Differentiation Therapy in Thyroid Carcinoma
2012-03-21

Current treatment of thyroid carcinomaThe standard treatment of well-differentiated TC is surgery followed by radioiodine remnant ablation.As only thyrocytes are tak i n g u p i o d i d e t o a r e a s o n a b l e d e g r e e , radioiodine treatment is very specific and has a low rate of adverse effects.In case of insufficient iodine uptake options are few and survival is poor.External beam radiation is used as a palliative therapeutic option but these tumors usually are not responsive to this www.intechopen.comUpdates in the Understanding and Management of Thyroid Cancer 252 therapy.Adriamycin is the only cytostatic drug approved by the FDA for treatment of radioiodine refractory thyroid carcinoma.ATC do not express thyrotropin receptors; they neither take up iodide nor produce thyroglobulin.Surgical resection is only recommended for localized disease, which is rarely the case.In the advanced stage patients do not profit from removal of the tumor mass.Palliation to improve survival includes tracheotomy, radiation and chemotherapy or a combination of the three treatments.Tyrosine kinase inhibitors, PPAR-y activators, retinoids, bortezomib, galdanomycin, VEGF receptor antagonists, stimulation of antigen presenting dendritic cells and p53 gene therapy are not yet approved for treatment of metastatic thyroid cancer and reserved for patients with life-threatening disease.This review focuses on re-differentiation as mode of therapeutic action.Tyrosine kinase inhibitors, which target general tumor features like proliferation and apoptosis, currently represent the most promising group of compounds for the treatment of radioiodinerefractive TC.Their mode of action and the most promising candidates will be shortly addressed. Targeted therapy Definition and types of targeted therapiesTargeted therapies interfere with a specific molecular target, which has a critical role in tumor growth and progression.For targeted therapies antisense drugs, monoclonal antibodies and small molecules may be used.Targeted therapies, which intend to remove a block in normal cell differentiation, are termed 'differentiation therapy'.The following molecules are involved in transformation and progression of TC and are, therefore, used in drug development for targeted therapies (Table 1). Tyrosine Kinase Inhibitors (TKI)Receptors over-expressed in cancer cells stimulate cell growth and proliferation through a cascade of tyrosine kinases (TKs) (Figure 2).TKIs may either compete with the ligand by binding to the extracellular domain or they may bind to the ATP-binding site of the kinase.Examples for ligand analogues are monoclonal antibodies like the anti-human epidermal growth factor receptor 2 antibody Herceptin® (trastuzumab), which is very successful in the treatment of breast cancer.By contrast, anti-EGFR antibodies show no significant anti-tumor action in PTC cell lines (Gabler et al., 1997).Small molecule inhibitors, also called ATP mimetics, hinder the binding of ATP to the ATP binding pocket of protein kinases.Other compounds bind to the substrate-binding domain.By this binding autophosphorylation and signal transduction is inhibited.TKIs can inhibit proliferation and induce cell differentiation and apoptosis.As the catalytic domain of the TKs is very similar, most TKIs are not specific for one growth factor.The most promising TKIs are briefly mentioned in the following section.For more information, the reader is referred to one of the more recent reviews (e.g.