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.
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.
|Hong, Jidong; Liao, Zhongxing; Zhuang, Yan et al. (2018) Prognostic Factors as a Function of Disease-free Interval After Definitive (Chemo)radiation for Non-Small Cell Lung Cancer Using Conditional Survival Analysis. Am J Clin Oncol 41:46-52|
|Adeegbe, Dennis O; Liu, Yan; Lizotte, Patrick H et al. (2017) Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer. Cancer Discov 7:852-867|
|Skinner, Heath D; Giri, Uma; Yang, Liang P et al. (2017) Integrative Analysis Identifies a Novel AXL-PI3 Kinase-PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer. Clin Cancer Res 23:2713-2722|
|Cascone, Tina; Xu, Li; Lin, Heather Y et al. (2017) The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non-Small Cell Lung Cancer. Clin Cancer Res 23:5489-5501|
|Ferrarotto, Renata; Mitani, Yoshitsugu; Diao, Lixia et al. (2017) Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors. J Clin Oncol 35:352-360|
|Ferrarotto, Renata; Goonatilake, Ruchitha; Yoo, Suk Young et al. (2016) Epithelial-Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor-Mediated Apoptosis in Non-Small Cell Lung Cancer. Clin Cancer Res 22:1674-1686|
|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|
|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|
|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|
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