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
logy
Mec
hani
sms
Ther
apy
Dia
gnos
is
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
apy
Dia
gnos
is
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
logy
Mec
hani
sms
Ther
apy
Dia
gnos
is
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
logy
Mec
hani
sms
Ther
apy
Dia
gnos
is
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