1. MBBS Cancer Biology Module 2006 Tumour Vasculature and Therapeutic Strategies Barbara Pedley

2. 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?

3. Formation of new vessels from pre-existing vasculature Required for tumour growth (>1mm3) and metastasis Angiogeni c Stimulus Cell Migration Cell Differentiation Cell Division BM & ECM Breakdown Tumour Angiogenesis tumour

4. Angiogenic Switch Initiated by switch in balance from anti- to pro-angiogenic factors

5. 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

6. Normal v tumour vessels tumour normal Well Oxygenated

7. 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

9. 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.

10. Effect of angiostatin on corneal vessel proliferation I. Endogenous inhibitors eg angiostatin AngiostatinSaline

11. 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)

12. 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

13. Bevacizumab (Avastin TM) - 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!

14. 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 N V V

15. Effect of colchicine therapy: 1945

16. Radionuclide 131 I RADIOIMMUNOTHERAPY Tumour cell Antibody DNA strand breaks Antigen eg CEA CT scans showing response before after Bystander effect Cell death

17. Basis of Combined Therapies Antibody Combretastatin 24h N V Therapy: RIT + CA4-P Blood vessel distribution

18. A Phase I/II Trial of Radioimmunotherapy with 131 I-A5B7 anti-CEA Antibody in Combination with CA4-P for Advanced Gastrointestinal Carcinoma STUDY PH1-092

19. 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 therapies altered gene expression increased metastatic potential However...….. Tumour v normal blood vessels:

20. 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