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VEGF, recettori e sviluppo
di inibitori selettivi
Raffaella Giavazzi
Istituto di Ricerche Faramacologiche
MarioNegri
Angiogenesis is Required for Sustained
Tumor Growth
VEGF
(also VEGFA)
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•Related molecules: VEGFB,C,D
and placental growth factor
•Key mediators of angiogenesis
•MW 45KD
•Homodimeric glycoprotein
•Binds VEGFRs,neuropilin1, heparin
•Four isoform
•VEGF121
•VEGF165
•VEGF186
•VEGF206
VASCULAR GROWTH FACTORS
& THEIR RECEPTORS
Yancopoulos et al.
Nature 407:242, 2000
Ferrara N et al
Nature Reviews Cancer 2003
VEGF: A CENTRAL MEDIATOR
OF ANGIOGENESIS
Gerber and Ferrara, Cancer Res. 65, 671, 2005
REGULATION OF VEGF IN TUMOR CELLS
by:
 Oncogenes (ras, src, …..)
 Tumor Supressor Genes (p53, vHippelLindau, PTEN…..)
 Activated Signaling Pathways (src, Akt/PKB,…..)
 Transcription Factors (HIF, NF-kB,….).
 Environmental Factors (hypoxia, low pH,….)
 Growth Factors/Cytokines & their Receptors (EGFR,IL-1,..
 Hormones
VEGF EXPRESSION IS INDUCED BY
TUMOR HYPOXIA
•Hypoxia is a major inducer
of VEGF gene expression
•VEGF mRNA is rapidly induced in
the presence of hypoxiain in various
cell type
•VEGF is highly expressed in
•tumor cells near area of necrosis
Carmeliet & Jain,
Nature 407:249, 2000
VEGF OVEREXPRESSION CAUSES THE FORMATION OF
STRUCTURALLY AND FUNCTIONALLY
ABNORMAL BLOOD VESSELS
 Poorly organized, tortuous, hyperpermeable
 Fewer pericytes
 Dependent on growth factors for survival and prolifertion
Normal
Tumor (VEGF)
Ani-VEGF
Anti-VEGF
Adapted from: Jain & Carmeliet, Le Scienze 401:59, 2002
VEGF OVEREXPRESSION
Ovary
1A9
Tumor
VS1
1A9
VS1
Manenti et al. Mol. Cancer Ther 2005
VEGF IN CANCER DEVELOPMENT
AND PROGRESSION
 Highly expressed in several
 Elevated VEGF plasma
levels in cancer patients
 Increased tumor VEGF
expression associated with
tumor progression
and poor prognosis
tumor types
• Brain
•
•
•
•
•
•
•
Colon and rectum
Lung
Breast
Kidney
Bladder
Ovary
---------------
VEGF IN OVARIAN CARCINOMA PATIENTS
100000
10000
10000
100
10
VEGF pg/ml
VEGF pg/ml
1000
1000
1
healthy
non
malignant
ovarian
carcinoma
ascites
plasma
Manenti et al.. E J Cancer, 2003
VEGF IS A KEY PROANGIOGENIC FACTOR
VEGF is directly implicated in
endothelial cell adhesion,
proliferation, and migration
VEGF is directly
involved in proteolytic
destruction of the ECM
VEGF is a survival factor for
newly formed vasculature
VEGF is directly
implicated in vascular
permeability and
vessel maturation
VEGF is directly involved in capillary tube formation
Most therapeutic approaches to angiogenesis modulation are focused
on endothelial cell functions during blood vessel formation
VEGF &
lymphangiogenesis
VEGF overexpression leads to
lymphatic vessel in exp. tumors
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Lymphangiogenesis:
•a route of tumor metastasis
•stimulated by binding of
VEGF-C and D to VEGFR3
•promoted by VEGF
interaction with VEGFR2
Role of VEGF-C/D in
lumphatic metastasis in
cancer
a, Tumour cells and tumour-associated
macrophages secrete lymphangiogenic
growth factor VEGF-C or VEGF-D, which
induces sprouting of nearby lymphatic
vessels, facilitating the access of tumor
cells into the vessel lumen.
b, Aggregates of tumour cells are
transported to the regional lymph node,
from which they can spread to distant
organs through either blood or lymphatic
vessels. Blockage of VEGFR-3 signalling
inhibits metastasis in most mouse tumour
xenograft models by stabilizing lymphatic
vessels.
c, Nude mice were implanted with
luciferase-tagged tumour cells, which
metastasize to the ipsilateral axillary
lymph node
d, By contrast, metastasis was abolished
in mice treated with adenovirus encoding
a VEGF-C/D trap75.
Alitalo et al.Nature 2005
Lymphangiogenesis & Metastasis
Tumor lymphangiogenesis: A novel prognostic indicator
for cutaneous melanoma metastasis and survival.
Dadraset SS. al. Am J Path 162:1951, 2003
OTHERS VEGF FUNCTIONS
 VEGF is implicated in intraocular neovascularization
(diabetes mellitus,….age-related macular degeneration,
AMD)
 Role of VEGF in motoneurone degeneration (amytropic
lateral sclerosis, ALS)
TARGETING VEGF
IN CACER
VEGF INHIBITORS UNDER INVESTIGATION
Agent
Bevacuzimab*(Avastin)
Class
hMAB
Target
Comp any
VEGF -A
Genentech
CDP-791
Peg-DiFab
VEGFR-2
Celltech
VEGF-trap
VEGF-A,PIGF
Aventis/Reg eneron
IMC -1121
Soluble
receptor
MAB
VEGFR-2
ImClo ne
2C3
MAB
VEGF-A
Peregrine
PTK-787/ ZK22854
TKI
VEGFR-1,-2
Novartis
AEE788
TKI
VEGFR-2,EGFR
Novartis
Bay 43-9006
RAF KI
also VEGFR-1,-2,
PDGFR
Bayer/Onyx
SU11248
TKI
VEGFR-1,-2,PDGFR
Pfizer
AG13925
TKI
VEGFR-1,-2
Pfizer
AG13736
TKI
VEGFR-1,-2
Pfizer
CEP-7055
TKI
VEGFR-1,-2,-3
Cephalon
CP-547,632
TKI
VEGFR-1,-2
Pfizer
ZD6474
TKI
ZD2171
TKI
VEGFR-1,-2
AstraZene ca
GW786024
TKI
VEGFR-1,-2,-3
Glaxo SmithKline
AMG706
TKI
VEGFR-1,-2,-3
Amgen
Modified fromHicklin & Ellis, J. Clin. Onc. 2005
VEGFR-1,-2,
-3,EGFR
AstraZene ca
RECEPTOR TARGETING AGENTS
% Proliferation
150
HOC
100
50
0
1E-09
HUVEC
1E-08
1E-07
1E-06
1E-05
1E-04
SU 5416 (M)
Tumor weight (mg)
500
Vehicle
Vascular Index = 45
400
300
200
DC101
100
Vascuar index = 18
0
0
10
20
30
40
Days after tumor transplant
50
NEUTRALIZING ANTI-VEGF
MOMOCLONAL ANTIBODY
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POTENTIAL EFFECTS OF INHIBITING VEGF
Prevention of the growth of new tumor blood vessels

suppression of primary and metastatic tumor growth
Regression of tumor vasculature and restoration of
vascular permeability and intratumoral pressure

improved access for other anticancer agents (and O2)
Vascular regression

possible tumor dormancy
From : Jain RK. Nat Med 2001; Willett CG, et al. Nat Med 2004
TO CLINICAL TRIALS ….