Targeted Therapies - little & large explained Chris Clarke Macmillan 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 1 st 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 Histology 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: 1 st 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 t 1/2 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  Magnetic balls!! MTC-DOX Dose Limiting toxicity  Neutropenia  Mucositis  Hand-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.