Onco-rencontres scientifiques franco - suisses

CCL - CGE

Tumor micronvironment and angiogenesis

January 13-14 2005

Curzio RüeggCentre Pluridisciplinaire d'Oncologie (CePO)

and ISREC, NCCR Molecular Oncology,Lausanne, Switzerland

Cancer: a systemic disease

Tumor cells

Angiogenesis

Lymph Node Metastasis

Lymph-angiogenesis

Invasion

Stromal cells

Metastasis

BMD cells

Inflammatory / BMD cells Bone Marrow

Inhibiting angiogenesis as a novel anti-cancer approach

Conventional anti-cancer Therapy:targeting cancer cells

?

Inhibiting angiogenesis as anti-cancer therapy: from a concept to a clinical treatment

The VEGF story

1971

VEGF cloning

1983 1989Late 1800 1993 2004

Avastin®registrationfor CRC

Anti-VEGF mAbE4.6.1

Tumors are vascularized

Inhibition of tumor AGas therapeuticstrategy

VPF

Modified after Ferrara, Nat Rev Cancer (2002), 2; 795

Inhibiting angiogenesis as anti-cancer therapy: from a concept to a clinical treatment

Bevacuzimab extends survival of patients with metastatic colorectal cancer (In combination with chemotherapy)

Antiangiogenesis works, but …

…still many open questions !!

Tumor microenvironment and angiogenesis

Tumor Biology

Monitoring DiagnosisPrediction

Therapy

Tumor microenvironment and angiogenesis

Gerhard Christofori, UNIBASTumor lymphangiogenesis and metastasis

Michel Aguet, ISRECTumor Stroma

Curzio Rüegg, CePOInflammation and tumor angiogenesis

Ivan Stamenkovic, IUPTumor Stroma

Cathrin Brisken, ISRECSignaling pathways in breast cancer

Jörg Hülsken, ISREC Tissue homeostasis and cancerogenesis

Jürg Tschopp, UNILApoptosis-inducing factors

Felix Naef, ISRECGene networks in cancer

Monika Hegi, CHUVGene expression in glioblastoma

Vincent Piguet, HUG Gene expression in melanoma

Richard Iggo, ISRECGene expression in breast cancer

Tumor microenvironment and angiogenesis research

Experimental Oncology

Clinical Oncology

AcademiaIndustry

Bio

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Mec

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Ther

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TNF

Tumor Necrosis Factor rapidly enhances drug accumulation in the tumor tissue and leads to vascular disruption later on

Melphalan

TNF

Hyperthermia

Pump

O2/CO2

3 w0 3 d

Courtesy of F. J. Lejeune

TNF and IFNγ suppress vascular integrin αVβ3 function

α5β1 β1

quiescent vessel EC activation

angiogenicvessel

αVβ3 αVβ3

EC apoptosis

ILP with Melphalan, TNF and IFNγ

Nature Med. (1998) 4, 408

Integrin-PKB-dependent signaling promotes endothelial cell survival and represents a potential therapeutic target to disrupt angiogenesis

TNF-R1

InflammationSurvival

TNF

AKTNFkB

Non-angiogenic EC

β1 > αVβ3 integrins

Angiogenic EC

αVβ3 > β1 integrins

Inflammation Cell death

TNF-R1

TNF

NFkBAKT

Degraded / provisional ECM

EMD 121974

Zoledronate

Multicentric Cilengitide phase I/II clinical trial in newly diagnosed GlioblastomaCoordinator : PD Dr. R. Stupp, CePO

Dg RTOp

TMZ

9 MoCilengitide(EMD121974)0 Mo 6 Mo

Primary Endopioints: ToxicityActivity (PFS)

Secondary Endpoints: Activity (OS)Biomarkers markers in serum

Tumor microenvironment and angiogenesis research

Experimental Oncology

Clinical Oncology

AcademiaIndustry

Bio

logy

Mec

hani

sms

Ther

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gnos

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COX2

TNF

VEGF production ↑EC proliferation / survival ↑

Proliferation ↑Migration/invasion ↑Survival ↑Drug resistance↑Activation of carcinogens ↑

COX-2 promotes tumorigenesis and tumor angiogenesis

An apple a day keeps the doctor away!CancerASPIRIN®

NSAIDsCOXIBs

Nature Rev. Cancer 2001, 1, 11

COXIB NS-398 inhibit HUVEC spreading and migration

Spreading Migration

Nature Med. (2001) 7, 1041

Fibr

onec

tin

Control SC-560 NS-398

Vitr

onec

tin

100

50

0

Cel

l mig

ratio

n (C

/ H

PF)

Con

trol

SC

-560

NS

-398

Indo

* *

0

50

100

150

Cel

l mig

ratio

n (C

/ H

PF)

α5β

1α

Vβ3

Constitutive active Rac reverses the anti-angiogenic effects of NS-398

NS398FGF2 / φNX FGF2 / φNXN17

NS398FGF2 / φNXL61

Nature Med. (2001) 7, 1041

FGF2 / φNX

Active Rac

Total Rac

Ctrl NS398PMA

NS398 NS398PGE2

IndoPMA

Indo

Vitronectin

IndoCtrl NS398

Fibronectin

Integrin - COX-2 Co(x)nnection

αVβ3, αXβ1 αVβ3

Rac

EPR 2 / 4

PGs

COX-2

COX-2

PKA

cAMPCOX-2

Degradation

SFKMAPKSAPK

PGs

Stromal fibroblasts

Inflammatory cells

Cancer cells

COX-2+

Migration - Angiogenesis

COX-2 target genes

COX-2

?

COX-2 in melanoma

In collaboration with Dr. F. Beerman

X

?

Gene expression profiling

QuickTime™ and aTIFF (LZW) decompressor

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ErbB2…….

Are COXIB potential anti-cance drugs ?

02/2002 02/2004 02/2002 02/2004

02/2002

02/2004

Clinical - Laboratory trialA phase II study in HNT tumors with biological / molecular endpoints of tumor angiogenesis.

Celecoxib 2x400 mg/d

Suspect Ca Pan-Endo Diagnosis 2-6 weeks Surgery

Biopsy Surgery

Primary endopoints: Determine changes in molecular markers of COX-2 activity & angiogenesis

Tumor tissue: Biochemistry COX-2; PGE2; Pi-ERK, Pi-PKB, ErbB2, VEGF, MMP-9Blood VEGF, MMP-9,….

Secondary endopoints:

Clinical Safety, activity

Tumor tissue: Immunohistology MVD, Apoptosis, ProliferationAffyMetryx Changes in gene expression (in responding patients)

Tumor microenvironment and angiogenesis research

Experimental Oncology

Clinical Oncology

AcademiaIndustry

Bio

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Mec

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Ther

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COX2

TNF

BMDC

How to monitor Tumor Angiogenesis and anti-angiogenic therapies

Circulating Factors

Vascular Imaging

Circulating ECP / EC

Tumor TissueFactors, MVD

BM-derived cells / leukocytes in tumor progression

Nature Med (2003), 9, 702

Ischemic organ / Tumor

VEGFMMP-9

Genetic models of multistep tumorigenesis

In collaboration with Prof. Gerhard Christofori

Rip1Tag2xRipVEGF-CF4/80 CD31 DAPI

N. Imaizumi

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QuickTime™ and aTIFF (LZW) decompressor

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Matrigel PlugF4/80 CD31 DAPI

N. Imaizumi, Y. Monnier

Bone marrow-derived ‘monocyte-like’ cells recruit to Rip1Tag2 tumors

CX3CR1-GFP mouse

NI301205B.012

100

101

102

103

104

FL2-

Hei

ght

100 101 102 103 104

FL1-Height

CD

11b

NI301205B.013

100

101

102

103

104

FL2-

Hei

ght

100 101 102 103 104

FL1-Height

F4/8

0

100 101 102 103 104

FL1-Height

NI301205B.014

100

101

102

103

104

FL3-

Hei

ght

GFP

CD

3e

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Gene expression profiling

Identification of surrogate markers of AG

N. Imaizumi

Bone marrow-derived ‘monocyte-like’ cells recruit to Rip1Tag2 tumors

Lymphocytes

Monocytes

R1 R2

R3

20%

14%

CD34

CD

45FSC

SSC 14%

CD14 positive50% Fl

t-1

44% 42%

2.5%

Tie2

0.4%

Clinical study

Breast cancer patient 870LeukapheresisStimulated with G-CSF

Transcriptome

Proteome

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Individual markers

J. Laurent, E. Faes

Future developments

BMD cells

Bone Marrow

Molecular- Functional Imaging

Molecular Diagnostic & Monitoring

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.Genomics

Lymphangiogenesis

New therapeutic targets

Flt-1

Tie2

Drug design

Cross-talk BM - AG - IS

Proteomics

Future developments

Lausanne Cancer Center

Experimental Oncology

Clinical Oncology

RadiotherapyISREC - NCCR

AcademiaIndustry

Bio

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Mec

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Ther

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RadiologyPathology

CHUV Surgery

ENTLICR

EPFL

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Clinical Oncology

Serge LeyvrazRoger StuppJean BauerNicolas KettererKhalil ZamanVerena Volter

RadiotherapyRené O Mirimanoff

ENTPhilippe Monnier

RadiologyJean-Yves MeuwlyReto Meuli

NeurosurgeryMonika Hegi

Pediatric OncologyNicole Gross

Thoracic SurgeryBear Ris

Experimental Oncology

Agnese Mariotti Gian Carlo Alghisi Jelena Zaric Grégory Bieler Lionel PonsonnetMeriem Hasmim Robert Driscoll Patricia Werffeli-GeorgeNatsuko ImaizumiYan MonnierLaetitia PansierFrédérique BaruthioJulien LaurentEveline FaesAnne PapanicolauNicole Mutter

Past membersFerdy Lejeune

ISRECMichel Aguet

Exp. PathologyIvan Stamenkovic

LICRJean-Charles Cerottini

Department of BiochemistryJürg Tschopp-Nicolas FaselClaude Bron

UNIBASGerhard Christofori

Merck, KGaASimon Goodman

NovartisJeannette Wood

..and many collaborators

Support:SNF, NCCR Molecular Oncology, Roche Research Foundation, Swiss Cancer League/O�CS,

Medic, Leenards Foundation, Novartis, Pfizer, Merck, San Salvatore, BCV