Head and neck squamous cell carcinomas (HNSCC) are frequently lethal and predictive biomarkers to guide therapy are lacking. EGFR targeting was FDA-approved in 2006 for HNSCC. EGFR signaling is activated by direct stimulation and transactivation by G-protein-coupled receptors (GPCR). We previously identified GPCR- induced activation of phosphoinositide-3-kinase (PI3K) both upstream and downstream of EGFR. Co-targeting of PI3K in combination with EGFR inhibition was associated with enhanced antitumor effects in HNSCC preclinical models. We recently completed a randomized, placebo-controlled, window-of-opportunity clinical trial where treatment with erlotinib plus the GPCR inhibitor/NSAID sulindac significantly reduced tumor proliferation. Aspirin, like sulindac, inhibits cyclooxygenase (COX) and GPCR signaling. A recent study in colon cancer reported that aspirin use in patients whose tumors harbored PIK3CA mutations was associated with significantly longer survival compared with patients whose tumors contained wild-type (WT) PIK3CA. We have now determined the mutational profile of HNSCC and find PIK3CA genetic alterations in nearly 25% of tumors. Preliminary results indicate that PIK3CA mutation enhances sensitivity to NSAID treatment. As NSAIDs are well tolerated, this provides an immediate opportunity to implement potentially effective approaches for PIK3CA mutant HNSCC. We developed novel HNSCC models to identify oncogenic """"""""driver"""""""" mutations in this cancer. In addition, we can assess PIK3CA mutation and amplification in human HNSCC tumors to be grown as heterotopic tumorgrafts in mice and in a HNSCC cohort with known NSAID use. This project will elucidate the role of PIK3CA alterations in mediating sensitivity to NSAIDs, alone or in combination with EGFR blockade in HNSCC.

Public Health Relevance

Head and neck squamous cell carcinomas (HNSCC) account for the majority of tumors that arise in the mucosal of the head and neck. EGFR is the only FDA-approved molecular therapeutic target, yet the critical therapeutic biomarker(s) for HNSCC remains unknown. We recently determined the mutational profile of 74 HNSCC, and PIK3CA mutations or gene amplification was detected in nearly one third of HNSCC, suggesting that PI3K pathway activation represents a biomarker of HNSCC. We have developed novel HPV-positive and HPV-negative HNSCC models to identify oncogenic driver mutations. The proposed studies will: 1) determine the contribution of PIK3CA alterations to HNSCC growth and sensitivity to NSAIDs, alone or in combination with EGFR targeting strategies in HNSCC cell lines;2) elucidate the role of PIK3CA mutation or gene amplification in conjunction with NSAID use in mediating disease-specific survival in a clinical cohort of HNSCC patients;and 3) determine the antitumor effects of NSAIDs, alone or in combination with EGFR blockade, using preclinical HNSCC models of mutant and WT PIK3CA.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA098372-11
Application #
8606299
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Forry, Suzanne L
Project Start
2014-07-01
Project End
2018-05-31
Budget Start
2014-07-01
Budget End
2015-05-31
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Li, Hua; Wheeler, Sarah; Park, Yongseok et al. (2016) Proteomic Characterization of Head and Neck Cancer Patient-Derived Xenografts. Mol Cancer Res 14:278-86
Van Allen, Eliezer M; Lui, Vivian W Y; Egloff, Ann Marie et al. (2015) Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma. JAMA Oncol 1:238-44
Hammerman, Peter S; Hayes, D Neil; Grandis, Jennifer R (2015) Therapeutic insights from genomic studies of head and neck squamous cell carcinomas. Cancer Discov 5:239-44
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
Parfenov, Michael; Pedamallu, Chandra Sekhar; Gehlenborg, Nils et al. (2014) Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci U S A 111:15544-9
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
Chiosea, Simion I; Grandis, Jennifer R; Lui, Vivian W Y et al. (2013) PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma. BMC Cancer 13:602
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 E; Morariu, Elena M; Bednash, Joseph S et al. (2012) Lyn kinase mediates cell motility and tumor growth in EGFRvIII-expressing head and neck cancer. Clin Cancer Res 18:2850-60

Showing the most recent 10 out of 41 publications