GKA deel 1 college 14

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  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GK 2009 a.a.m.thomas@uu.nl
  • GKA deel 1 college 14

    1. 2. Angiogenesis inhibitors Folkman Sci Am 275-3, 1996 <ul><li>Phase I: small trial, toxicity, maximum safe dose </li></ul><ul><li>Phase II: small trials for efficacy </li></ul><ul><li>Phase III: large trials that compare new therapy with best available treatment </li></ul><ul><li>Endostatin </li></ul><ul><li>Angiostatin </li></ul><ul><ul><li>Fragment plasminogen </li></ul></ul><ul><li>Aimed against non-tumor cells </li></ul><ul><ul><ul><li> Prevents resistence </li></ul></ul></ul>GK 2009 Drug Possible mechanism of action Current status CAI Inhibits Ca²+ influx, suppresses endothelial cells Phases I and II CM101 Induces inflammation in tumors, destroying growing capillaries Phase I Interferon  Decreases FGF production (made by tumor cells) Phase II Interleukin-1,2 Increases production of angiogenic inhibitor Phase I Marimastat Inhibits enzymes that destroy ECM Phases II and III Thalidomide Unknown? Phases I and II TNP-470 Inhibits proliferation endothelial cells Phases I and II Platelet factor 4 Inhibits proliferation endothelial cells Phases I and II Pentosan polysulfate Blocks effect of growth factors on endothelial cells Phases I
    2. 3. Angiogenesis inhibitors Folkman Sci Am 275-3, 1996 <ul><li>Mechanisms of angiogenesis drugs </li></ul><ul><ul><li>Becker, Nature Biotechnol 2004, 22, 15-18 </li></ul></ul><ul><ul><li>VEGF: vascular endothelial growth factor </li></ul></ul><ul><ul><ul><li>Mitogen for endothelial cells, just as FGF </li></ul></ul></ul>GK 2009 VEGF FGF
    3. 4. Surgery of primary tumor allows metastasis to grow Folkman Sci Am 275-3, 1996 <ul><li>Surgery removes </li></ul><ul><ul><li>Primary tumor </li></ul></ul><ul><ul><li>Source of angiostatin  growth metastasis </li></ul></ul>GK 2009 =============== http://angiogenesis.amgen.com/
    4. 5. From bench top to bedside Barinaga, Science 278, 1997, 1036-1039 <ul><li>Newer version: Nature Biotech 2004, 22, 15-18 </li></ul><ul><ul><li>Copy in reader </li></ul></ul>GK 2009
    5. 6. From bench top to bedside Barinaga, Science 278, 1997, 1036-1039 <ul><li>Newer version: Nature Biotech 2004, 22, 15-18 </li></ul><ul><ul><li>Copy in reader </li></ul></ul>GK 2009 Herceptine ONYX-015 Gleevec Farnesyl
    6. 7. Fatty anchor of Ras Barinaga, Science 278, 1997, 1036-1039 <ul><li>Ras has farnesyl = lipid modification </li></ul><ul><li>FT: farnesyl transferase </li></ul><ul><li>FT-inhibitor inhibits </li></ul><ul><ul><li>All types of tumors </li></ul></ul><ul><ul><li>??? </li></ul></ul>GK 2009                                       
    7. 8. Effect van ONYX-015 Barinaga, Science 278, 1997, 1036-1039 GK 2009 The ‘adeno-trick’: Ellisen en Haber
    8. 9. Cancer drug: Gleevec=Glivec=imatinib=STI-571 <ul><li>ATP-analogue, small organic molecule </li></ul><ul><li>Binds ATP-binding site of </li></ul><ul><ul><li>PDGF-R, a tyrosine kinase </li></ul></ul><ul><ul><ul><li>Some tumors </li></ul></ul></ul><ul><ul><li>BCR-ABL </li></ul></ul><ul><ul><ul><li>Leukemia by translocation ABL to BCR </li></ul></ul></ul><ul><ul><ul><li>Philadelphia chromosome </li></ul></ul></ul><ul><ul><li>c-KIT </li></ul></ul><ul><ul><ul><li>Regulates immune system </li></ul></ul></ul><ul><li>Gleevec inhibits some tumors </li></ul><ul><ul><li>In spite of (!) -effect on c-KIT </li></ul></ul><ul><ul><li>C-KIT overexpression in gastro-intestinal tumor </li></ul></ul><ul><ul><li>Resistance against Gleevec: Y253F </li></ul></ul><ul><li>Comparable: Iressa blocks EGF-receptor </li></ul><ul><ul><ul><ul><ul><li>N Engl J Med 347, 2002, 462-463 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Nature 416, 2002, 470-474 </li></ul></ul></ul></ul></ul>GK 2009
    9. 10. Gleevec <ul><li>Fits ATP-binding site of some tyrosine kinases </li></ul><ul><li>“ Promiscuous” </li></ul><ul><ul><li>‘ Playing dirty’ </li></ul></ul><ul><ul><ul><li>Frantz, Nature 437, 2005, 942-43 </li></ul></ul></ul>GK 2009 ============== Becker, Nature Biotechnol 2004, 22, 15-18 <ul><li>CML: Chronic myelogenous leukemia </li></ul>
    10. 11. Targeting Tyrosine Kinases in Cancer: The Second Wave Jose Baselga, Science 2006, 312, 1175-1178 <ul><li>Tumor types, genetics </li></ul><ul><ul><li>Elements that lead to improved drugs </li></ul></ul>GK 2009 ===============
    11. 12. The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 GK 2009
    12. 13. The hallmarks of cancer Hanahan & Weinberg, Cell 100, 2000, 57-70 GK 2009 Mantovani Nature 457, 36-37(2009)

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