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

Public Health Relevance

The goal of this project is to develop a new method of preventing spread of head and neck cancer to other organs, which is invariably fatal. We have identified two important proteins epidermal growth factor and cyclooxygenase-2 that are important in cancer growth and spread. We hypothesize that blocking the function of both proteins would be an effective strategy to prevent spread of head and neck cancer to other organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
5R03DE021741-02
Application #
8301554
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Venkatachalam, Sundaresan
Project Start
2011-07-15
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$127,125
Indirect Cost
$52,125
Name
Icahn School of Medicine at Mount Sinai
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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