Targeted Therapies - little & large explained

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. 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 Targeting- receptor(cell/tissue) specific

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 Burkitt’s lymphoma Marginal zone Histology Follicular small cell Small cleaved Waldenström’s Mantle cell CLL/PLL CLL 0 100 200 300 400 500 Mean channel fluorescence Adapted with permission from Maloney GD. Semin Hematol 2000;37(4 Suppl. 7):17

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 can’t 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 • 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 angiogenesisInhibits apoptosisPromotes metastases

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 t1/2free doxorubicin - 10mins • Caelyx 56 hours –remains intravascular • Exploit leaky vascular nature of tumours to penetrate tumour cells

23. 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 Benefits of Caelyx

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

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.