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Transcript
Website for lectures and course book: http://www.homepages.ucl.ac.uk/ ~regobto/ Elements of Cancer Cure Loss of homeostasis Death Loss of tumour suppressor gene function Gain of oncogene function DNA repair Limitation of exposure Anti-carcinogens Metastasis Multistep gene damage Large tumour masses Resistance to apoptosis Generation of tumour vasculature Genetic instability Single cancer cell Inheritance, Environment, Viruses, Age Immortalisation Treatment Invasion Uncontrolled proliferation A Model of Cancer Inheritance, Environment, Viruses, Age DNA repair, limitation of exposure, anti-carcinogens Multistep gene damage Single cancer cell A Model of Cancer Inheritance, Environment, Viruses, Age DNA repair, limitation of exposure, anti-carcinogens Genetic instability Multistep gene damage Single cancer cell Immortalisation Uncontrolled proliferation Resistance to apoptosis Loss of tumour suppressor, gain of oncogene function A Model of Cancer Inheritance, Environment, Viruses, Age DNA repair, limitation of exposure, anti-carcinogens Genetic instability Multistep gene damage Single cancer cell Immortalisation Uncontrolled proliferation Resistance to apoptosis Loss of tumour suppressor, gain of oncogene function Aberrant protein production Invasion Large tumour masses tumour vasculature Metastasis Loss of homeostasis Death Paraneoplastic syndromes Does this help to design therapy? Inheritance, Environment, Viruses, Age DNA repair, limitation of exposure, anti-carcinogens Single cancer cell Immortalisation Uncontrolled proliferation Loss of tumour suppressor, gain of oncogene function Aberrant protein production Invasion Large tumour masses tumour vasculature Metastasis Loss of homeostasis Death Paraneoplastic syndromes Cure and control Resistance to apoptosis Treatment Genetic instability Multistep gene damage Prevention A Model of Cancer 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 Resistance to apoptosis Induction of apoptosis – Rituximab – Geldanamycin – Antisense to BCL2 – Restoration of wild type p53 function 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 Immunogenicity 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 But - human CDRs can be immunogenic Vascular • Vascular endothelial proliferation inhibitors – anti-VEGF neutralising antibody – thalidomide • Vascular endothelial poisons – Combretastatin – DMXAA Invasion • Inhibitors of matrix metalloproteases • Inhibitors of integrins Metastasis • Antibodies to chemokine receptors Large tumour masses • • • • Surgery Radiation Laser Radiofrequency ablation Paraneoplastic syndromes • • • • Cachexia Neurological syndromes Connective tissue syndromes Hormonal syndromes Treat the cause + symptomatic measures Loss of Homeostasis • General medicine – Tissue – Organ – System Colon cancer survival 1971-2001 ’76-80 ’81-5 ’86-90 ’91-5 ’96-9 2001-5 % survival ’71-5 1 year 5 year males 1 year 5 year females Understanding cancer and its therapy New & improved: ●treatments ●diagnosis ●prognostics Clinical features Environment Psychosocial Germline - genetic variation - epigenetics - gene expression -proteins, - pathways, cells, - tissues, - whole person Patient Information Shared & Integrated - target - delivery - therapeutic mechanism - effect of therapy on germline & somatic events Treatment Tumour Clinical features Somatic - genetic variation - epigenetics - gene expression - proteins, - pathways,
