The incidence of differentiated thyroid cancer is rising at the second fastest rate of all malignancies in the United States, making it an increasingly important public health problem. While patients with early stage thyroid cancer are usually successfully treated, the survival rate for patients with distant metastatic or nvasive disease is approximately 40% at 5 years. The pathways responsible for thyroid cancer progression are not clear. We have observed that the invasive fronts of aggressive thyroid cancers display an epithelial to mesenchymal transition (EMT)-like gene expression profile that differs from the central regions of the tumors. The association between EMT and thyroid cancer invasion was further demonstrated in a larger validation series in which overexpression of vimentin was independently associated with tumor invasiveness. The overexpression of mesenchymal proteins occurred in invasive PTCs that expressed BRAF V600E or RET/PTC oncogenes. In vitro studies demonstrated the requirement of vimentin expression for thyroid cancer migration and for the development of a mesenchymal phenotype in thyroid cancer cells. p21- activated kinases (PAKs) are master regulators of actin rearrangement and cell polarity and motility that are downstream of PDK1 and other pathways activated in thyroid cancer. Enhanced expression of PAK regulators and effectors was noted in the expression arrays and increased levels of total and phosphorylated PAK were identified in primary thyroid cancers. Subsequent in vitro data support an association between PAK activity and expression and function of RET/PTC and BRAF V600E oncogenes, and a role for PAK in thyroid cancer motility. Because our goal is to target invasive or progressive thyroid cancers, we also tested OSU-03012, a novel kinase inhibitor that competes with targets involved in EMT in vitro. The goal of this proposal is to define the role and upstream regulation of PAK in thyroid cancer EMT;determine the downstream mechanism for PAK-regulated EMT focused on pathways identified in our preliminary studies; and to determine if OSU-03012 influences thyroid cancer cell development and progression in vivo.

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