Transcript New Options for patients with imatinib

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