Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download New Drug Developements
Document related concepts
Transcript
Targeted Therapies explained little & large 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 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 0 100 200 300 400 500 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 • 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 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) • • • • • 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.
