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 wild-type EGFR blockade. We have accumulated extensive evidence that GPCR-mediated signaling through EGFR-dependent and EGFR-independent pathways contributes to SCCHN growth and survival. Patients who do not respond to cetuximab are likely to succumb to their head and neck cancer. We currently do not know how to identify SCCHN patients who will benefit from EGFR targeting. Our working hypothesis is that persistent GPCR signaling in the setting of EGFR blockade contributes to tumor progression. Completion of these studies will elucidate mechanisms of resistance to EGFR targeting strategies thus facilitating the design of therapeutic regimens to enhance clinical response. To accomplish the goals of this proposal, we will: 1) determine the GPCR-stimulated pathways in SCCHN that are activated upstream or downstream of EGFR with the goal of identifying therapeutic targets;2) elucidate the EGFR-independent pathways induced by GPCR in SCCHN;and 3) determine the antitumor effects of EGFR targeting in combination with key GPCR signaling intermediates in preclinical SCCHN models.

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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. Specifically, we will test the hypothesis that persistent G-protein-coupled receptor (GPCR) signaling in the setting of EGFR blockade contributes to limited clinical responses to EGFR targeting in SCCHN. In addition, we will test the hypothesis that GPCR signaling contributes to cetuximab resistance in 2 SCCHN patient cohorts and that GPCR targeting in combination with EGFR blockade modulates expression of proteins and phosphoproteins in human SCCHN tumors from subjects treated on a clinical protocol.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Salnikow, Konstantin
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University of Pittsburgh
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Panupinthu, N; Yu, S; Zhang, D et al. (2014) Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. Oncogene 33:2846-56
Gross, Neil D; Bauman, Julie E; Gooding, William E et al. (2014) Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer. Clin Cancer Res 20:3289-98
Li, Hua; Wawrose, John S; Gooding, William E et al. (2014) Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. Mol Cancer Res 12:571-82
Egloff, Ann Marie; Liu, Xuwan; Davis, Autumn L Gaither et al. (2013) Elevated gastrin-releasing peptide receptor mRNA expression in buccal mucosa: association with head and neck squamous cell carcinoma. Head Neck 35:270-9
Wheeler, Sarah; Siwak, Doris R; Chai, Raymond et al. (2012) Tumor epidermal growth factor receptor and EGFR PY1068 are independent prognostic indicators for head and neck squamous cell carcinoma. Clin Cancer Res 18:2278-89
Bhola, Neil E; Freilino, Maria L; Joyce, Sonali C et al. (2012) Antitumor mechanisms of targeting the PDK1 pathway in head and neck cancer. Mol Cancer Ther 11:1236-46
Bhola, Neil E; Thomas, Sufi M; Freilino, Maria et al. (2011) Targeting GPCR-mediated p70S6K activity may improve head and neck cancer response to cetuximab. Clin Cancer Res 17:4996-5004
Quesnelle, Kelly M; Grandis, Jennifer R (2011) Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance. Clin Cancer Res 17:5935-44
Sharafinski, Mark E; Ferris, Robert L; Ferrone, Soldano et al. (2010) Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck 32:1412-21
Zou, Huafei; Thomas, Sufi M; Yan, Zhen-Wen et al. (2009) Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells. FASEB J 23:425-32

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