الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Thyroid carcinomas comprise a heterogeneous group of tumors and can be divided into:
1- Differentiated thyroid carcinoma: that arises from follicular cells and includes PTC, FTC, and Hurthle cell carcinoma. They are generally treated by thyroidectomy, radioiodine ablation therapy, and thyrotropin suppressive therapy.
2- Medullary thyroid carcinoma: arises from parafollicular (C) cells and treated by total thyroidectomy.
3- Anaplastic thyroid carcinoma: arises denovo or from well differentiated thyroid carcinoma and characterized by its aggressive course and its resistance against radiation and conventional chemotherapy.
The term advanced thyroid cancer refers to all thyroid tumors resistant to conventional therapies, and comprises PDTC, ATC, and metastatic or recurrent cancers which do not respond to radioiodine. Standard chemotherapies have a limited efficacy in such cases.
MAPK and PI3K/AKT are the two signaling pathways identified in thyroid cancer with numerous growth factors regulating them like VEGF, EGF, FGF, and RET. Various proto-oncogenes and oncogenes like RAS, BRAF, and MET also play a role in the signal transduction systems.
Targeted agents for advanced thyroid carcinoma can be divided into:
1- Tyrosine kinase inhibitors: A new class of drugs that combat the dysregulated tyrosine kinases at various steps in the activation pathways.
Vandetanib and Cabozantinib were approved by FDA for treatment of the advanced MTC. Sorafenib was approved for treatment of the advanced DTC. Other TKIs like Lenvatinib, Pazopanib, Axitinib, Motesanib, Sunitinib, Imatinib, Gefitinib, and cediranib are still under more trials in patients with advanced thyroid carcinomas.
2- RAS-MAPK and PI3K/AKT/mTOR pathway inhibitors: Includes
A- Farnesyltransferase inhibitors: Unfarnesylated RAS proteins are unable to transmit signals from cell surface leading to inhibition of cell growth and induction of apoptosis. Tipifarnib is an inhibitor of farnesyltransferase and further trials about it are ongoing.
B- MEK inhibitors: leads to down regulation of MAPK pathway leading to inhibition of cell growth, induction of apoptosis, and enhances the expression of thyroid hormone biosynthesis genes. Selumetinib and GSK 1120212 are examples of MEK inhibitors.
C- RAF inhibitors: Inhibition of BRAF kinase leads to down regulation of MAPK pathway. Vemurafenib, GSK 2118436, and XL 281 are among RAF inhibitors but still under trials.
D- mTOR inhibitors: mTOR inhibition leads to down regulation of PI3K/AKT/mTOR pathway resulting in inhibition of cell growth and induction of apoptosis. Everolimus and Temsirolimus are mTOR inhibitors that still under clinical trials.
3- Vascular targeting agents: Beyond direct inhibitors of angiogenic kinases such as VEGFR, other drugs are capable of either inhibiting angiogenesis or disrupt the existing tumor vasculature. Thalidomide and Fosbretabulin have been of particular interest following the reported responses in patients with anaplastic thyroid carcinoma.
4- Proteasome inhibitors: which disrupt signaling pathways inappropriately activated in cancer cells. Bortezomib is a proteasome inhibitor to which MTC and ATC cell lines were very sensitive.
5- Redifferentiation drugs: Attempts had been made to reinduce the susceptibility to 131-I with retinoids. PPAR- activation leads to activation of PTEN which inhibits PI3K, so compounds agonizing PPAR- such Thiazolidenediones and Inolitazone may be beneficial in DTC.
6- Epigenetic drugs: DNA hypermethylation and histone deacetylation are 2 common epigenetic mechanisms that have been implicated in the progression of thyroid carcinoma, especially the loss of radioiodine avidity. So, DNA methylation inhibitors (Azacitidine and Decitabine) as well as histone deacetylase inhibitors (Depsipeptide, Vorinostat, Valporic acid, and Panobinostat) has been associated with enhanced iodine uptake by non-avid cell line but more trials are ongoing about these drugs.
7- Targeted radiotherapy: using [(90) Yttrium-DOTA]. Octreotide which is long acting somatostatin analog that can suppress thyroid cell growth in vitro, but still under clinical trials.