Squamous cell carcinoma of the head and neck (SCCHN) is a serious healthcare problem in the United States and worldwide. Thus, the development of preventive approaches using specific natural or synthetic chemical corn-pounds (chemoprevention) is highly desirable to reduce the incidence of SCCHN. Several chemo-pre-ventive regimens have been tested in preclinical and clinical settings, but no promising regimens have 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 factor receptor (EGFR), to prevent advanced premalignant lesions of the head and neck. Both PPE and EGFR-TKI have shown strong anticancer activity and chemopreventive efficacy as single agents in a variety of cancer types, including SCCHN. Our preliminary studies have shown that the combination of epigallocatechin gallate (EGCG), a major polyphenol extracted from green tea, with erlotinib synergistically inhibited the growth of SCCHN cells in vitro and in vivo. This inhibitory effect was associated with the induction of cell cycle arrest and apoptosis. Furthermore, this combination cooperatively reduced phosphorylation levels of EGFR 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 malignant epithelial cells. Based on these findings, we hypothesize that combined treatment with PPE and erlotinib can additively/synergistically inhibit carcinogenesis, as reflected by biomarker expression, in patients with premalignant 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) To conduct a phase I trial of combined treatment with PPE and erlotinib in patients with premalignant lesions of the head and neck; (3) To identify biomarkers relevant for this treatment in patients' specimens and explore correlative alterations in the proposed biomarkers with clinical and pathological findings. The clinical development of this combination of agents as a cancer preventive regimen may contribute to reducing the incidence of SCCHN. This may be further enhanced by the identification of tumor markers that can serve as indicators for treatment efficacy.