Squamous cell carcinoma of the head and neck (SCCHN) is a serious healthcare problem in the UnitedStates and worldwide. Thus, the development of preventive approaches using specific natural or syntheticchemical corn-pounds (chemoprevention) is highly desirable to reduce the incidence of SCCHN. Severalchemo-pre-ventive regimens have been tested in preclinical and clinical settings, but no promising regimenshave been well documented. In this study, we propose to use a combination of green tea polyphenon E(PPE) and erlotinib (Tarceva or OSI-774), a tyrosine kinase inhibitor (TKI) of the epidermal growth factorreceptor (EGFR), to prevent advanced premalignant lesions of the head and neck. Both PPE and EGFR-TKIhave shown strong anticancer activity and chemopreventive efficacy as single agents in a variety of cancertypes, including SCCHN. Our preliminary studies have shown that the combination of epigallocatechingallate (EGCG), a major polyphenol extracted from green tea, with erlotinib synergistically inhibited thegrowth of SCCHN cells in vitro and in vivo. This inhibitory effect was associated with the induction of cellcycle arrest and apoptosis. Furthermore, this combination cooperatively reduced phosphorylation levels ofEGFR and AKT. Both EGCG and erlotinib also regulate expression and cell surface localization of E-cadherin, suggesting that they may inhibit epithelial to mesenchymal transition (EMT) of the malignantepithelial cells. Based on these findings, we hypothesize that combined treatment with PPE and erlotinibcan additively/synergistically inhibit carcinogenesis, as reflected by biomarker expression, in patients withpremalignant lesions of the head and neck. To test this hypothesis we propose the following specific aims:(1) To under-stand the underlying mechanisms of the effect of combined treatment with EGCG (and/or PPE)and erlotinib on signal transduction pathways responsible for SCCHN progression and survival; (2) Toconduct a phase I trial of combined treatment with PPE and erlotinib in patients with premalignant lesions ofthe head and neck; (3) To identify biomarkers relevant for this treatment in patients' specimens and explorecorrelative alterations in the proposed biomarkers with clinical and pathological findings. The clinicaldevelopment of this combination of agents as a cancer preventive regimen may contribute to reducing theincidence of SCCHN. This may be further enhanced by the identification of tumor markers that can serve asindicators for treatment efficacy.
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