The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinomas of the head and neck (SCCHN) where EGFR expression levels in the tumor correlate with decreased survival. The EGFR monoclonal antibody, cetuximab, was FDA-approved in 2006 for the treatment of SCCHN and is the first new drug for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited, underscoring the importance of elucidating the mechanisms of persistent tumor growth in the setting of EGFR blockade. We have accumulated extensive evidence that EGFR-mediated activation of selected Signal Transducers and Activators of Transcription (STATs) and Src family kinases contribute to SCCHN growth and survival. We recently reported that a mutant EGFR, EGFRvIII is expressed in up to 40% of SCCHN where EGFRvIII is associated with therapeutic resistance, including resistance to cetuximab. Therefore, we propose to test the overall hypothesis that the loss of growth control in SCCHN is mediated by aberrant EGFR signaling though both mutant and wild-type receptors involving selective activation of STAT proteins and/or Src kinases, with the ultimate aim of designing novel treatment strategies to target these pathways. To accomplish the goals of this proposal, we will: 1) determine the role of Src kinases in EGFR-mediated and EGFR-independent growth pathways in SCCHN;2) elucidate the contribution of STAT5 activation to SCCHN progression and response to EGFR blockade;and 3) determine the role of STAT and Src signaling in mediating the oncogenic properties of EGFRvIII in SCCHN.

Public Health Relevance

The proposed studies will elucidate the mechanisms of resistance to EGFR targeting strategies in preclinical models of squamous cell carcinoma of the head and neck. In addition, we will test the hypothesis that STATs, Src family kinases and EGFRvIII contribute to cetuximab resistance in 2 SCCHN patient cohorts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077308-15
Application #
8284471
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
1998-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2012
Total Cost
$269,843
Indirect Cost
$91,729
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Peyser, Noah D; Pendleton, Kelsey; Gooding, William E et al. (2016) Genomic and Transcriptomic Alterations Associated with STAT3 Activation in Head and Neck Cancer. PLoS One 11:e0166185
Peyser, N D; Freilino, M; Wang, L et al. (2016) Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. Oncogene 35:1163-9
Peyser, Noah D; Wang, Lin; Zeng, Yan et al. (2016) STAT3 as a Chemoprevention Target in Carcinogen-Induced Head and Neck Squamous Cell Carcinoma. Cancer Prev Res (Phila) 9:657-63
Sen, Malabika; Pollock, Netanya I; Black, John et al. (2015) JAK kinase inhibition abrogates STAT3 activation and head and neck squamous cell carcinoma tumor growth. Neoplasia 17:256-64
Du, Yu; Grandis, Jennifer R (2015) Receptor-type protein tyrosine phosphatases in cancer. Chin J Cancer 34:61-9
Wheeler, Sarah E; Egloff, Ann Marie; Wang, Lin et al. (2015) Challenges in EGFRvIII detection in head and neck squamous cell carcinoma. PLoS One 10:e0117781
Peyser, Noah D; Du, Yu; Li, Hua et al. (2015) Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer. PLoS One 10:e0135750
Pollock, Netanya I; Grandis, Jennifer R (2015) HER2 as a therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res 21:526-33
Lui, Vivian Wai Yan; Peyser, Noah D; Ng, Patrick Kwok-Shing et al. (2014) Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer. Proc Natl Acad Sci U S A 111:1114-9
Nakajima, Erica C; Laymon, Charles; Oborski, Matthew et al. (2014) Quantifying metabolic heterogeneity in head and neck tumors in real time: 2-DG uptake is highest in hypoxic tumor regions. PLoS One 9:e102452

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