Angiogenesis as a therapeutic target · Carmeliet P. Angiogenesis in health and disease. Nat Med....
Transcript of Angiogenesis as a therapeutic target · Carmeliet P. Angiogenesis in health and disease. Nat Med....
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Prof. Gerhard ChristoforiProf. Gerhard Christofori
Institute of Biochemistry and GeneticsInstitute of Biochemistry and GeneticsDepartment of Clinical-Biological SciencesDepartment of Clinical-Biological Sciences
University of BaselUniversity of Basel
Angiogenesis as aAngiogenesis as a therapeutic targettherapeutic target
LectureLectureExperimentelle KrebsforschungExperimentelle Krebsforschung
SS 07SS 07
MultistageMultistage Tumorigenesis Tumorigenesis
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Multistage Colorectal CarcinogenesisMultistage Colorectal Carcinogenesis
Tumor angiogenesis Tumor angiogenesis
Bergers and Benjamin, 2002, Nat. Rev. Cancer
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Increased Increased microvessel microvessel density in tumorsdensity in tumors(for example (for example ductal ductal breast carcinoma)breast carcinoma)
Vasculogenesis/AngiogenesisVasculogenesis/Angiogenesis
Carmeliet, 2003
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Tumor angiogenesis in transplanted tumorsTumor angiogenesis in transplanted tumors
Weinberg, 2006
Genetic manipulation of miceGenetic manipulation of mice
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The Rip1Tag The Rip1Tag TransgeneTransgene
Hanahan, Nature, 1985
Rip1Tag2 Rip1Tag2 tumorigenesistumorigenesis
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Multistage Multistage Tumorigenesis Tumorigenesis in Rip1Tag2 Transgenic Micein Rip1Tag2 Transgenic Mice
““The The angiogenic angiogenic switchswitch””
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Cellular Events in Tumor Angiogenesis Cellular Events in Tumor Angiogenesis
Key Key Angiogenic Angiogenic FactorsFactors
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Clinical Science www.Clinical Science www.clinsciclinsci.org .org ClinClin. . SciSci. (2005) 109, 227-241. (2005) 109, 227-241
VEGF Family MembersVEGF Family Members
Vascular Endothelial Growth Factors and their Receptors Vascular Endothelial Growth Factors and their Receptors
Cross et al., TIBS, 2003
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Hemangioblast
Hematopoietic precursor
VEGFR-2
Alitalo 2001, Stacker 1999
Blood cells
Hematopoiesis
Hematopoietic cells Angioblast
Primary vascular plexus
VEGF-AVEGFR-1VEGFR-2
Vasculogenesis
Enlarged embryonic vasculature(arteries & veins)
VEGF-AVEGFR-1VEGFR-2VEGFR-3
Angiogenesis
EG-VEGFEndothelial
differentiation
„permeable blood vessels“in steroidogenic glands
„tight blood vessels“e.g. brain
Lymphangioblast
VEGF-C VEGF-D VEGFR-3
VEGF-C VEGF-D VEGFR-3
Lymphangiogenesis
prox-1
Lymphatic vessels
VEGFs VEGFs inin Vasculogenesis Vasculogenesis/Angiogenesis/Angiogenesis
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Clinical Science www.Clinical Science www.clinsciclinsci.org .org ClinClin. . SciSci. (2005) 109, 227-241. (2005) 109, 227-241
VEGFs VEGFs and theirand their ReceptorsReceptors
Chick CAM AssayChick CAM Assay
Chorio-Allantoic-MembraneChorio-Allantoic-Membrane+/- VEGF-A+/- VEGF-A
VEGF-Knock-outVEGF-Knock-outheterozygous lethal!heterozygous lethal!
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Hypoxia-induction of VEGF-A gene expressionHypoxia-induction of VEGF-A gene expression
Harris, 2001
HIF-1HIF-1αα regulation regulation
Harris, 2001
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Harris, 2001
Vascular Endothelial Growth FactorsVascular Endothelial Growth Factors
and their Receptorsand their Receptors
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TheThe Angiogenic Angiogenic SwitchSwitch
VEGF sequestered by ECM
VEGF released by MMP activity(mast cells,
Vascular Endothelial Growth Factor-AVascular Endothelial Growth Factor-A
Cross et al., TIBS, 2003
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Activation ofActivation ofVascular Endothelial Growth Factor-AVascular Endothelial Growth Factor-A
Ferrara et al., 2003
MMPs MMPs in breast (and other) tumorsin breast (and other) tumors
Egeblad and Werb, 2002
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Angiogenic Angiogenic Factors and the ECMFactors and the ECM
Sund et al., 2004
A Simplified Picture of Tumor Angiogenesis A Simplified Picture of Tumor Angiogenesis
VEGFs VEGF receptorsFGFs FGF receptorsAngiopoietins Tie-2 (Tie-1?)PDGF B PDGF-β receptorTGFβ TGFβ receptors
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AngiopoietinsAngiopoietins
Jones et al., 2001
VEGFs VEGFs and and AngiopoietinsAngiopoietins
Jones et al., 2001
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The Fine Balance of Angiogenesis Regulation The Fine Balance of Angiogenesis Regulation
Bergers and Benjamin, 2002, Nat. Rev. Cancer
Angiogenesis InhibitorsAngiogenesis Inhibitors
EndogenousEndogenousTherapeuticTherapeutic
chemicalschemicalsantibodiesantibodiespeptides/proteinspeptides/proteins
Folkman, 2004
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Angiogenesis InhibitorsAngiogenesis Inhibitors
Cilengitide
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Endogenous angiogenesis inhibitorsEndogenous angiogenesis inhibitors
Experimental Therapy in Rip1Tag2 MiceExperimental Therapy in Rip1Tag2 Mice
Interferon α/βTNP470AngiostatinEndostatinThrombospondinMMP inhibitorsCathepsin inhibitorsGlivec (imatinib
VEFR receptor inhibitors(PTK787,Sugen 6668, …)VEGF-Trap, FGF-TrapVEGF receptor antibodiesImmunoliposomesExendin-4 (GLP1R peptide)AEW471 (IGF1 receptor inhibitor)PDGF receptor inhibitors
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Bergers et al. Science 1999
Anti-Anti-Angiogenic Angiogenic Therapy in Rip1Tag2 MiceTherapy in Rip1Tag2 Mice
Weinberg, 2006
Anti-Angiogenic Anti-Angiogenic Therapy in Rip1Tag2 MiceTherapy in Rip1Tag2 Mice
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A selection of A selection of anti-angiogenic anti-angiogenic drugs approved drugs approved or or in clinical trialsin clinical trials
Approved for CRCfirst and second line
VEGF-A expression and anti-VEGF-A therapy (VEGF-A expression and anti-VEGF-A therapy (AvastinAvastin))
Borgstrom et al., 1999
Hanrahan et al., 2003
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Avastin Avastin in Colorectal Cancerin Colorectal Cancer
Hurwitz et al., 2004
Resistance to Resistance to anti-angiogenic anti-angiogenic therapy?therapy?
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Fibroblast Growth Factors and their Receptors Fibroblast Growth Factors and their Receptors
Soluble Receptor ConstructsSoluble Receptor Constructs
Compagni et al., Cancer Res. 2000
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VEGFs VEGFs and and FGFs FGFs are required for Tumor Angiogenesis:are required for Tumor Angiogenesis:Rip1Tag2Rip1Tag2 tumorigenesis tumorigenesis in vivoin vivo
Compagni et al., Cancer Res. 2000
A selection of A selection of anti-angiogenic anti-angiogenic drugs approved drugs approved or or in clinical trialsin clinical trials
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A selection of A selection of anti-angiogenic anti-angiogenic drugs approved drugs approved or or in clinical trialsin clinical trials
Maturation of Vessels Maturation of Vessels
Pietras and Hanahan, 2005
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Two Vascular Systems!Two Vascular Systems!
Jones et al., 2001
The Lymphatic SystemThe Lymphatic System
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Lymphatic vesselsLymphatic vessels
Papoutsi et al. Dev. Dyn. 2001
Lymphatic vessel development Lymphatic vessel development
Prox-1 as Prox-1 as master control gene?master control gene?
Oliver and Detmar, 2002
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ProxProx-1-induced lymphatic differentiation -1-induced lymphatic differentiation
Petrova et al., 2002
Tumor angiogenesis andTumor angiogenesis and lymphangiogenesis lymphangiogenesis
Vasculogenesis = De novo formation of blood vessels
Angiogenesis = Formation of blood vessels from pre-existing blood vesselsLymphangiogenesis = Formation of lymphatic vessels
Ruoslahti, 2002
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Lymphangiogenesis Lymphangiogenesis and angiogenesis in tumors and angiogenesis in tumors
Crnic et al., 2004
VEGF Family Members and their ReceptorsVEGF Family Members and their Receptors
ANGIOGENESIS LYMPHANGIOGENESIS
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Rip1VEGF-C
wt
ForcedForced Lymphangiogenesis Lymphangiogenesis in Rip1VEGF-C Mice in Rip1VEGF-C Mice
Mandriota et al., 2001
Rip1Tag2;Rip1VEGF-C
METLN
ForcedForced Lymphangiogenesis Lymphangiogenesis in Rip1Tag2 Mice in Rip1Tag2 Mice
Mandriota et al., 2001
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Anti-angiogenic Anti-angiogenic therapytherapy
• ± general mechanism in solid tumors
• no or low resistance
• defined targets
• no angiogenesis in adults, low side effects
• synergism with chemo- and radiotherapy
• anti-metastatic?
• efficacy?
• longterm treatment, side effects?
• resistance afterall?
• lymphangiogenesis - lymph node metastasis
• inflammation!
Reviews:
Carmeliet P. Angiogenesis in health and disease.Nat Med. 2003 Jun;9(6):653-60.
Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease.Cancer Cell. 2002 Apr;1(3):219-27.
Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancermetastasis. Nat Rev Cancer. 2002 Aug;2(8):573-83.
Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch.Nat Rev Cancer. 2003 Jun;3(6):401-10.
Ferrara N, Gerber HP, LeCouter J.The biology of VEGF and its receptors.Nat Med. 2003 Jun;9(6):669-76.
Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002Oct;2(10):795-803.
Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov.2007 Apr;6(4):273-86.