Chemoradiotherapy (CRT) is a frontline non-surgical treatment for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Prior work from this group and others demonstrated that epidermal growth factor receptor (EGFR) expression was associated with CRT resistance, and that adding the anti-EGFR antibody cetuximab (CET) to RT improved outcomes in a subset of HNSCC patients. Furthermore, human papilloma virus (HPV) was identified as a strong prognostic marker in HNSCC patients treated with CRT. Nevertheless, a substantial percentage of patients experience CRT resistance with local relapse or distant metastases. There are cun-ently no validated markers to identify which HNSCC patients are most likely to benefit from CRT regimens, and the mechanisms underlying resistance to these regimens, and how to overcome it, remain unclear. These needs are particularly critical for patients with HPV-negative disease. We hypothesize that by systematic gene expression and proteomic profiling of HNSCC tumors from patients treated with CRT regimens, candidate predictive markers can be identified and subsequently validated using tumor annotated specimens from two large randomized phase III trials, Furthermore, we believe that therapeutic strategies for overcoming this resistance can be identified. Our preliminary data supports these hypotheses. Thus far we have identified several novel markers associated with CRT response including Ku80, a double-strand break repair protein;a post-operative RT (PORT) signature;and an epithelial-to-mesenchymal transition (EMT) signature. We have also identified several targets, including telomerase and Chk2, for overcoming radioresistance. Therefore, to address the unmet needs we proposed the following aims: 1) We will develop candidate gene expression and proteomic markers of CRT resistance using archival HNSCC specimens, and will then prioritize them together with our predefined candidates and markers from Projects 1 and 3, for further testing. 2) The top priority markers will be tested and potentially validated using specimens from two large phase III CRT studies (RTOG 0129 &0522). 3) We will evaluate Which pathways can be targeted to overcome therapeutic resistance of HNSCC cells in vitno. Therefore, this project has the potential to yield validated markers of as well as new strategies for overcoming CRT resistance. The project also benefits from, and contributes to, the efforts of Projects 1 and 3 and other major grant programs investigating related issues including the HN and Lung SPOREs.

Public Health Relevance

This project has the potential to directly advance the treatment of HNSCC in several ways. Identification of predictive markers for rational selection of better suited therapy for individual patients with defined tumor features will improve tumor control while reducing unnecessary patient distress and the financial burden to patients and society. Furthermore, markers and mechanisms of resistance to CRT will be identified and strategies for overcoming it will be developed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1-RPRB-O (M1))
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Bernhard, Eric J
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
Other Domestic Higher Education
United States
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Nilsson, Monique B; Giri, Uma; Gudikote, Jayanthi et al. (2016) KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib. Clin Cancer Res 22:1940-50
Mak, Milena P; Tong, Pan; Diao, Lixia et al. (2016) A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition. Clin Cancer Res 22:609-20
Skinner, Heath D; Giri, Uma; Yang, Liang et al. (2016) Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer. Clin Cancer Res 22:4643-50
Cardnell, Robert J; Feng, Ying; Mukherjee, Seema et al. (2016) Activation of the PI3K/mTOR Pathway following PARP Inhibition in Small Cell Lung Cancer. PLoS One 11:e0152584
Guijarro-Muñoz, Irene; Roarty, Emily B; Heymach, John V (2016) Bevacizumab beyond disease progression for advanced non-small cell lung cancer: Does persistence have its rewards? Cancer 122:1047-9
Cascone, Tina; Heymach, John V (2015) Can the Lung Cancer Pie Be Divided into Angiogenic Slices? Clin Cancer Res 21:5188-90
Skoulidis, Ferdinandos; Byers, Lauren A; Diao, Lixia et al. (2015) Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 5:860-77
Chen, Limo; Gibbons, Don L; Goswami, Sangeeta et al. (2014) Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 5:5241
Lin, Steven H; Zhang, Jing; Giri, Uma et al. (2014) A high content clonogenic survival drug screen identifies mek inhibitors as potent radiation sensitizers for KRAS mutant non-small-cell lung cancer. J Thorac Oncol 9:965-73
Lin, Steven H; Wang, Jing; Saintigny, Pierre et al. (2014) Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition. BMC Genomics 15:1079

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