eine verhängnisvolle affäre: wie tumoren blut- und ... page 1 eine verhängnisvolle affäre: wie...
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Eine verhängnisvolle Affäre: Wie Tumoren Blut- und Lymphgefäße für ihre Zwecke nutzen
Hellmut G. AugustinMedical Faculty Mannheim, University of Heidelberg (CBTM) and
German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance)
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German Federal Statistics Agency
Neoplasia
25,7%
5,9%
4,9%
4,1%12,1%
47,3%
Pulmonarydiseases
Gastrointestinaldiseases
Non-naturalcauses of death
Otherfatalities
Cardiovasculardisease
Other disesase of thecardiovascular system
Cerebrovasculardiseases
Cardiacinsufficiency
Other ischemia cardiacdiseases
Myocardial infarct
22,8%
20,1%
15,0%
24,0%
18,1%
The vasculature is causally involved in most cases of human death
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Tumor biology research in the 21st century: Identification of novel therapeutic targets
• Classical tumor therapy:
iron and radiation (“Stahl und Strahl”) → Surgery, radiotherapy, chemotherapy
Problem: Classical tumor therapies non specifically target proliferating cells
• Today: targeted therapies attacking specific targets of tumor cells, e.g., Herceptin, Gleevec
• Future: The neoplastically transformed tumor cells may not be the primary target of anti-tumor therapies. Instead, tumor-host interactions may be targetet
• Tumor-Host-Interactions:- Interactions with the immune system- Invasion into the normal tissue
- Tumor blood supply (tumor angiogenesis)
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vesselsblood vessels
recruitedcells
stromatumor cellsfibroblasts
lymphatics
Multi-compartment analysis of malignant tumor growth
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palpabletumor
(109 cells)
radiodiagnostic tumor detection
(108 cells)
death of the patient(1012 cells)
tumor promotion tumor progression metastasis
tumor cell-centric researchcomplex tumor-host interaction research
(the tumor as an organ)tumor initiation(clonal event)
Basic and translational tumor biology research: Quo vadis?
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Development of the vascular system
mesodermal progenitor cells
blood cells
endothelial cells organization ofendothelial cells
primary capillary plexus
Vasculogenesis
mature vessels
Angiogenesis
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female reproduction
peripheral vascular disease
insufficientangiogenesis
myocardial infarct
Physiological and pathological angiogenesis
increasedangiogenesis
retinopathiestumors
physiologogicalangiogenesis
embryonic development
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Growth andmetastasisIn situ Tumor
EC Proliferationtumor growth
AngiostimulatorsAngioinhibitors
Induction of angiogenesis
Tumor angiogenesis
Antiangiogenesis-mediated
tumor regression
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Lymph nodemetastasis
Metastasis viathe blood stream
Primary tumor
Angiogenesis is a prerequisite for metastasis
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tumor
capillary
Malignant tumors need blood vessels
www.targetvegf.com
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angiogenic factors
angiogenesis
The “Angiogenic Switch” induces formation of blood vessels
www.targetvegf.com
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tumor cells
vascularization
Angiogenesis induces growth and metastasis of tumors
www.targetvegf.com
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Tumors
Rheumatoid arthritis
Ischemic retinopathies
AMD, age-dependent macular degeneration
Chronic transplant rejection
Psoriasis
Atherosclerosis
Restenosis
Obesity
Pulmonary hypertension
Chronic respiratory diseases
Cerebral ischemia
Dementia (CADASIL)
Pathological angiogenesis is not restricted to tumor growth
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TAF
1970 1980 1990 2000 2006
FDA approval of Bevacizumab
500
1000
2000
1500
3500
3000
2500
0
4000
Evolution of angiogenesis research according to citations
Angiogenesis-dependencyof malignant tumor growth
Judah Folkman
Activators InhibitorsVEGF/VEGFR
Discovery of VPF
Harold Dvorak
Discovery of VEGF
Napoleone Ferrara
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Angiogenesis-regulating growth factors and their receptors
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Angiogenesis-regulating signaling systems
VEGF/VEGFRVasculogenesis
Sprouting
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cell membrane
Binding domain
Tyrosine kinase domain I-P
-P
P-
P-
VEGF
Angiogenesis
Tyrosine kinase domain II
Vascular endothelial growth factor (VEGF) interacts with VEGFR
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Deletion of VEGF or its receptor causes embronic lethality
Deletion of one allele of VEGF during development is already lethal
Flk1 +/+ Flk1 +/- Flk1 -/-
E 8.5
Shalaby et al.Nature 1995
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VEGF/VEGFRVasculogenesis
Sprouting
Ephrin/EphSema/NP/Plexins
Netrins/UncNotch/DeltaSlit/Robo
AssemblyGuidance
Ang/TiePDGF/PDGFR
DifferentiationMaturationQuiescence
Angiogenesis-regulating signaling systems
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Disruption of endothelialcells
www.targetvegf.com
Anti-angiogenesis: Therapeutic manipulation of angiogenesis
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Regressionof blood vessels
Shrinking tumor
www.targetvegf.com
Anti-angiogenesis: Therapeutic manipulation of angiogenesis
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From: Molls and Vaupel, eds. Blood Perfusion and Microenvironment of Human Tumors, 2002
Normal colorectal mucosa Adjacent colorectal tumor
Punchline: The chaotropic tumor vasculature is different from the normal, organized organ vasculature. Any molecular difference can in principle be therapeutically exploited!
Anti-angiogenesis: Therapeutic manipulation of angiogenesis
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• VEGF is overexpressed in most tumors.
• VEGF is regulated by hypoxia, cytokines and oncogenes.
• VEGF activates several signalling cascades in endothelial cells.
VEGF is the the primary target for anti-angiogenic therapy
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Tumor cell
Endothelial cells
VEGF-receptors
Growth factors producedby tumors, e.g. VEGF
Strategies to inhibit (tumor) angiogenesis
XX
Blockade ofreceptor activation
antibodysoluble receptors
Sunitinib (Sutent) (Pfizer)Sorafenib (Nexavar) (Bayer-Schering)
Avastin (Bevacizumab)(Genentech/Roche)VEGF Trap
(Regeneron/Sanofi-Aventis)
VEGF Production(Antisense/Aptamer) (Macugen, Eyetech)
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Phase III trial/Roche and Genentech
815 patients with colorectal carcinomas
Irinotecan/5-FU/FA (IFL) ± Avastin
Increase of survival rate from 15.6 month to 20.3 month after Avastin treatment
Costs per patient
26.000 EUR
Extension of mean survival duration from 15.6 months to 20.3
months.
5 months may not be much in absolute terms; yet, relatively
speaking, it‘s 25%.
Likewise: Data are not parametrically distributed.
VEGF inhibiting antibody Bevacizumab (Avastin)
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KEYWORD: COMBINATION
synergy EITHER: Inhibition of factors of
the angiogenic cascade
OR: exploitation of endogenous
angiogenesis inhbitors
radiotherapy other angiogenesis targetschemotherapy
good synergy
What’s in the pipeline after anti-VEGF therapies?