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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?