Transcript New Drug Developements

Targeted Therapies
explained
little & large
Chris Clarke
Macmillan Lead Pharmacist
LNR Cancer Network
Traditional chemotherapy
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Cell cycle “non-specific”
Cell cycle “specific”!!
Developed through observation
Simple formulations
Toxic
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
Cluster Differentiation (CD)
molecules
• Cell membrane
molecules that are
used to identify
different cells
• Classifies cells into
subsets.
• Design therapy to
target CD molecules
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
Monoclonal Antibodymechanisms 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.
CD20 monoclonal antibodies
• CD20 - expressed on B cells
– Rituximab (MabThera)
– iodine-131 tositumomab (Bexxar)
– yttrium-90 ibritumomab tiuxetan (Zevalin)
CD20 expression in B-cell
malignancies
Hairy cell
Large cell
Burkitt’s lymphoma
Marginal zone
Follicular small cell
Small cleaved
Waldenström’s
Mantle cell
CLL/PLL
CLL
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Mean channel fluorescence
Adapted with permission from Maloney GD. Semin Hematol 2000;37(4 Suppl. 7):17
Other Monoclonal Antibodies
• Alemtuzumab (Campath) CD 52
• Trastuzumab (Herceptin) HER2 (Erb B)
• Cetuximab (Erbitux) HER1/Erb 1/EGFR
• Bevacizumab (Avastin) VEGF -binds VEGF
so can’t bind to VEGF-Receptors
• Gemtuzumab Ozogamicin (Mylotarg) CD 33
Mylotarg-the Target Antigen: CD33
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Cell surface protein on myeloid cells
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Integral membrane protein with an extracellular
domain
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Restricted expression-leukaemic cells but not
pluripotent stem cells or non-haematological
cells
• Antibody/antigen complex internalized
The Anti-CD33 Mylotarg
Calicheamicin
MYLOTARG™
Mechanism of Action I
MYLOTARG™
Mechanism of Action II
Calicheamicin 800 x more
potent than doxorubicin
Epidermal Growth Factor Receptor
• 1970’s: 1st evidence of
activity in tumour growth
• Trans-membrane protein
involved in cell proliferation
• Present in normal tissue
• Over expressed on cancer
cells
• Regulates angiogenesis
Inhibits apoptosis
Promotes metastases
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
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
CML
Target with pharmacokinetics
Capecitabine
• 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
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
Benefits of Caelyx
Reduced incidence
Alopecia
Cardiotoxicity
Drug resistance
Severe extravasation
Dose Limiting toxicity
Neutropenia
Mucositis
Hand-foot syndrome
(PPE)-? due to
prolonged exposure
Magnetic balls!! MTC-DOX
AQ4N
• Hypoxia is characteristic of most solid tumours
• Up to 20% of tumour mass
• Resistant to radiotherapy and chemotherapeutic agents
• AQ4N is a pro-drug developed in Leicester.
• Converted to cytotoxic metabolite AQ4 in
hypoxic cells
AQ4 effects on solid tumours
• Intercalation with DNA
• Potent inhibitor of topoisomerase IInuclear enzyme responsible for cell
division
• Makes hypoxic cells more sensitive to
radiotherapy
Other modes of targeted inhibition
• Proteosome inhibitionbortezomib (Velcade)
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Cox-2 inhibition
Somatostatin analogues
Pharmacogenomics
Cancer vaccines
Gene therapy
Summary
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Need pathology data
Clinical trials critical for development
New formulations
New side effects
Impact on other therapy choices
Equity of access.