The loss of growth control in squamous cell carcinoma of the head and neck (SCCHN) is characterized by acquisition of an autocrine regulatory pathway involving the epidermal growth factor receptor (EGFR). In 2006, the FDA approved the EGFR monoclonal antibody cetuximab for the treatment of SCCHN making it the first new drug approved 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. Co-targeting of oncogenic pathways that are activated in the setting of EGFR blockade in conjunction with cetuximab administration may enhance therapeutic benefits. In the previous funding period, this project focused on elucidating interactions between G-protein-coupled receptors (GPCR) and EGFR in SCCHN with the long-term goal of designing a clinical trial combining EGFR and GPCR inhibitors for head and neck cancer patients. We demonstrated the critical role of Src family kinases (SFK) in GPCR-induced EGFR activation. In the absence of a pan-GPCR inhibitor for clinical use, we have elected to refocus this project on co-targeting of SFK and EGFR in this renewal application. New preliminary data also implicates activation of c-Met in the setting of EGFR resistance or blockade. Our working hypothesis is that persistent signaling through alternate kinases in the setting of EGFR blockade contributes to the limited clinical responses to EGFR targeting in SCCHN. The over-riding hypothesis is that there are defined alternative pathways that bypass a cancer cell's need for EGFR signaling, and represent potential targets for combination therapy. The two candidates we have identified are SFK and c-Met. Completion of these studies will elucidate mechanisms of resistance to EGFR targeting strategies thus facilitating the design of therapeutic regimens to enhance clinical response. We will accomplish this goal by determining: 1) the anti-tumor mechanisms of combined inhibition of EGFR and Src family kinases in SCCHN preclinical models of EGFR inhibitor resistance;2) the role of HGF/c-Met signaling in mediating resistance of SCCHN to EGFR inhibition and/or as an alternative target for SCCHN therapy;and 3) the therapeutic potential of cetuximab plus dasatinib in SCCHN patients.

Public Health Relevance

Cetuximab is FDA-approved for the treatment of head and neck cancer but is effective in only a subset of patients. In newly developed models of EGFR-inhibitor resistance, we have found evidence of persistent signaling through alternative kinases including Src family kinases (SFK) and c-Met. In this project we will determine if co-targeting of EGFR in combination with blockade of SFK or c-Met can enhance anti-tumor effects in preclinical SCCHN models. Finally, we will test the efficacy of combined inhibition of EGFR and SFK in a phase II clinical trial in SCCHN patients. These studies should enable the optimization of molecular targeting strategies for this cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097190-10
Application #
8707197
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
$163,598
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Li, Jing; Jie, Hyun-Bae; Lei, Yu et al. (2015) PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res 75:508-18
Johnson, Daniel E (2015) The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. Endocr Relat Cancer 22:T1-17
Sen, Malabika; Paul, Kathleen; Freilino, Maria L et al. (2014) Systemic administration of a cyclic signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide inhibits tumor growth without inducing toxicological effects. Mol Med 20:46-56
Parikh, Rahul A; Appleman, Leonard J; Bauman, Julie E et al. (2014) Upregulation of the ATR-CHEK1 pathway in oral squamous cell carcinomas. Genes Chromosomes Cancer 53:25-37
Johnston, Paul A; Sen, Malabika; Hua, Yun et al. (2014) High-content pSTAT3/1 imaging assays to screen for selective inhibitors of STAT3 pathway activation in head and neck cancer cell lines. Assay Drug Dev Technol 12:55-79
Qian, Wei; Wang, Jingnan; Roginskaya, Vera et al. (2014) Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells. Oncotarget 5:4180-94
Klein, Jonah D; Sano, Daisuke; Sen, Malabika et al. (2014) STAT3 oligonucleotide inhibits tumor angiogenesis in preclinical models of squamous cell carcinoma. PLoS One 9:e81819
Peyser, Noah D; Grandis, Jennifer R (2014) Genetic mutations in head and neck cancer: utilizing existing treatments. Pharmacogenomics 15:1553-5
Li, Changyou; Egloff, Ann Marie; Sen, Malabika et al. (2014) Caspase-8 mutations in head and neck cancer confer resistance to death receptor-mediated apoptosis and enhance migration, invasion, and tumor growth. Mol Oncol 8:1220-30

Showing the most recent 10 out of 150 publications