Treatment directed to signalling molecules in patients with advanced differentiated thyroid cancer

Jose M G Sáez
Anti-cancer Agents in Medicinal Chemistry 2013, 13 (3): 483-95
Mutation detection in samples from thyroid cancer with the addition of BRAF mutation, and also the detection of RAS, RET/PTC, and PAX8/PPARγ mutations, may also contribute to cancer diagnosis. On the other hand, the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway) and PI3K/Akt (lipid kinase phoshoinositid-3-kinase signaling pathway) play an important role in the transmission of cell signals. The genes, coding the signaling cascade proteins (RET, RAS, BRAF, PI3K, PTEN, AKT), are mutated or aberrantly expressed in thyroid cancer derived from follicular thyroid cells. Genetic and epigenetic alternations, concerning MAPK/ERK and PI3K/Akt signaling pathways, contribute to their activation and interaction as a consequence of malignant follicular cell transformation. The understanding of this molecular mechanism provides access to novel molecular prognostic and therapeutic strategies for inhibiting the oncogenic activity of the signaling pathways. This ability to investigate tumour biology allows for the selection of different drugs. Nowadays the most relevant are treatments directed to tyrosine kinase receptors that bind for a wide variety of ligands and are frequently mutated and induce a constitutive activation such that a chimerical protein expression takes place in follicular cells in the domain of RET, as well as in other receptors. Many molecules such as: motesanib, sorafenib, vandetanib, sunitinib, XL-184, imatinib, axitinib, pazopanib, lenvatinib, combretastatin, gefitinib, cetuximab, bortezomib and thiazoldonedione have been developed. Some of them also can act in receptors of vascular endothelial growth factor and epidermal growth factor receptors. Information obtained through cytological or biopsy samples permits the study of complex metabolic or genetic pathways, thus providing researchers with a high throughput tool for elucidating changes in the global expression patterns seen in tumour cells and allowing for different therapeutic strategies in thyroid cancer which take into account the predominant altered pathways observed in these samples.

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