Angiogénèse: cible de nouvelles molécules en cancérologie .

Leonardo da Vinci
Angiogénèse:
cible de nouvelles
molécules en
cancérologie .
Les régionales de cancérologie
Bordeaux oct 2006
ARMAND
Jean–Pierre
Directeur médical
IGR&D
Institut Gustave
Roussy
Villejuif France

•HER Faimily:
Growth factor Ab (C225,
Herceptin)
Tyrosine kinase inhibitors
(OSI, ZD1839)
•PI3K pathway: mTORi
(CCI779, RAD001…)
•PKC inhibitors (eg,
ISIS3521)
•Farnesyl transferase
inhibitors (SCH66336,
R115777, BMS214662)
•PDGFR and c-kit inhibitors
(STI 571)
•MMP inhibitors
•Modulators of chemokines
and their receptors
•Src inhibitors
•anti-bcl2
•ONYX-015
•RPR/IGN Adp53
•Survivin
•TRAILagonists
ANTI-INVASIVE AGENTS
SIGNAL TRANSDUCTION
INHIBITORS
CELL CYCLE INHIBITORS
APOPTOSIS MODULATORS
•Antibodies:
VEGF (Avastin)
Integrins (Vitaxine,
EMD12974…)
•SMALL MOLECULES:
ANTI-ANGIOGENIC
•flavopiridol
•cdki (BMS387032, roscovitine)
•Anti-telomerase
•Telomere interacting agents
•
•Carcinogenesis is a multi Carcinogenesis is a multi- -step process and step process and Cure will require Cure will require multispecific multispecific
intervention
intervention

LE MONDE 05/98 plantu les monoclonaux,les inhibiteurs de TKI mono ou
multi cibles
ANGIOGENESE
ANGIOGENESE

Regulation of
Regulation of A Angiogenesi ngiogenesis s
Pro-angiogenic
factors
Cytokines
VEGF
bFGF
PDGF
IL-8
EPO
IGF
TGF α,
α,α,
α, β
ββ
β
Enzymes
TP
MMPs
Anti-angiogenic proteins
Protein fragments
Endostatin
Angiostatin
Histidin rich
glycoprotein
Inhibitory proteins
Platelet factor-4
IFN α,
α,α,
α, β
ββ
β
Thrombospondin
TIMP
Soluble receptors
s-VEGF-R
s-FGF-R

P
P
P
P
HIF
COX-2↑
↑↑
↑
NO↑
↑↑
↑
Oncogenes↑
↑↑
↑
bFGF
IL-8 EGF IGF-1
PDGF
H2O2
VEGF release
Binding and activation
of VEGF receptor
Other functions of VEGF
•Monocyte chemotaxis
•DC maturation
•AML blast survival
Proliferation
ANGIOGENESIS
Survival Migration
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
Vasodilation
VEGF
Permeability
VEGF
VEGF: a Central Mediator of Tumor Vasculature : a Central Mediator of Tumor Vasculature
Development and Maintenance
Development and Maintenance