Angiogenesis as a therapeutic target

Transcription

1 Angiogenesis as a therapeutic target Lecture Experimentelle Krebsforschung SS 07 Prof. Gerhard Christofori Institute of Biochemistry and Genetics Department of Clinical-Biological Sciences University of Basel Multistage Tumorigenesis

2 Multistage Colorectal Carcinogenesis Tumor angiogenesis Bergers and Benjamin, 2002, Nat. Rev. Cancer

3 Increased microvessel density in tumors (for example ductal breast carcinoma) Vasculogenesis/Angiogenesis Carmeliet, 2003

4 Tumor angiogenesis in transplanted tumors Weinberg, 2006 Genetic manipulation of mice

5 The Rip1Tag Transgene Hanahan, Nature, 1985 Rip1Tag2 tumorigenesis

6 Multistage Tumorigenesis in Rip1Tag2 Transgenic Mice The angiogenic switch

7 Cellular Events in Tumor Angiogenesis Key Angiogenic Factors

8 VEGF Family Members Clinical Science clinsci.org Clin. Sci.. (2005) 109, Vascular Endothelial Growth Factors and their Receptors Cross et al., TIBS, 2003

9 VEGFs in Vasculogenesis/Angiogenesis Hemangioblast VEGFR-2 Hematopoietic precursor Hematopoietic cells Hematopoiesis Blood cells VEGF-A VEGFR-1 VEGFR-2 Angioblast Primary vascular plexus Vasculogenesis VEGF-A VEGFR-1 Angiogenesis VEGFR-2 VEGFR-3 Enlarged embryonic vasculature (arteries & veins) Lymphangioblast VEGF-C VEGF-D VEGFR-3 EG-VEGF Endothelial differentiation Lymphangiogenesis VEGF-C VEGF-D VEGFR-3 prox-1 permeable blood vessels in steroidogenic glands tight blood vessels e.g. brain Lymphatic vessels Alitalo 2001, Stacker 1999

10 VEGFs and their Receptors Clinical Science clinsci.org Clin. Sci.. (2005) 109, Chick CAM Assay Chorio-Allantoic-Membrane +/- VEGF-A VEGF-Knock-out heterozygous lethal!

11 Hypoxia-induction of VEGF-A gene expression Harris, 2001 HIF-1α regulation Harris, 2001

12 Harris, 2001 Vascular Endothelial Growth Factors and their Receptors

13 The Angiogenic Switch VEGF sequestered by ECM VEGF released by MMP activity (mast cells, Vascular Endothelial Growth Factor-A Cross et al., TIBS, 2003

14 Activation of Vascular Endothelial Growth Factor-A Ferrara et al., 2003 MMPs in breast (and other) tumors Egeblad and Werb, 2002

15 Angiogenic Factors and the ECM Sund et al., 2004 A Simplified Picture of Tumor Angiogenesis VEGFs FGFs Angiopoietins PDGF B TGFβ VEGF receptors FGF receptors Tie-2 (Tie-1?) PDGF-β receptor TGFβ receptors

16 Angiopoietins Jones et al., 2001 VEGFs and Angiopoietins Jones et al., 2001

17 The Fine Balance of Angiogenesis Regulation Bergers and Benjamin, 2002, Nat. Rev. Cancer Angiogenesis Inhibitors Endogenous Therapeutic chemicals antibodies peptides/proteins Folkman, 2004

18 Angiogenesis Inhibitors Cilengitide

19 Endogenous angiogenesis inhibitors Experimental Therapy in Rip1Tag2 Mice Interferon α/β TNP470 Angiostatin Endostatin Thrombospondin MMP inhibitors Cathepsin inhibitors Glivec (imatinib VEFR receptor inhibitors (PTK787,Sugen 6668, ) VEGF-Trap, FGF-Trap VEGF receptor antibodies Immunoliposomes Exendin-4 (GLP1R peptide) AEW471 (IGF1 receptor inhibitor) PDGF receptor inhibitors

20 Anti-Angiogenic Angiogenic Therapy in Rip1Tag2 Mice Bergers et al. Science 1999 Anti-Angiogenic Therapy in Rip1Tag2 Mice Weinberg, 2006

21 A selection of anti-angiogenic drugs approved or in clinical trials Approved for CRC first and second line VEGF-A expression and anti-vegf-a therapy (Avastin( Avastin) Hanrahan et al., 2003 Borgstrom et al., 1999

22 Avastin in Colorectal Cancer Hurwitz et al., 2004 Resistance to anti-angiogenic therapy?

23 Fibroblast Growth Factors and their Receptors Soluble Receptor Constructs Compagni et al., Cancer Res. 2000

24 VEGFs and FGFs are required for Tumor Angiogenesis: Rip1Tag2 tumorigenesis in vivo Compagni et al., Cancer Res A selection of anti-angiogenic drugs approved or in clinical trials

25 A selection of anti-angiogenic drugs approved or in clinical trials Maturation of Vessels Pietras and Hanahan, 2005

26 Two Vascular Systems! Jones et al., 2001 The Lymphatic System

27 Lymphatic vessels Papoutsi et al. Dev. Dyn Lymphatic vessel development Prox-1 as master control gene? Oliver and Detmar, 2002

28 Prox-1-induced lymphatic differentiation Petrova et al., 2002 Tumor angiogenesis and lymphangiogenesis Vasculogenesis = De novo formation of blood vessels Angiogenesis = Formation of blood vessels from pre-existing blood vessels Lymphangiogenesis = Formation of lymphatic vessels Ruoslahti, 2002

29 Lymphangiogenesis and angiogenesis in tumors Crnic et al., 2004 VEGF Family Members and their Receptors ANGIOGENESIS LYMPHANGIOGENESIS

30 Forced Lymphangiogenesis in Rip1VEGF-C Mice wt Rip1VEGF-C Mandriota et al., 2001 Forced Lymphangiogenesis in Rip1Tag2 Mice Rip1Tag2;Rip1VEGF-C LN MET Mandriota et al., 2001

31 Anti-angiogenic therapy ± 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 Jun;9(6): Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell Apr;1(3): Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer Aug;2(8): Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer Jun;3(6): Ferrara N, Gerber HP, LeCouter J.The biology of VEGF and its receptors. Nat Med Jun;9(6): Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer Oct;2(10): Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov Apr;6(4):