The major cause of treatment failure in early stage (stage I/II) squamous cell carcinoma of the head and neck (SCCHN) is development of second primary tumors (SPTs). Recently, several natural or synthetic chemical compounds that target specific molecular pathways have been developed for use in treatment and prevention of cancer. As a novel approach to prevention of SPT developments, we are proposing a clinical trial for patients with early stage of SCCHN using a combination of two types of agents, tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptors (EGFR) and cyclooxygenase-2 inhibitor (COX-2I) to prevent progression of tumorigenesis of SCCHN. Simultaneously blocking these two targets, we believe, is a novel approach and shows additive or synergistic inhibitory effects for SCCHN in preliminary data. We will test the following hypotheses: 1) combination of EGFR-TKIs and COX-2Is to delay or prevent SPT formation by inhibition of cell cycle progression, induction of apoptosis, and blocking angiogenesis;2) overexpression of COX-2 in tumor cells to lead to immune dysfunction of both innate and adaptive immune responses, which are mediated via PGE2 release and accompanied by STAT-3 phosphorylation on the tumor cells. Inhibition of these molecular pathways with EGFR-TKIs and COX-2Is leads to the restoration of immune reactivity and improved antitumor response. To test these hypotheses, we proposed the following specific aims:
Aim 1, to evaluate the safety and efficacy of the combined EGFR-TKI (Erlotinib) and COX-2I (Celecoxib) regimen in reducing the risk of SPT development and recurrence in patients with early stage (stage I/II) SCCHN;
Aim 2, to understand the contribution of abnormal EGFR and COX-2 mediated pathways to the development of SPT and to study effects of the treatment with combined EGFR selective TKIs and COX-2Is on the cell cycle progression, apoptosis, and angiogenesis by analyzing relevant biomarkers using tumor samples derived from patients who participate in the clinical trial;
Aim 3, to evaluate in vivo and in vitro effects of the combination of EGFR-selective TKIs and COX-2Is on the immune system of the host in a series of experiments designed to: a) utilize immune cells isolated from the circulation of patients participating in the clinical trial and b) ex vivo modeling of interactions between the selected SCCHN cell lines treated with the drug combination and normal human lymphocytes or their subsets. The clinical trial and biomarker studies will be conducted with various methodologies, including pharmacokinetic studies, immunohistochemistry, immunoblot, RT-PCR, IMCPL monitoring, and statistical analyses.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-ONC-E (02))
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Timmer, William C
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Shin, Dong M; Zhang, Hongzheng; Saba, Nabil F et al. (2013) Chemoprevention of head and neck cancer by simultaneous blocking of epidermal growth factor receptor and cyclooxygenase-2 signaling pathways: preclinical and clinical studies. Clin Cancer Res 19:1244-56
Whiteside, Theresa L (2010) Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression. Expert Opin Biol Ther 10:1019-35
Kim, Joseph W; Amin, A R M Ruhul; Shin, Dong M (2010) Chemoprevention of head and neck cancer with green tea polyphenols. Cancer Prev Res (Phila) 3:900-9
Rahman, Mohammad Aminur; Amin, A R M Ruhul; Shin, Dong M (2010) Chemopreventive potential of natural compounds in head and neck cancer. Nutr Cancer 62:973-87
Amin, A R M Ruhul; Wang, Dongsheng; Zhang, Hongzheng et al. (2010) Enhanced anti-tumor activity by the combination of the natural compounds (-)-epigallocatechin-3-gallate and luteolin: potential role of p53. J Biol Chem 285:34557-65
Amin, A R M Ruhul; Kucuk, Omer; Khuri, Fadlo R et al. (2009) Perspectives for cancer prevention with natural compounds. J Clin Oncol 27:2712-25
Amin, A R M Ruhul; Khuri, Fadlo R; Chen, Zhuo Georgia et al. (2009) Synergistic growth inhibition of squamous cell carcinoma of the head and neck by erlotinib and epigallocatechin-3-gallate: the role of p53-dependent inhibition of nuclear factor-kappaB. Cancer Prev Res (Phila Pa) 2:538-45
Klass, Carmen M; Choe, Mi Sun; Hurwitz, Selwyn J et al. (2009) Sequence dependence of cell growth inhibition by EGFR-tyrosine kinase inhibitor ZD1839, docetaxel, and cisplatin in head and neck cancer. Head Neck 31:1263-73
Szczepanski, Miroslaw J; Czystowska, Malgorzata; Szajnik, Marta et al. (2009) Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res 69:3105-13
Saba, Nabil F; Choi, Misun; Muller, Susan et al. (2009) Role of cyclooxygenase-2 in tumor progression and survival of head and neck squamous cell carcinoma. Cancer Prev Res (Phila Pa) 2:823-9

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