VEGF, recettori e sviluppo di inibitori selettivi

Roma, 2-3 febbraio 2006

Raffaella GiavazziIstituto di Ricerche Faramacologiche

MarioNegri

Angiogenesis is Required for Sustained Tumor Growth

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•Related molecules: VEGFB,C,Dand placental growth factor•Key mediators of angiogenesis•MW 45KD•Homodimeric glycoprotein•Binds VEGFRs,neuropilin1, heparin•Four isoform

•VEGF121

•VEGF165

•VEGF186

•VEGF206

VEGF (also VEGFA)

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 CELLSby:

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

Carmeliet & Jain,Nature 407:249, 2000

•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

VEGF OVEREXPRESSION CAUSES THE FORMATION OF STRUCTURALLY AND FUNCTIONALLY

ABNORMAL BLOOD VESSELS

Poorly organized, tortuous, hyperpermeableFewer pericytesDependent on growth factors for survival and prolifertion

Normal Anti-VEGFAni-VEGFTumor (VEGF)

Adapted from: Jain & Carmeliet, Le Scienze 401:59, 2002

VEGF OVEREXPRESSION

Ovary Tumor

VS1 VS11A9 1A9

Manenti et al. Mol. Cancer Ther 2005

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• ---------------

Manenti et al.. E J Cancer, 2003

VEGF IN OVARIAN CARCINOMA PATIENTS

1000

10000

100000

ascites

1

10

100

1000

10000

healthynon

malignantovarian

carcinoma

plasma

VE

GF

pg/

ml

VE

GF

pg/

ml

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

VEGFVEGF is directly involved in proteolytic destruction of the ECM

VEGF is directly involved in capillary tube formation

VEGF is directly implicated in vascular

permeability andvessel maturation

Most therapeutic approaches to angiogenesis modulation are focused on endothelial cell functions during blood vessel formation

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VEGF & lymphangiogenesis

Lymphangiogenesis:

•a route of tumor metastasis

•stimulated by binding of VEGF-C and D to VEGFR3

•promoted by VEGF interaction with VEGFR2

VEGF overexpression leads tolymphatic vessel in exp. tumors

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

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

Lymphangiogenesis & Metastasis

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

Agent

Class

Target

Company

Bevacuzimab*(Avastin)

hMAB

VEGF-A

Genentech

CDP-791

Peg-DiFab VEGFR-2 Celltech

VEGF-trap Soluble receptor

VEGF-A,PIGF Aventis/Regeneron

IMC-1121 MAB

VEGFR-2 ImClone

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

VEGFR-1,-2, -3,EGFR

AstraZeneca

ZD2171 TKI VEGFR-1,-2 AstraZeneca

GW786024 TKI VEGFR-1,-2,-3 GlaxoSmithKline

AMG706 TKI VEGFR-1,-2,-3 Amgen

Modified fromHicklin & Ellis, J. Clin. Onc. 2005

VEGF INHIBITORS UNDER INVESTIGATION

0

100

200

300

400

500

0 10 20 30 40 50Days after tumor transplant

Tum

or

wei

ght

(mg)

DC101Vascuar index = 18

VehicleVascular Index = 45

% P

rolif

erat

ion

0

50

100

150

1E-09

SU 5416 (M)

HUVEC

HOC

1E-08 1E-07 1E-06 1E-05 1E-04

RECEPTOR TARGETING AGENTS

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 ….