1. Underlying Principles and Future Targets for Molecular Therapy of SCCHN Prof. Tim H. Brümmendorf Dept. of Hematology and Oncology University Hospital Eppendorf Hamburg

2. 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 Protein kinases Serine/Threonine kinases Tyrosine kinases Non-receptor tyrosine kinases Receptor tyrosine kinases PDGFR c-Kit Flt-3 VEGFR Abl Src Aurora kinases A-C mTOR Polo-like kinase

3. Receptor tyrosine kinases (RTKs) Selected RTKs involved in malignant transformation modified from Blume-Jensen and Hunter 2001 EGFRInsulinRPDGFRVEGFRFGFRNGFRHGFR CRD FNIII a b IgD AB LRD a b

4. Activation of RTKs (I) Dimerization Binding of the hormone to the receptorReceptor dimerization causes autophosphorylation Receptor dimer Monomeric receptor GDP Inactive Ras EGF Modifed from Lodish: Molecular cell biology

5. Activation of RTKs (II) Signaling through adaptor proteins Coupling of inactive Ras through Sos/GBR2Sos exchanges GDP and activated Ras dissociates GTP Active Ras Signaling Modifed from Lodish: Molecular cell biology

6. Thariat et al. Int J Rad Oncol Biol Phys 2007 EGF-R signalling and downstream pathways

7. Non-receptor tyrosine kinases Selected non-RTKs involved in malignant transformation modified from Blume-Jensen and Hunter 2001 SH2SH3kinase SH2SH3kinase DNA actin FERMKinase-likekinase SRC ABL JAK 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

8. modifiziert nach Kantarjian H et al. Hematology. 2000:90-109 BCR-ABL Zytoskelett- proteine P MYC ? Zellkern P RAS-GAP RAS-GTP SAPK P CBL CRK PI-3K P BAD 14-3-3 P BCLX L 14-3-3 Mitochondrium BCLX L BAD RAS-GDP AKT ERK P STAT1+5 P GRB-2 SOS SHC DOK CRKL P MEK1/2 RAF-1 Apoptoseweg RAS-Weg Adhäsionsweg P : Phosphat P BCR-ABL Signaltransduktionswege

9. Imatinib (Glivec) treatment in Chronic myeloid leukemia (CML) O 2-Phenylaminopyrimidin Y = Tyrosine P = Phosphate Bcr-Abl ATP Substrate STI571 Bcr-Abl P P P P modifiziert von: Garcia-Manero et al., Cancer 2003 *modifiziert von: Druker et al. ASCO 2006 IFN-alpha*

10. Signalling pathways and targets involved in SCCHN and their potential inhibitors LeTourneau et al. Europ. J. Cancer 2007

11. LeTourneau et al. Europ. J. Cancer 2007 Antitumor activity of selected targeted agents in > phase I development in SCCHN

12. 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