Role of p21-activated kinases in thyroid cancer

p21 激活激酶在甲状腺癌中的作用

基本信息

批准号：
10377551
负责人：
Matthew D Ringel
金额：
$ 36.76万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377551
关键词：
1-Phosphatidylinositol 3-Kinase Acute BRAF gene Binding Cell Line Cell Proliferation Cell division Cells Centrosome Cessation of life Chronic Clinic Complex Data Diagnosis Disease Distant Metastasis Gene Expression Profile Goals Human I131 isotope In Vitro In complete remission Indolent KRAS2 gene Knock-in MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of thyroid Mediating Methods Mitosis Mitotic Activity Modeling Molecular Mutate Mutation Outcome Papillary thyroid carcinoma Pathway interactions Patients Phosphorylation Play Prognosis Publishing Ras/Raf Regulation Reporting Research Resistance Resistance development Role Sampling Signal Transduction Signaling Molecule System Taxonomy Testing Therapeutic Thyroid Gland Tissues Work base cancer cell cell growth cell motility improved in vivo inducible gene expression inhibitor knock-down melanoma member mortality mouse model mutant novel novel therapeutics overexpression p21 activated kinase p21-activated kinase 1 patient derived xenograft model protein complex response synergism therapeutic evaluation therapeutic target therapy resistant tumor tumor progression tumorigenesis

项目摘要

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. 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 and that the complex occurs in mitosis consistent with a role in regulation cell division and growth. 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 identified acquired mutations in upstream regulators of PAK in tumor samples from patients who developed resistance to BRAF inhibition. 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. The hypotheses of this project is that PAK is a critical signaling node downstream of BRAF involved in thyroid cancer tumorigenesis and progression in vivo; that the mechanism of the interaction can be elucidated, and that it can be exploited to develop improved primary and secondary therapies for patients with progressive thyroid cancer and other patients with BRAF-mutated tumors.

进行性转移性乳头状甲状腺癌（PTC）的患者预后较差。尽管开发新疗法的进展是难以捉摸的，而且不可抑制的反应是最佳报告的结果。局部侵袭和远处转移的存在是PTC死亡的两个预测指标。我们专注于定义这些特征的关键调节因子，以确定改善治疗的新目标。我们确定p21激活的激酶（PAK）信号在侵略性PTC的侵入性锋线中被激活，并确定它调节了人类甲状腺癌细胞的运动和体外增殖。由于BRAF激活与肿瘤攻击性之间的关联，我们分析了这两个信号分子之间的关系。我们证明了PAK活性受BRAF的高度调节，BRAF击倒了抑制的PAK活性。而且，这种效果独立于MEK。随后，我们确定了PAK与BRAF的过表达和内源系统之间的物理相互作用，并且该复合物发生在有丝分裂中，与调节细胞分裂和生长中的作用一致。我们已经在体内表明，甲状腺中BRAF V600E的急性激活与磷酸化PAK水平升高有关。最后，我们已经确定了来自对BRAF抑制作用的患者的肿瘤样品中PAK上游调节剂中获得的突变。这些数据表明，PAK是BRAF的关键下游靶标，它在PTC进展中起着RAS/RAF/ERK途径激活的肿瘤的重要作用。该项目的假设是，PAK是BRAF下游的关键信号传导节点，参与体内甲状腺癌肿瘤发生和进展。可以阐明这种相互作用的机制，并可以利用它为进行性甲状腺癌和其他BRAF突破性肿瘤患者改善原发性和二级疗法。