Targeted Therapies-little & large explained

Chris ClarkeMacmillan Lead Pharmacist

LNR Cancer Network

Traditional chemotherapy

• 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 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.

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

His

tolo

gy

0 100 200 300 400 500

Burkitt’s lymphoma

CLL

CLL/PLL

Follicular small cell

Hairy cell

Large cell

Waldenström’s

Mantle cell

Marginal zone

Small cleaved

Adapted with permission from Maloney GD. Semin Hematol 2000;37(4 Suppl. 7):17

Mean channel fluorescence

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

• 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

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 apoptosisPromotes 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 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

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 incidenceAlopeciaCardiotoxicityDrug resistanceSevere extravasation

Magnetic balls!! MTC-DOX

Dose Limiting toxicityNeutropeniaMucositisHand-foot syndrome

(PPE)-? due to prolonged exposure

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

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

Other modes of targeted inhibition

• Proteosome inhibition-bortezomib (Velcade)

• Cox-2 inhibition• Somatostatin analogues• Pharmacogenomics• Cancer vaccines• Gene therapy

Summary

• Need pathology data

• Clinical trials critical for development

• New formulations

• New side effects

• Impact on other therapy choices

• Equity of access.