1. Website for lectures and course book: http://www.homepages.ucl.ac.uk/ ~regobto/ http://www.homepages.ucl.ac.uk/ ~regobto/

2. Cure Death DNA repair Limitation of exposure Anti-carcinogens Large tumour masses Generation of tumour vasculature Genetic instability Immortalisation Inheritance, Environment, Viruses, Age Invasion Loss of homeostasis Loss of tumour suppressor gene function Gain of oncogene function Metastasis Multistep gene damage Resistance to apoptosis Single cancer cell Treatment Uncontrolled proliferation Elements of Cancer

3. DNA repair, limitation of exposure, anti-carcinogens Inheritance, Environment, Viruses, Age Multistep gene damage Single cancer cell A Model of Cancer

4. DNA repair, limitation of exposure, anti-carcinogens Immortalisation Inheritance, Environment, Viruses, Age Loss of tumour suppressor, gain of oncogene function Multistep gene damage Single cancer cell Uncontrolled proliferation A Model of Cancer Resistance to apoptosis Genetic instability

5. Death DNA repair, limitation of exposure, anti-carcinogens Large tumour masses Immortalisation Inheritance, Environment, Viruses, Age tumour vasculatureInvasion Loss of homeostasis Loss of tumour suppressor, gain of oncogene function Metastasis Multistep gene damage Single cancer cell Uncontrolled proliferation A Model of Cancer Resistance to apoptosis Genetic instability Aberrant protein production Paraneoplastic syndromes

6. Does this help to design therapy?

7. Cure and control Death DNA repair, limitation of exposure, anti-carcinogens Large tumour masses Immortalisation Inheritance, Environment, Viruses, Age tumour vasculatureInvasion Loss of homeostasis Loss of tumour suppressor, gain of oncogene function Metastasis Multistep gene damage Single cancer cell Treatment Uncontrolled proliferation A Model of Cancer Resistance to apoptosis Genetic instability Prevention Aberrant protein production Paraneoplastic syndromes

8. Proliferation Cytotoxic chemotherapy Selective delivery of cytotoxic therapy –antibodies delivering a toxin –antibody-targeted enzymes activating a prodrug Radiation –radioimmunotherapy Hormones Cytokines Signalling inhibiton –Small molecules eg glivec, iressa –Antibodies eg herceptin

9. Resistance to apoptosis Induction of apoptosis –Rituximab –Geldanamycin –Antisense to BCL2 –Restoration of wild type p53 function

10. Aberrant protein expression Antibody targeting to tumour protein Stimulation of natural effector mechanisms –antibody dependent cell mediated cytotoxicity (ADCC) eg rituxumab, herceptin –complement activation eg rituximab

11. Developments in therapeutic antibodies Murine monoclonal antibody derived entirely from mice Chimeric antibody mouse V-regions and human C-regions Humanized antibody only antigen binding regions (CDRs) from mouse Human antibodies from phage libraries Human antibodies from mice made in mice which have human antibody genes Immunogenicity But - human CDRs can be immunogenic

12. Vascular Vascular endothelial proliferation inhibitors –anti-VEGF neutralising antibody –thalidomide Vascular endothelial poisons –Combretastatin –DMXAA

13. Invasion Inhibitors of matrix metalloproteases Inhibitors of integrins

14. Metastasis Antibodies to chemokine receptors

15. Large tumour masses Surgery Radiation Laser Radiofrequency ablation

16. Paraneoplastic syndromes Cachexia Neurological syndromes Connective tissue syndromes Hormonal syndromes Treat the cause + symptomatic measures

17. Loss of Homeostasis General medicine –Tissue –Organ –System

18. Colon cancer survival 1971-2001 1 year5 year1 year5 year 71-576-8096-92001-581-586-9091-5 males females % survival

19. Understanding cancer and its therapy