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Role of Activated EGFR and COX-2 in Metastasis and Escape from Tumor Dormancy

激活的 EGFR 和 COX-2 在转移和逃离肿瘤休眠中的作用

基本信息

批准号：
8093367
负责人：
Andrew Sikora
金额：
$ 12.71万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8093367
关键词：
Antibodies Biological Breast Cancer Model Cetuximab Clinical Colorectal Cancer DNA Data Development Distant Metastasis EGFR Protein Overexpression Effectiveness Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epiregulin Erlotinib Frequencies Goals Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Human Papillomavirus Immunohistochemistry Ligand Binding Ligands Link Literature Lung Malignant Neoplasms Measures Methods Modeling Monoclonal Antibodies Mutation Neoplasm Metastasis Nodal Non-Small-Cell Lung Carcinoma Organ Outcome PTGS2 gene Patients Pattern Phase I Clinical Trials Phenotype Plasminogen Activator Pre-Clinical Model Primary Neoplasm Prostaglandin-Endoperoxide Synthase Proteins Radiation Radiation therapy Radiosurgery Receptor Activation Receptor Inhibition Recurrence Resistance Risk Role Signal Pathway Subgroup Testing Tobacco Treatment Failure Tumor Escape Urokinase Validation celecoxib chemotherapy cohort cyclooxygenase 2 disorder control experience genetic analysis high risk inhibitor/antagonist innovation novel strategies outcome forecast overexpression prevent receptor research study response small molecule therapeutic target tumor tumorigenic

项目摘要

Significance Due to recent advances in locoregional treatment, distant metastases are emerging as an increasingly important pattern of treatment failure in head and neck squamous cell carcinoma (HNSCC). Using T-HEp3 preclinical model, preliminary data suggests a link between escape from tumor dormancy and metastatic phenotype. These experiments, supplemented by genetic analyses, suggest an important role for both epidermal growth factor receptor (EGFR) activation and cyclooygeanase-2 (COX-2) overexpression in HSNC metastasis. Further, the T-HEp3 model demonstrates urkinase plasminogen activator (uPAR)-driven ligand-independent activation of EGFR resulting in intrinsic resistance to monoclonal antibodies (mAB) that prevent ligand binding to the EGFR receptor. Our long range goal is to understand how to prevent metastases, maintain tumor dormancy and overcome resistance to cetuximab be selectively targeting EGFR and COX-2 using small molecule inhibitors. A more immediate goal is to validate the role of uPAR in inherent resistance to antibody-EGFR mAb therapy. Innovation Our overarching hypothesis proposes that combined EGFR and COX-2 inhibition, in combination with effective locoregional therapy, can effectively prevent distant metastases in HNSCC by inducing and maintaining tumor dormancy. This represents a completely new approach to HNSCC treatment. Specific Aims The specific aims to this hypothesis will: 1) Determine the role of EGFR & COX-2 in escape from dormancy and metastasis development in T-HEp3 HNSCC model; 2) Determine the role of uPAR on resistance to anti-EGFR mAb. Reemphasis of the proposal's innovation: Collectively, these studies will define the critical role of COX-2 and EGFR in the development of distant metastases in HNSCC and highlight a role of uPAR in intrinsic resistance to anti-EGFR mAb. Information from this project will facilitate the clinical development of rational anti-metastasis therapy in HNSCC. Reemphasis of the proposal's innovation Collectively, these studies will define the critical role of COX-2 and EGFR in the development of distant metastases in HNSCC and highlight a role of uPAR in intrinsic resistance to anti-EGFR mAb. Information from this project will facilitate the clinical development of rational antimetastasis therapy in HNSCC. Keywords: head and neck cancer, metastasis, tumor dormancy, EGFR, COX-2

意义