Herceptin and cancer

Cancer
1. Can be caused by
  1. Physical carcinogens
    1. Ultraviolet and ionizing radiation
  2. Biological carcinogens
    1. Infections from certain viruses, bacteria or parasites
  3. Chemical carcinogens
    1. Asbestos
    2. Tobacco smoke
Human epidermal growth factor receptors
1. HER
2. Family of structurally-related cell surface proteins
3. HER proteins undergo a conformational change upon ligand binding
  1. essential for dimerization and signalling
  2. Exception HER2
4. HER2/HER3 pair has strongest mitogenic signalling
5. Signalling pathways
  1. Ligand binding causes a conformational change which leads to dimerisation
    1. Dimerisation activates the tyrosine kinase domain
      1. HER2 is in a conformation which promotes dimerisation
    2. Different combinations of receptors stimulate different signalling pathways
      1. HER pathways:
        Stimulate cell proliferation
        Stimulates cell survival
        Are anti apoptotic
6. Are proto-oncogenes
  1. Can become oncogenic by
    1. Over expression
    2. Mutation
  2. 1984
    1. Published that a mutant form of HER2 causes cancer in rats
HER2
1. Frequently amplified in breast cancer samples
  1. Gene amplification
    1. When DNA replication goes wrong the cell can end up with hundreds of copies of a gene
      1. Normal cells are diploid so 2n
        The copy number of a gene can be determine by using a technique called fluorescence in situ hybridisation
        FISH
    2. If the gene is a proto-oncogene like HER2 this can cause cancer
    3. Gene amplification of HER2 leads to increased levels of the receptor
      1. Normal breast tissue has around 20,000 copies per cell
      2. Cancerous tissue can have up to 2 million copies per cell
2. Negative prognostic marker for several cancers
  1. Over-expression of HER2 correlates with poor survival rates
  2. Median survival for breast cancer patients without treatment
    1. HER2 positive 3 years
    2. HER2 normal 6-7 years
3. HER2 over-expressing breast cancer can be targeted using theraputic antibodies
  1. Antibodies
    1. Can be raised against nearly any protein
    2. Are very specific
    3. Binding can interfere with receptor signalling
    4. Binding can target cells for destruction by the bodies immune system
  2. First step in making a theraputic antibody
    1. Making a monoclonal antibody
      1. Process published in 1975
        monoclonal antibodies recognise a single epitope on an antigen
        As you have a cell line that makes that antibody, vast quantities of the antibody can be made
        It was thought that monoclonal antibodies would revolutionise medicine
        However, murine antibodies are not well tolerated in humans
        This is solved by a process called humanisation
  3. 4D5
    1. Treating HER2 overexpressing cells with 4D5 - which binds the extracellular domain of HER2 - inhibits their proliferation
    2. Monoclonal antibody
    3. Injecting mice with 4D5 surpresses tumour growth
    4. Injected radio-labelled 4D5 targets HER2 positive breast cancer cells in women
    5. Humanised version
      1. Herceptin (Trastuzumab)
Herceptin
1. An IgG1 molecule consists of
  1. 2 heavy chains
  2. 2 light chains
  3. Complementary determining regions(CDR's)
    1. Hypervariable regions of the antibody
      1. Involved in antigen binding
    2. Up to 6 CDRs can be involved in binding an antigen
2. How its generated
  1. 1) Clone the murine heavy and light chain cDNA encoding 4D5
    1. 2) Clone the murine CDRs of 4D5 into human IgG1 heavy and light chain plasmids
      1. 3) The humanised antibody is then made by transfecting CHO cells with light chain and heavy chain plasmids
Future directions
1. Cancer returns in around 25% of women treated with herceptin/chemotherapy
  1. The cancer is resistant to herceptin treatment
2. HER2 dimerisation inhibitors
  1. Pertuzumab gained FDA approval in 2012
    1. Used in combination with herceptin and chemotherapy
    2. Increases disease free survival in HER2 positive metastatic cancer by 6 months
3. Antibody drug conjugates
  1. Trastuzuman emtansine gained FDA approval in 2013
    1. Delivers toxic drug to HER2 positive tumours
    2. Increases overall survival by 6 months
4. Targeting other HER family members
  1. Theraputic antibodies being developed against HER3

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	Criado por Kristi Brogden mais de 10 anos atrás