mbbs cancer biology module 2006 tumour vasculature and therapeutic strategies barbara 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?

• 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