Therapies of the future

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Advances in molecular biology, immunology and cell biology have greatly expanded our understanding of abnormalities underlying malignancy. This chapters reviews tyrosine kinase inhibitors; immunotherapy; photodynamic therapy, other novel approaches.

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9.1 Cell signalling pathways associated with features of malignancy. This is a simplified schematic of some of the pathways used by cells that promote cell proliferation, survival, angiogenesis and migration. Receptor tyrosine kinases and membrane adhesion molecules (integrins) interact with extracellular ligands that trigger propagation of signals within the cell. Dependent downstream signalling partners ultimately activate transcription factors that affect DNA transcription and cell function. In addition to various stimulatory cascades, there are numerous inhibitors of signal transduction (not shown) that normally help to control and regulate cell function.
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9.2 Targeting tyrosine kinases in malignancy. Over-expression of receptor tyrosine kinases on the cell surface can result in excessive stimulation when ligand (lig) in the extracellular environment binds and activates (i.e. phosphorylates, P) large numbers of receptors that in turn promote cell growth and malignant behaviour (left). Alternatively, activating mutations in the regulatory juxtamembrane domain (red/white star, left) account for autophosphorylation of the receptor’s cytoplasmic kinase domain (P), independent of external ligand binding, resulting in continuous intracellular signalling stimulatory to growth. Monoclonal antibody (mAb) that specifically binds to the receptor’s extracellular domain can block ligand binding by competitive inhibition and extinguish generation of stimulatory signals (centre). Small molecules (tyrosine kinase inhibitors, TKI) that compete for the ATP binding pocket in the receptor’s cytoplasmic domain suppress downstream signalling by preventing receptor phosphorylation (right).
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9.3 Feline oral SCCs express EGFR. Positively staining feline SCC cells from the oral cavity appear brown (left) after binding cetuximab, a monoclonal antibody that recognizes EFGR. An irrelevant antibody was used on the control tissue (right), followed by the reagents needed to generate the brown colour (immunoperoxidase methodology). Control tissues were counterstained with haematoxylin. Widespread EGFR expression by feline oral SCC, demonstrated by strong cetuximab binding, suggests a possible role for cetuximab in the treatment of cats with this malignancy. Humans with oral SCC are routinely treated with the combination of cetuximab and radiation therapy. (Immunohistochemistry kindly provided by Eric Armstrong in the laboratory of Dr Paul Harari, University of Wisconsin-Madison, Madison, Wisconsin)
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