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Targeting FAK and Src in thyroid cancer

靶向 FAK 和 Src 在甲状腺癌中的作用

基本信息

批准号：
10194410
负责人：
Rebecca Elizabeth Schweppe
金额：
$ 53.12万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194410
关键词：
Acute Address Advanced Malignant Neoplasm Antitumor Response BCAR1 gene Binding Bypass Cancer Cell Growth Cancer Etiology Cancer Model Cancer Patient Cells Cessation of life Chronic Clinic Combined Modality Therapy Complex Dasatinib Data Dependence Development Disease Disease Progression Distant Metastasis Focal Adhesion Kinase 1 Genetic Goals Growth In Vitro Invaded JUN gene MAP Kinase Gene MMP9 gene Malignant Neoplasms Malignant neoplasm of thyroid Maps Matrix Metalloproteinases Mediating Mediator of activation protein Metalloproteases Modeling Molecular Mutation Neoplasm Metastasis Oncogenic Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenocopy Phenotype Phosphotransferases Play Population Regulation Resistance Resistance development Role Sampling Signal Pathway Signal Transduction Testing Thyroid Gland Treatment Failure Tumor Cell Invasion Tumor Cell Line Up-Regulation base biomarker identification cancer cell clinically relevant effective therapy genetic approach in vivo inhibitor/antagonist metastasis prevention metastatic process novel novel strategies novel therapeutics overexpression response scaffold src-Family Kinases synergism targeted agent targeted treatment therapeutic target thyroid neoplasm transcriptional reprogramming tumor tumor growth tumor progression tumorigenic

项目摘要

PROJECT SUMMARY Current therapies for patients with advanced thyroid cancer are rarely curative. Extrathyroidal invasion and metastasis are the most common causes of thyroid cancer-related deaths, and little progress has been made in the development of new therapies for these patients. The Focal Adhesion Kinase (FAK) and Src kinase pathway has emerged as a major player in cancer progression, especially relating to metastasis, yet how Src and FAK promote disease progression and the metastatic process is not well understood. We have shown that FAK is overexpressed and phosphorylated in patient thyroid tumor samples, and that inhibition of Src inhibits thyroid cancer growth and metastasis in vitro and in vivo. We have mapped FAK as a key downstream target of Src, and that the FAK adaptor/scaffolding function, but not kinase activity, is critical for thyroid cancer growth and metastasis. While these data demonstrate a major pro-tumorigenic role for FAK and Src in thyroid cancer, it is clear that the development of resistance to single-agent targeted therapies is inevitable. To address this problem, we have developed a model of acquired resistance to the Src inhibitor, dasatinib, with the goal of identifying targets for upfront combination therapies. Using this model of acquired resistance, we have identified a switch to a more invasive phenotype, which is driven by a key switch in dependency from FAK adaptor/scaffolding function to FAK kinase activity, which may regulated by a c-Met-FAK complex, resulting in an increased reliance on the p130Cas>c-Jun signaling axis. We have further shown that this more invasive phenotype is accompanied by an altered secretome and metalloprotease activity, and that IL-1beta and MMP play key roles in this response. Thus, the goals of this proposal are to define the role of the IL- 1beta>c-Met-FAK>p130Cas>c-Jun>MMP signaling axis in thyroid tumor growth and invasion, and to understand the regulation and function of FAK as a central mediator of this phenotype switch. In Aim 1 we will use genetic and pharmacologic approaches to define the mechanism of synergy of FAK and Src inhibition and the role of the p130Cas>c-Jun signaling module. In Aim 2, we will define the role of FAK in mediating a more invasive phenotype, and the role of IL-1beta and MMPs in this response. In Aim 3, we will investigate how c- Met regulates FAK function, and use an in vivo orthotopic thyroid cancer model and an experimental metastasis model to define the role of FAK as an in vivo target in combination with Src inhibition. Successful completion of these aims will define the role of FAK as a molecular switch in response to Src-directed therapies, and in the regulation of a more invasive phenotype. Overall, these studies will determine the role of FAK and Src as therapeutic targets for patients with advanced thyroid cancer, and the prevention of metastases, as well as other poorly differentiated cancers with oncogenic FAK and Src signaling.

项目总结