Загрузил Дмитрий Хоченков

Inhibition of VEGF signaling

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Inhibition of VEGF signaling
Disrupting the process
of angiogenesis
Putting progress into practice
Angiogenesis
•
•
Angiogenesis is the formation of new blood vessels from
pre-existing vasculature
Angiogenesis is highly dependent on the VEGF signaling
pathway
–
•
•
•
VEGFR-2 is the most important VEGF signaling pathway for
angiogenesis
VEGF is frequently overexpressed in cancer and is
associated with poor prognosis
Without a blood supply, tumors do not grow larger than
1–2mm
As tumors grow they become hypoxic, which leads to
the up-regulation of angiogenic factors such as VEGF
–
Stimulates the production of new vasculature
Tumor angiogenesis
5. Intravasation
1. Secretion of
angiogenic
factors
2. Proteolytic
destruction
of ECM
Tumor
4. Appearance
of new tumor
vasculature
3. Endothelial
cell proliferation
and migration
Sprouting capillary
ECM, extracellular matrix
Summary of VEGF function
•
VEGF is a key angiogenic regulator directly
implicated in
– endothelial cell proliferation
– endothelial cell migration
– endothelial cell protease expression
– endothelial cell adhesion
– capillary tube formation
– vessel maturation/pericyte recruitment
•
It also acts as
– a survival factor for newly formed vasculature
– Vascular Permeability Factor
Activation of VEGF receptor signaling
PlGF
VEGF-A
VEGF-B
VEGF-A
VEGF-C
VEGF-D
VEGF-C
VEGF-D
Blood vascular
endothelial cell
VEGFR-1
VEGFR-2
VEGFR-3
Lymphatic
vascular
endothelial
cell
Proliferation, vascular permeability, migration, survival
PlGF, placental growth factor
VEGFR, vascular endothelial growth factor receptor
Inhibition of VEGF signaling
•
Inhibiting VEGF signaling
– inhibits growth of new tumor vessels
– decreases vascular density, diameter and
permeability
– may induce regression of recently developed
tumor microvessels
•
Therapeutic inhibition of tumor angiogenesis
should be effective in a broad range of solid
malignancies
•
Target tissue is in direct contact with blood,
facilitating drug delivery
Approaches to the inhibition
of VEGF signaling
Ligands
Monoclonal
antibody
VEGF-A
VEGF-B
VEGF-C
VEGF-D
Anti-VEGF
antibodies
Blood vascular
endothelial cell
Lymphatic
vascular
endothelial
cell
VEGFR-1
VEGFR-2
VEGFR-3
Approaches to the inhibition
of VEGF signaling
Ligands
VEGF-A
VEGF-B
VEGF-C
VEGF-D
VEGFR-TKIs
Lymphatic
vascular
endothelial
cell
Blood vascular
endothelial cell
VEGFR-TKI
VEGFR-1
Inhibition
X
X
VEGFR-2
X
Angiogenesis
VEGFR-3
X
Lymphangiogenesis
VEGFR-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor
VEGFR tyrosine kinase research at
AstraZeneca
•
Preclinical studies have evaluated the potency,
selectivity, anti-angiogenic and antitumor
activity of VEGFR tyrosine kinase inhibitors
(VEGFR-TKIs) at AstraZeneca
•
The lead VEGFR-TKI is currently in Phase II/III
trials in NSCLC and CRC, and work is also
ongoing to determine the activity in a wide
range of other tumors
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