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Underlying Principles and Future Targets for Molecular Therapy of SCCHN Prof. Tim H. Brümmendorf Dept. of Hematology and Oncology University Hospital Eppendorf Hamburg Protein kinases Introduction • Approximately 32.000 genes are encoded by the human genome • About 6.000 of this genes are involved in signal tranduction pathways • Among these, 520 are protein kinases (app. 130 tyrosine kinases) • Kinases katalyze transfer of phosphate from ATP to AA residues in polypeptides Serine/Threonine kinases Aurora kinases A-C mTOR Polo-like kinase Protein kinases Non-receptor tyrosine kinases Abl Src Tyrosine kinases Receptor tyrosine kinases PDGFR c-Kit Flt-3 VEGFR Receptor tyrosine kinases (RTKs) Selected RTKs involved in malignant transformation EGFR InsulinR a PDGFR VEGFR FGFR NGFR HGFR a b IgD CRD LRD FNIII b AB modified from Blume-Jensen and Hunter 2001 Activation of RTKs (I) Dimerization Binding of the hormone to the receptor Receptor dimerization causes autophosphorylation EGF Receptor dimer Monomeric receptor GDP Inactive Ras Modifed from Lodish: Molecular cell biology Activation of RTKs (II) Signaling through adaptor proteins Coupling of inactive Ras through Sos/GBR2 Sos exchanges GDP and activated Ras dissociates GTP Active Ras Signaling Modifed from Lodish: Molecular cell biology EGF-R signalling and downstream pathways Thariat et al. Int J Rad Oncol Biol Phys 2007 Non-receptor tyrosine kinases Selected non-RTKs involved in malignant transformation SRC SH2 SH3 kinase ABL SH2 SH3 kinase JAK FERM actin DNA Kinase-like kinase • non-RTKs are typically kept in an inactive state by • inhibitory proteins and • through intramolecular autoinhibition • Activation occurs by • Dissociation of inhibitors • Recruitment to transmembrane receptors (causing oligomerization/autophosph.) • trans-phosphorylation from other kinases modified from Blume-Jensen and Hunter 2001 BCR-ABL Signaltransduktionswege P GRB-2 SHC SOS Adhäsionsweg P STAT1+5 BCR-ABL P Zytoskelettproteine DOK ? RAS-GTP RAS-GDP SAPK RAF-1 P P AKT MEK1/2 ERK BCLXL Mitochondrium : Phosphat modifiziert nach Kantarjian H et al. Hematology. 2000:90-109 P P BCLXL P PI-3K P RAS-Weg P MYC CRKL CBL CRK RAS-GAP BAD BAD 14-3-3 14-3-3 Apoptoseweg Imatinib (Glivec) treatment in Chronic myeloid leukemia (CML) O IFN-alpha* 2-Phenylaminopyrimidin *modifiziert von: Druker et al. ASCO 2006 Y = Tyrosine P = Phosphate Bcr-Abl Bcr-Abl P P P ATP STI571 Substrate P modifiziert von: Garcia-Manero et al., Cancer 2003 Signalling pathways and targets involved in SCCHN and their potential inhibitors LeTourneau et al. Europ. J. Cancer 2007 Antitumor activity of selected targeted agents in > phase I development in SCCHN LeTourneau et al. Europ. J. Cancer 2007 Conclusion • A number of promising new targeted treatments are currently beeing evaluated in SCCHN • However, the specific role of most of these targets in SCCHN is insufficiently defined: deregulation causative or epiphenomenal ? • Intensified research efforts on the identification of novel (ideally non-redundant) targets and/or synergistic targeted approaches is clearly warranted • Novel biomarkers for response prediction are urgently needed • Ideally, promising compounds should be evaluated early in systemic treatement
