The incidence of differentiated thyroid cancer is rising at the second fastest rate of all malignancies in theUnited States, making it an increasingly important public health problem. While patients with early stagethyroid cancer are usually successfully treated, the survival rate for patients with distant metastatic ornvasive disease is approximately 40% at 5 years. The pathways responsible for thyroid cancer progressionare not clear. We have observed that the invasive fronts of aggressive thyroid cancers display an epithelial tomesenchymal 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 validationseries in which overexpression of vimentin was independently associated with tumor invasiveness. Theoverexpression of mesenchymal proteins occurred in invasive PTCs that expressed BRAF V600E orRET/PTC oncogenes. In vitro studies demonstrated the requirement of vimentin expression for thyroidcancer 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 aredownstream of PDK1 and other pathways activated in thyroid cancer. Enhanced expression of PAKregulators and effectors was noted in the expression arrays and increased levels of total and phosphorylatedPAK were identified in primary thyroid cancers. Subsequent in vitro data support an association betweenPAK activity and expression and function of RET/PTC and BRAF V600E oncogenes, and a role for PAK inthyroid cancer motility. Because our goal is to target invasive or progressive thyroid cancers, we also testedOSU-03012, a novel kinase inhibitor that competes with targets involved in EMT in vitro. The goal of thisproposal is to define the role and upstream regulation of PAK in thyroid cancer EMT; determine thedownstream 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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