p21 Activated Kinase in Thyroid Cancer

进行性转移性乳头状甲状腺癌(PTC)患者预后较差。尽管取得了进步 在开发新的治疗方法方面，完全反应是难以捉摸的，非持久反应是最好的 报告结果。局部大体侵犯和远处转移是死亡的两个预测因素。 来自PTC。我们专注于定义这些功能的关键监管机构，以努力确定新的目标 以提高治疗水平。我们发现p21激活的蛋白激酶(PAK)信号在侵袭性血管病变中被激活。 侵袭性甲状腺癌的前沿，并确定它调节人甲状腺癌细胞的运动和 体外增殖。我们阐明了PAK1是导致这种效应的主要异构体。因为 BRAF活化与肿瘤侵袭性的关系分析 这两个信号分子。我们证明PAK活性受到BRAF的高度调节，并且 BRAF基因敲除可抑制PAK活性。此外，这种效应不依赖于MEK。我们随后 发现PAK与BRAF在物理上相互作用，既有过表达系统，也有内源性系统。我们有 活体研究表明，BRAF V600E在甲状腺中的急性激活与血清中 磷酸化PAK。最后，我们已经证明了已经转移的侵袭性PTC 高水平激活PAK。这些数据表明，PAK是BRAF的关键下游目标 在RAS/RAF/ERK通路激活的肿瘤PTC进展中起重要作用。最后， 我们还设计、开发和测试了几种新型化合物，它们可以抑制PAK和其他几种 在体外降低细胞活力和活力的激酶。这个项目的假设是PAK是一个以前的 BRAF下游未知的关键信号节点参与甲状腺癌的发生和发展 在体内的进展；相互作用的机制可以被阐明，并且新的抑制剂WE 已经开发出在临床前模型中具有活性和耐受性的药物。

Patients with progressive metastatic papillary thyroid cancer (PTC) have a poor prognosis. Despite advances in developing new therapies complete responses have been elusive and non-durable responses are the best reported outcomes. The presence of gross local invasion and distant metastases are two predictors of death from PTC. We have focused on defining key regulators of these features in an effort to identify novel targets to improve treatment. We identified that the p21 activated kinase (PAK) signaling is activated in the invasive fronts of aggressive PTCs and determined that it regulated human thyroid cancer cell motility and proliferation in vitro. We clarified that PAK1 is the primary isoform responsible for this effect. Because of the association between BRAF activation and tumor aggressiveness we analyzed the relationship between these two signaling molecules. We demonstrated that PAK activity was highly regulated by BRAF and that BRAF knock down inhibited PAK activity. Moreover, this effect was independent of MEK. We subsequently identified that PAK physically interacts with BRAF both overexpression and endogenous systems. We have shown in vivo that acute activation of BRAF V600E in the thyroid is associated with increased levels of phosphorylated PAK. Finally, we have demonstrated that aggressive PTCs that have metastasized have high levels activated PAK. These data point to PAK being a critical downstream target of BRAF which plays an important functional role in PTC progression for tumors with RAS/RAF/ERK pathway activation. Finally, we also have designed, developed, and tested several novel compounds that inhibit PAK and several other kinases reducing cell motility and viability in vitro. The hypotheses of this project is that PAK is a previously unrecognized critical signaling node downstream of BRAF involved in thyroid cancer tumongenesis and progression in vivo; that the mechanism ofthe interaction can be elucidated, and that the novel inhibitors we have developed will be active and tolerated in vivo in preclinical models.