mbbs cancer biology module 2006 tumour vasculature and therapeutic strategies barbara pedley
TRANSCRIPT
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?
• Formation of new vessels from pre-existing vasculature
• Required for tumour growth (>1mm3) and metastasis
Angiogenic Stimulus
Cell Migration
CellDifferentiation
Cell Division
BM & ECM Breakdown
Tumour Angiogenesis
tumour
Angiogenic Switch
Anti-angiogenic factors eg:AngiostatinEndostatin
Thrombospondin
Pro-angiogenic factors eg:
VEGFFGFPDGF
Initiated by switch in balance from anti- to pro-angiogenic factors
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
tumour normal
Well Oxygenated
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
BUT: Tumour Vessel Abnormalities are Targetable
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.
Effect of angiostatin on corneal vessel proliferation
I. Endogenous inhibitors eg angiostatin
AngiostatinSaline
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, 2005Expensive!
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
Untreated 24 h post drug
V
NVV
Effect of colchicine therapy: 1945
Radionuclide 131I
RADIOIMMUNOTHERAPY
Tumour cell
Antibody
DNA strand breaks
Antigen eg CEA
CT scans showing response
before
after
Bystander effect
Cell death
0
0.5
1
1.5
2
2.5
0 18 35 53 74 92
days post injection
tum
our
volu
me
cm3
control
RIT
RIT + combretastatin
combretastatin
Basis of Combined Therapies
Antibody Combretastatin 24h
N
V
Therapy: RIT + CA4-P
Blood vessel distribution
A Phase I/II Trial of Radioimmunotherapy A Phase I/II Trial of Radioimmunotherapy with with 131131I-A5B7 anti-CEA Antibody in I-A5B7 anti-CEA Antibody in
Combination with CA4-P for Advanced Combination with CA4-P for Advanced Gastrointestinal CarcinomaGastrointestinal Carcinoma
STUDY PH1-092STUDY PH1-092
Summary of Tumour 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 therapiesaltered gene expressionincreased metastatic potential
However...…..
Tumour v normal blood vessels:
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