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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
