Underlying Principles and Future Targets for Molecular Therap y of SCCHN

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

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

3. EGFR InsulinR PDGFR VEGFR FGFR NGFR HGFR a b a IgD CRD LRD AB FNIII b Receptor tyrosine kinases (RTKs) Selected RTKs involved in malignant transformation modified from Blume-Jensen and Hunter 2001

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

5. GTP Active Ras Signaling Activation of RTKs (II)Signaling through adaptor proteins Coupling of inactive Ras through Sos/GBR2 Sos exchanges GDP and activated Ras dissociates Modifed from Lodish: Molecular cell biology

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

7. SRC SH2 SH3 kinase ABL SH2 SH3 kinase DNA actin JAK FERM Kinase-like kinase Non-receptor tyrosine kinases Selected non-RTKs involved in malignant transformation • 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

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

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

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

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

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