Therapeutic potential of cellular signalling pathway inhibition: conclusions

1
Understanding the therapeutic potential of
cellular signalling pathway inhibition
Nico van Zandwijk Sydney University,Asbestos
Diseases Research Institute,Sydney, Australia
2
Building the foundations improvements in
first-line advanced NSCLC therapy
Schiller, et al. NEJM 2002 Sandler, et al. NEJM
2006
BSC best supportive care
3
Angiogenesis essential for the growth and
malignant progression of tumours
Premalignant tumour
Malignant tumour
Tumourgrowth
Vascularinvasion
Micro- metastases
Metastatic growth
Angiogenicswitch
Stages at which angiogenesis plays a role
intumour progression
Adapted from Poon, et al. JCO 2001
4
Angiogenesis is a tightly regulated balance
The angiogenic switch
Pro-angiogenic factors (e.g. VEGF, PlGF, bFGF,
IL-8)
Anti-angiogenic factors (e.g. thrombospondin-1,
angiostatin, IFN-?/?)
bFGF basic fibroblast growth factor
ILinterleukinPIGF placenta growth
factorVEGF vascular endothelial growth factor
Hanahan Folkman. Cell 1996
5
VEGF is central to theangiogenic switch in
tumours
PDGF
Hypoxia
IGF-1
EGF
IL-8
Binding and activation of VEGFR
VEGF release
bFGF
COX-2 Nitric oxide Oncogenes
Increased expression (MMP, tPA, uPA, uPAr, eNOS,
etc.)
Proliferation
Survival
Migration
Permeability
ANGIOGENESIS
COX cyclooxygenase EGF epidermal growth
factorIGF insulin-like growth factorPDGF
platelet-derived growth factorVEGFR vascular
endothelial growth factor receptor
Ferrara, et al. Endocr Rev 1997 Kerbel, et al.
Nat Rev Cancer 2002
6
Angiogenesis the key role of VEGF
7
Key landmarks in understanding angiogenesis and
its role in tumour development
1990s
1Ferrara. Nat Rev Cancer 2002 2Folkman. NEJM 1971
8
Targeting angiogenesis VEGF ligand versus VEGF
receptor
9
Inhibition of VEGF active development programme
for angiogenesis inhibitors
Antibodies inhibiting VEGF receptors
Soluble VEGF receptors (e.g. VEGF-TRAP)
Anti-VEGF antibodies(e.g. Avastin)
VEGF
VEGFR-2
Small molecule VEGFR inhibitors (TKIs) (e.g.
sunitinib, sorafenib, vatalanib, vandetanib)
Migration, permeability, DNA synthesis, survival
Ribozymes (e.g. Angiozyme)
Lymphangiogenesis
Angiogenesis
TKI tyrosine kinase inhibitor
10
Avastin is the first and only anti-angiogenic
that directly inhibits VEGF, the key mediator of
angiogenesis

• Avastin
• inhibits angiogenesis through a novel mechanism
  of action
• prevents the binding of VEGF to its receptors
• is the only anti-VEGF agent currently in clinical
  use for the treatment of advanced NSCLC

VEGF
Avastin
X
X
Growth Proliferation Migration Survival
11
EGFR pathway is mediated by a family of ligands
and membrane receptors
Salomon, et al. Hematol 1995 Woodburn. Pharmacol
Ther 1999
HER human epidermal growth factor receptorTGF
transforming growth factor
12
EGFR pathway is complex but well understood
Extracellular
Intracellular
Transactivation
Src PLCg GAP Grb2 Shc Nck Vav Grb7 Crk
Ras
PKC
Abl
JNK
PI3K Akt
MAPK
Proliferation, invasion, metastasis, angiogenesis
and inhibition of apoptosis
Woodburn. Pharmacol Ther 1999 Lynch, et al. NEJM
2004Knowlden, et al. Endocrinol 2003
Chakravarti, et al. Cancer Res 2002
13
Inhibition of tyrosine kinase phosphorylationhas
a range of anti-tumour effects
Tarceva
Apoptosis

• Sensitivity to
• other therapies
• (e.g. chemotherapy)

Etessami Bourhis. Drugs Future 2000 Moyer, et
al. Cancer Res 1997Harari Huang. Semin Radiat
Oncol 2002
inhibition
14
Key landmarks in understanding the EGFR pathway
and its role in tumour development
1990s
1Cohen. J Biol Chem 1962 2Cohen, et al. J Biol
Chem 1980 3Ullrich, et al. Nature 1984
15
Therapeutic potential of cellular signalling
pathway inhibition conclusions
VEGF is the key mediator of tumour
angiogenesis and is essential for tumour growth
and metastasis
EGFR plays a vital role in the growth and
progression of malignant tumours