Veterans suffer at a disproportional rate from squamous cell carcinoma of the head and neck (SCCHN) due to carcinogen exposure from tobacco and alcohol. Despite aggressive treatments, SCCHN is a devastating disease that portends an overall 5-year survival of only ~50%. A comprehensive genomic analysis of SCCHN revealed that ~30% of these tumors overexpress a gene that encodes a calcium-activated chloride channel (TMEM16A/ ANO1). Mechanistic studies have shown that TMEM16A contributes to tumor cell growth by activating the EGFR-ERK1/2 pathway. EGFR is the only FDA-approved molecular therapeutic target in SCCHN, yet the critical therapeutic biomarker(s) that predict response to anti-EGFR therapy remains unknown. Here, we propose to investigate the how TMEM16A and EGFR interact with each other to promote tumor growth and progression. We propose the following studies: 1) determine whether chloride flux through TMEM16A is necessary and sufficient to activate EGFR signaling; 2) examine how TMEM16A interacts with EGFR, and if this interaction is necessary for tumor cell growth; and 3) use a patient samples and tissues derived from a mouse model of carcinogenesis to determine if TMEM16A expression / TMEM16A-EGFR interaction is required for the development of oral dysplasia and ultimately progression to invasive carcinoma. At the conclusion of this project, we intend to implicate TMEM16A as a direct therapeutic target for the treatment of Veterans with OSCC.

Public Health Relevance

Despite aggressive therapy, Veterans with squamous cell carcinoma of the head and neck (SCCHN) have a dismal prognosis. There is a need to identify novel targets in this disease. The calcium-activated chloride channel TMEM16A/ ANO1 is frequently overexpressed in these cancers and contributes to tumor cell growth. TMEM16A appears to interact with EGFR, and regulate EGFR signaling. There is a need to understand how TMEM16A promotes tumor growth, and the mechanism by which it interacts with EGFR. This proposal outlines studies that will elucidate the fundamental biology of TMEM16A and how it interacts with EGFR. We will address the unmet need by implicating TMEM16A as a potential therapeutic target for the treatment of Veterans with SCCHN.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003456-02
Application #
9378708
Study Section
Oncology B (ONCB)
Project Start
2016-10-01
Project End
2020-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
033127569
City
Pittsburgh
State
PA
Country
United States
Zip Code
15240
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Albergotti, William G; Jordan, Jessica; Anthony, Keely et al. (2017) A prospective evaluation of short-term dysphagia after transoral robotic surgery for squamous cell carcinoma of the oropharynx. Cancer 123:3132-3140
Pinilla-Macua, Itziar; Grassart, Alexandre; Duvvuri, Umamaheswar et al. (2017) EGF receptor signaling, phosphorylation, ubiquitylation and endocytosis in tumors in vivo. Elife 6: