1. Raffaella Giavazzi Istituto di Ricerche Faramacologiche MarioNegri
VEGF, recettori e sviluppo di inibitori selettivi Roma, 2-3 febbraio 2006
Raffaella Giavazzi
Istituto di Ricerche Faramacologiche
MarioNegri

2. Angiogenesis is Required for Sustained Tumor Growth

3. VEGF (also VEGFA) 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

4. VASCULAR GROWTH FACTORS
& THEIR RECEPTORS
Yancopoulos et al.
Nature 407:242, 2000

5. Ferrara N et al
Nature Reviews Cancer 2003

6. VEGF: A CENTRAL MEDIATOR
OF ANGIOGENESIS
Gerber and Ferrara, Cancer Res. 65, 671, 2005

7. 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

8. 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
Importante e il ruolo dell’hypoxia che induce HIF e poi vari geni tra cui VEGF
Carmeliet & Jain,
Nature 407:249, 2000

9. 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

10. VEGF OVEREXPRESSION Ovary Tumor 1A9 VS1 1A9 VS1
Manenti et al. Mol. Cancer Ther 2005

11. VEGF IN CANCER DEVELOPMENT AND PROGRESSION
Elevated VEGF plasma levels in cancer patients
Increased tumor VEGF expression associated with tumor progression
and poor prognosis
Highly expressed in several tumor types
Brain
Colon and rectum
Lung
Breast
Kidney
Bladder
Ovary

12. VEGF IN OVARIAN CARCINOMA PATIENTS
10000
100000
1000
10000
100
VEGF pg/ml
VEGF pg/ml 10
1000 1
healthy
non
ovarian
malignant
carcinoma
ascites
plasma
Manenti et al.. E J Cancer, 2003

13. VEGF IS A KEY PROANGIOGENIC FACTOR
VEGF is a survival factor for newly formed vasculature
VEGF is directly implicated in endothelial cell adhesion, proliferation, and migration
VEGF is directly involved in proteolytic destruction of the ECM
VEGF is directly involved in capillary tube formation
VEGF is directly implicated in vascular permeability and
vessel maturation
Most therapeutic approaches to angiogenesis modulation are focused on endothelial cell functions during blood vessel formation

14. VEGF & lymphangiogenesis
VEGF overexpression leads to
lymphatic vessel in exp. tumors
Lymphangiogenesis:
a route of tumor metastasis
stimulated by binding of VEGF-C and D to VEGFR3
promoted by VEGF interaction with VEGFR2

15. 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

16. Lymphangiogenesis & Metastasis
Tumor lymphangiogenesis: A novel prognostic indicator for cutaneous melanoma metastasis and survival.
Dadraset SS. al. Am J Path 162:1951, 2003

17. 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)

18. TARGETING VEGF IN CACER

19. VEGF INHIBITORS UNDER INVESTIGATION

20. RECEPTOR TARGETING AGENTS5
100
150
1E-09
SU 5416 (M)
HUVEC
HOC
1E-08
1E-07
1E-06
1E-05
1E-04
% Proliferation
100
200
300
400
500 10 20 30 40 50
Days after tumor transplant
Tumor weight (mg)
DC101
Vascuar index = 18
Vehicle
Vascular Index = 45

21. NEUTRALIZING ANTI-VEGF MOMOCLONAL ANTIBODY

22. 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

23. TO CLINICAL TRIALS ….