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Underlying Principles and Future Targets for Molecular Therapy of SCCHN
Prof. Tim H. BrümmendorfDept. 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
Protein kinases
Serine/Threonine kinases
Tyrosine kinases
Non-receptor tyrosine kinases
Receptor tyrosine kinases PDGFRc-KitFlt-3VEGFR
AblSrc
Aurora kinases A-CmTORPolo-like kinase
Receptor tyrosine kinases (RTKs)
Selected RTKs involved in malignant transformation
modified from Blume-Jensen and Hunter 2001
EGFR InsulinR PDGFR VEGFR FGFR NGFR HGFR
CRD
FNIII
a
b
IgD
AB
LRD
a b
Activation of RTKs (I) Dimerization
Binding of the hormone to the receptor Receptor dimerization causes autophosphorylation
Receptor dimer
Monomeric receptor
GDP
Inactive Ras
EGF
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
Non-receptor tyrosine kinases
Selected non-RTKs involved in malignant transformation
modified from Blume-Jensen and Hunter 2001
SH2 SH3 kinase
SH2 SH3 kinase DNA actin
FERM Kinase-like kinase
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
modifiziert nach Kantarjian H et al. Hematology. 2000:90-109
BCR-ABLZytoskelett-
proteine
P
MYC
?
Zellkern
P
RAS-GAP
RAS-GTP
SAPKP
CBL CRK
PI-3K P
BAD
14-3-3
P
BCLXL
14-3-3Mitochondrium
BCLXL
BAD
RAS-GDP
AKT
ERKP
STAT1+5P
GRB-2SOS
SHC DOK CRKL
PMEK1/2
RAF-1
Apoptoseweg
RAS-WegAdhäsionsweg
P: Phosphat
P
BCR-ABL Signaltransduktionswege
Imatinib (Glivec) treatment in Imatinib (Glivec) treatment in Chronic myeloid leukemia (CML)Chronic myeloid leukemia (CML)
O
2-Phenylaminopyrimidin
Y = TyrosineP = Phosphate
Bcr-Abl
ATP SubstrateSTI571
Bcr-Abl
PPP
P
modifiziert von: Garcia-Manero et al., Cancer 2003
*modifiziert von: Druker et al. ASCO 2006
IFN-alpha*
Signalling pathways and targets involved in SCCHN and their potential inhibitors
LeTourneau et al. Europ. J. Cancer 2007
LeTourneau et al. Europ. J. Cancer 2007
Antitumor activity of selected targeted agents in > phase I development in SCCHN
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
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