cell Interactions During HCC Angiogenesis

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Agents that Target the EGFR Signaling Pathway

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Agents that Target Angiogenic Signaling

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Cell membrane

Signaling Pathways for Angiogenesis: VEGFR and PDGFR in the Vasculature

Semela D, et al. J Hepatol 2004;41:864–80Clauss M. Semin Thromb Hemost 2000;26:561–69

RTK: VEGFR-1 VEGFR-2 VEGFR-3

PDGFR

c-MYCc-MYC c-JUNc-JUN

BcL-XLBcL-XL

BADBAD

ERK1/2ERK1/2

MEK1/2MEK1/2AktAkt

mTORmTOR

RafRaf

PKCPKC

NF-ҚBNF-ҚB

NF-ҚBNF-ҚB

PLCPLC

SHCSHCGrB2GrB2 GEFGEF

PI3KPI3K

PTENPTEN

AngiogenesisAngiogenesis

HBxHBx

RasRas

Cediranib

Bevacizumab

BMS-582664

Sorafenib

Sunitinib

Thalidomide

TSU-68

Site of action

p53

x x

x

x

x

x

xxx

x

x

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Signaling Pathways for Cell Proliferation and Survival: PI3K

Cell membrane

p53p53

c-JUNc-JUN

wnt Receptor

MEK1/2MEK1/2

Survival Transcription/translation

Survival Transcription/translation

PI3K

PI3K PTENPTEN

DSHDSH

GBPGBP

GSK3GSK3

-catenin

-catenin

NF-ҚBNF-ҚB

NF-ҚBNF-ҚB

c-MYCc-MYC

BcL-XLBcL-XL

HBxHBx

mTORBADBAD

RafRaf

PKCPKC

PLCPLC

-catenin

-catenin

ERK1/2ERK1/2

AktAkt

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: FGFREGFRIGF-IRc-MET

SHCSHCGrB2GrB2 GEFGEF

RasRas

Site of

action

Erlotinib

Gefitinib

Lapatinib

RAD001

Sorafenib

Sunitinib

x

x x

xxx

xxx

Receptor

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Signaling Pathways for Cell Proliferation and Survival: Raf/MEK/ERK

Cell Membrane

c-MYCc-MYC c-JUNc-JUN

Wnt Receptor

BcL-XLBcL-XL

BADBAD

ERK1/2ERK1/2

MEK1/2MEK1/2

-catenin

-catenin

GSK3GSK3

GBPGBP

DSHDSH

AktAktmTO

RmTO

R

RafRaf

PKCPKC

NF-ҚBNF-ҚB

RasRas

NF-ҚBNF-ҚB

PLCPLCPI3KPI3K

PTENPTEN

p53

SurvivalTranscription/Translation

SurvivalTranscription/Translation

-catenin

-catenin

1. Feitelson MA, et al. Surg Clin N Am 2004;84:339–542. Thorgeirsson S, Grisham JW. Nat Genet 2002;31:339–463. Wiesenauer CA, et al. J Am Coll Surg 2004;198:410–214. Hwang YH, et al. Hepatol Res 2004;29:113–21

RTK: FGFREGFRIGF-IRc-MET

Receptor

SHC

SHC

GrB2

GrB2

GEF

GEF

HBxHBx

x x

x

x

Site of

action

Erlotinib

Gefitinib

Lapatinib

RAD001

Sorafenib

Sunitinib

xxx

xxx

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Sorafenib Targets both Tumor-cell Proliferation and Angiogenesis In Vitro

KIT/Flt-3/RET

Angiogenesis

Raf

Endothelial cell or pericyte

Nucleus

VEGFR-2PDGFR-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 VEGFParacrine stimulation

Sorafenib

X X

X X

XX

X

X