Targeted Therapies -little

1
Targeted Therapies-little large explained

• Chris Clarke
• Macmillan Lead Pharmacist
• LNR Cancer Network

2
Traditional chemotherapy

• Cell cycle non-specific
• Cell cycle specific!!
• Developed through observation
• Simple formulations
• Toxic

3
With advances in knowledge

• Target tumour uptake
• Target specific cells- cancer v healthy
• Able to design therapy to target specific
  receptors
• Monoclonal antibodies
• Receptor target molecules
• Biochemical modulation
• Formulation modulation

4
Cluster Differentiation (CD) molecules

• Cell membrane molecules that are used to identify
  different cells
• Classifies cells into subsets.
• Design therapy to target CD molecules

5
Targeting- receptor(cell/tissue) specific

• Mechanism of action
• prevents internal signal transduction pathways
• Use tyrosine kinase inhibitors to block 1st step
  in intracellular signalling pathway
• Use antibody to prevent ligand binding or
  receptor dimerisation

6
Monoclonal Antibody-mechanisms of action

• MAb starve receptor of ligand by binding in
  preference
• MAb to mark cell for attack by immune system
• MAb delivered toxins or drug.

7
CD20 monoclonal antibodies

• CD20 - expressed on B cells
• Rituximab (MabThera)
• iodine-131 tositumomab (Bexxar)
• yttrium-90 ibritumomab tiuxetan (Zevalin)

8
CD20 expression in B-cell malignancies
Hairy cell
Large cell
Burkitts lymphoma
Marginal zone
Histology
Follicular small cell
Small cleaved
Waldenströms
Mantle cell
CLL/PLL
CLL
0 100 200 300 400 500
Mean channel fluorescence
Adapted with permission from Maloney GD. Semin
Hematol 200037(4 Suppl. 7)17
9
(No Transcript)
10
Other Monoclonal Antibodies

• Alemtuzumab (Campath) CD 52
• Trastuzumab (Herceptin) HER2 (Erb B)
• Cetuximab (Erbitux) HER1/Erb 1/EGFR
• Bevacizumab (Avastin) VEGF -binds VEGF so cant
  bind to VEGF-Receptors
• Gemtuzumab Ozogamicin (Mylotarg) CD 33

11
Mylotarg-the Target Antigen CD33

• Cell surface protein on myeloid cells
• Integral membrane protein with an extracellular
  domain
• Restricted expression-leukaemic cells but not
  pluripotent stem cells or non-haematological
  cells
• Antibody/antigen complex internalized

12
The Anti-CD33 Mylotarg
Calicheamicin
13
MYLOTARG Mechanism of Action I
14
MYLOTARG Mechanism of Action II
Calicheamicin 800 x more potent than doxorubicin
15
Epidermal Growth Factor Receptor

• 1970s 1st evidence of activity in tumour growth
• Trans-membrane protein involved in cell
  proliferation
• Present in normal tissue
• Over expressed on cancer cells
• Regulates angiogenesisInhibits
  apoptosisPromotes metastases

16
(No Transcript)
17
(No Transcript)
18
EGFR Over-expression

• Over-expression may predict response to hormonal
  and cytotoxic treatment- screening??
• Inhibitors include erlotinib gefitinib
• Success dependent on
• - presence of receptors
• multiple copies of the gene
• mutations in receptor/gene

19
Tyrosine Kinase inhibitors

• EGFR tyrosine kinase inhibitors
• erlotinib (Tarceva)
• gefitinib (Iressa)
• VEGF tyrosine kinase inhibitors
• Sorafenib (Nexavar)
• Sunitinib (Sutent) also c-kit TK inhibitor
• Bcr-Abl tyrosine kinase inhibitors
• Imatinib also PDGF c-kit receptors
• Dasatinib
• Nilotinib

20
CML
21
Target with pharmacokineticsCapecitabine

• Exploit biochemistry of the tumour
• Capecitabine is preferentially converted in
  tumour cells which have high levels of thymidine
  phosphorylase
• Exploit in tumours with high levels of enzyme

22
Caelyx

• STEALTH liposome covered in polyethylene glycol
• Pharmacokinetics prolonged t1/2 free
  doxorubicin - 10mins
• Caelyx 56 hours remains intravascular
• Exploit leaky vascular nature of tumours to
  penetrate tumour cells

23
Benefits of Caelyx

• Dose Limiting toxicity
• Neutropenia
• Mucositis
• Hand-foot syndrome(PPE)-? due to prolonged
  exposure

• Reduced incidence
• Alopecia
• Cardiotoxicity
• Drug resistance
• Severe extravasation
• Magnetic balls!! MTC-DOX

24
AQ4N

• Hypoxia is characteristic of most solid tumours
• Up to 20 of tumour mass
• Resistant to radiotherapy and chemo-therapeutic
  agents
• AQ4N is a pro-drug developed in Leicester.
• Converted to cytotoxic metabolite AQ4 in hypoxic
  cells

25
AQ4 effects on solid tumours

• Intercalation with DNA
• Potent inhibitor of topoisomerase II-nuclear
  enzyme responsible for cell division
• Makes hypoxic cells more sensitive to radiotherapy

26
(No Transcript)
27
Other modes of targeted inhibition

• Proteosome inhibition-bortezomib (Velcade)
• Cox-2 inhibition
• Somatostatin analogues
• Pharmacogenomics
• Cancer vaccines
• Gene therapy

28
Summary

• Need pathology data
• Clinical trials critical for development
• New formulations
• New side effects
• Impact on other therapy choices
• Equity of access.