Lesson 7 Promoting Proliferation

• CRICOS Provider 00115M
• MED3ATA Cancer Module

  
• Christine Hawkins
• Lecture 7.1: Promoting Proliferation
• Hallmark: Growth factor signalling
• La Trobe University
• Commonwealth of Australia
• Copyright Act 1968
• Warning: This material has been reproduced and communicated to you by or on behalf of La Trobe University under Section 113P of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.
• Throughout these cancer lectures: Brown text is examinable, Grey text is just for your interest: not examinable
• Molecular steps leading to cancer

  1. immature

  2. mature

  3. tumour

  4. DNA repair defects

  5. genetic instability

  6. Apoptosis inhibition

  7. Factor-independent proliferation

  8. Limitless replicative potential

  9. angiogenesis

  10. metastasis

  11. differentiation

  
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74.

  
• Receptor tyrosine kinases and growth factors

  • Alterations in cancer
  • Targeting overactive receptors
• Growth factor signalling


  1. Receptor tyrosine kinase

  2. Ras GDP

  3. Ras GTP

  4. adaptor

  5. Kinase cascade

  6. Cell cycle proteins

  7. Raf

  8. egBRaf
• Ligand-dependent proliferation
• Don't need to know names like MAPK, ERK etc
• Oncogenic alterations in growth factor signalling

  • Overexpression or stabilisation of receptor
  • Activating mutations in receptor
  • Autocrine production of ligand (cell stimulated by ligand secreted by itself)
  • Constitutively active Ras
  • Constitutively active BRAF

  
• Ligand-independent proliferation
• Cancerous change to growth factor signalling (1)

  1. constitutively active receptor

  2. receptor overexpression

  
• Receptor-targeting drugs: Some effective
• Antibodies that bind to receptor tyrosine kinases, as anti-cancer drugs

  • Antigen binding site (murine)
  • Constant regions (human)
  • Injection of murine antibodies into patients often elicits immune reactions (sometimes renal failure)
  • "humanised" versions
• Overexpression or activating mutations in receptor tyrosine kinases are common in various cancer types
• Antibodies that bind to the extracellular domains of these receptors have been developed as anti-cancer drugs

  
• The antibodies are made in animals then "humanised": mouse amino acids in the constant regions of the proteins are replaced with human sequences, to minimise immunological reactions caused by injecting murine proteins into humans
• HER2


  A receptor tyrosine kinase that is overexpressed in ~20% of breast cancers (and can less commonly be overactive due to point mutations)
• CRICOS Provider 00115M
• Trastuzumab (=Herceptin)


  A humanised monoclonal antibody that binds HER2 and targets cells expressing it for antibody-dependent cell mediated cytotoxicity

  
• MED3ATA Cancer Module
• Christine Hawkins
• Addition of trastuzumab to regimen for HER2 positive breast cancer patients significantly boosted survival. It is now part of the standard treatment for HER2 positive breast cancers
• Lecture 7.2: Promoting Proliferation
• Need to remember either name: trastuzumab or Herceptin
• Hallmark: Ras and BRaf
• La Trobe University
• Commonwealth of Australia
• Antibody-dependent cell mediated cytotoxicity (ADCC)


  • The main anti-cancer mechanism employed by antibodies that recognise receptor tyrosine kinases
  • Natural Killer cells bind to cancer cells coated in antibodies and release pore-forming and apoptosis-inducing proteins, killing the cancer cell
  • Other (minor) mechanisms have also been implicated, eg antibodies that bind to cancer-associated receptor tyrosine kinases can also prevent ligand binding to dampen growth factor signalling

  
• Copyright Act 1968
• Antibody-drug conjugates


  • Antibodies (like trastuzumab) that recognise extracellular antigens expressed solely or predominantly by cancer cells can be fused to toxins to create "Antibody Drug Conjugates" (ADCs), to preferentially target toxins to cancer cells
  • Ideally, the variable region of the antibody binds to the cancer cell, triggering internalisation of the antibody and its associated toxin
  • Once inside the cell, a linker between the drug and the antibody is cleaved by cellular enzymes, releasing an active form of the toxin which then kills the cell
  • ADCs have been made using many antibodies recognising multiple cancer-related proteins and various chemotherapy drugs as "payloads"

  
• Warning: This material has been reproduced and communicated to you by or on behalf of La Trobe University under Section 113P of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.
• Two trastuzumab antibody-drug conjugates, with different toxic payloads, have been approved for clinical use in Australia