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

Thariat et al. Int J Rad Oncol Biol Phys 2007

EGF-R signalling and downstream pathways

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