Transcript presentation Dr Pedley

MBBS Cancer Biology Module 2006
Tumour Vasculature
and Therapeutic Strategies
Barbara Pedley
TUMOUR ANGIOGENESIS
• What is tumour angiogenesis?
• Why is it important?
• Why is it a good target for therapy?
• What examples are there of cancer therapies
that selectively target the vasculature?
Tumour Angiogenesis
• Formation of new vessels from pre-existing vasculature
• Required for tumour growth (>1mm3) and metastasis
Cell
Differentiation
Cell Migration
Angiogeni
c
Stimulus
Cell Division
BM & ECM Breakdown
tumour
Angiogenic Switch
Initiated by switch in balance from anti- to pro-angiogenic factors
Pro-angiogenic factors eg:
VEGF
FGF
PDGF
Anti-angiogenic factors eg:
Angiostatin
Endostatin
Thrombospondin
Differences between tumour and normal
vessels
• High endothelial cell proliferation rate
(3-13 v 47-2000 day)
• Distorted and chaotic architecture, with
sluggish blood flow, shunts and dead ends
• Leaky vessels
• Frequently results in regions of hypoxia
Normal v tumour vessels
normal
Well Oxygenated
tumour
BUT: Tumour Vessel Abnormalities are Targetable
Advantages of Vessel v Tumour Cell Targeting
• Rapidly dividing
• Accessibility
• 1 capillary supports many tumour cells
• No drug resistance
• Applicable to all solid tumours
Tumour vessels
TUMOUR BLOOD VESSELS:
A TARGET FOR NOVEL THERAPEUTICS
I.
Endogenous inhibitors
II. Small molecule inhibitors & antibodies
III. Antivascular drugs
All in clinical trials
http//cancertrials.nci.nih.gov/news/angio/table.html
Kerbel R & Folkman J. Clinical translation of angiogenesis inhibitors.
Nature Reviews 2: 727-739, 2002.
Falm E. Angiogenic inhibitors in clinical development. BJC 90: 1-7, 2004.
Neri D & Bicknell R (2005). Tumour vascular targeting. Nature Reviews/ Cancer 5:
536-446.
I. Endogenous inhibitors eg angiostatin
Saline
Angiostatin
Effect of angiostatin on corneal vessel
proliferation
II. Small molecule inhibitors & antibodies
• Inhibitors of matrix metalloproteinases
block ECM breakdown
• Anti-integrin antibodies eg Vitaxin
block endothelial cell adhesion & survival
• Anti-VEGF antibodies eg Avastin
blocks growth factor function & signalling
The first anti-angiogenesis strategy to be licenced by the FDA
to treat human cancer (2004)
VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
• Expressed at high levels by many tumours
• Reacts with receptors on vascular endothelium
• Functions essential for tumour growth:
promotes angiogenesis
promotes vascular permeability
• Clinical importance
high VEGF levels in tumour and plasma frequently
correlate with poor prognosis
Bevacizumab (AvastinTM) - Survival
IFL: bolus 5-FU 500 mg/m2
leucovorin 20 mg/m2
irinotecan 125 mg/m2
Gerber & Ferrara, Cancer Res 65: 671-680, 2005
Expensive!
III Antivascular Drugs eg. Combretastatin
• tubulin binding agent/colchicine binding site
• targets angiogenic and established tumour vessels
• inhibits tumour blood flow
• destroys all but the tumour rim
V
V
V
Untreated
N
24 h post drug
Effect of colchicine therapy: 1945
RADIOIMMUNOTHERAPY
CT scans showing response
Radionuclide 131I
Antibody
Bystander
effect
Antigen
eg CEA
before
DNA strand breaks
Cell death
after
Tumour cell
Basis of Combined Therapies
V
N
Blood vessel distribution
Combretastatin 24h
Antibody
Therapy: RIT + CA4-P
2.5
tumour volume cm3
control
RIT
2
RIT + combretastatin
combretastatin
1.5
1
0.5
0
0
18
35
53
days post injection
74
92
A Phase I/II Trial of Radioimmunotherapy
with 131I-A5B7 anti-CEA Antibody in
Combination with CA4-P for Advanced
Gastrointestinal Carcinoma
STUDY PH1-092
Summary of Tumour Vessels
Tumour v normal blood vessels:
• High endothelial cell proliferation rate
• Abnormal morphology, biochemistry and physiology
• Development of hypoxia leads to:
increased angiogenesis and tumour growth
tumour resistance to conventional therapies
altered gene expression
increased metastatic potential
However...…..
Summary of Antivascular Therapy
• The abnormal vasculature of solid tumours provides
exciting new targets for therapy
• Low drug resistance v tumour cells
• Low toxicity
• Long-term dosing frequently required
• Combined therapies (eg anti-vascular + anti-tumour
cell) will frequently be required to eradicate tumours