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Squamous cell carcinoma of the head and neck (SCCHN) is a serious healthcare problem in the United States and worldwide. Thus development of preventive approaches using specific natural or synthetic chemical compounds (chemoprevention) would be highly desirable to reduce the incidence of SCCHN. Several chemopreventive regimens have been tested in preclinical and clinical setting, but no promising regimens have been well documented as far. In this study, we propose to use a combination of green tea Polyphphenon 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 as single agents have shown strong anticancer activity and chemopreventive efficacy in a variety of cancer types including SCCHN. Our preliminary study showed that the combination of epigallocatechin gallate (EGCG), a major polyphenol extracted from green tea, with Erlotinib synergistically inhibited growth of SCCHN both in vitro and in vivo. This inhibitory effect was associated with induction of cell cycle arrest and apoptosis. Furthermore, this combination cooperatively reduced the levels of phosphorylation of EGFR and AKT. Both EGCG and Erlotinib also regulate expression and cell surface localization of E-Cadherin (E-Cad), suggesting these two drugs may inhibit epithelial to mesenchymal transition (EMT) of the malignant epithelial cells. Based on these findings, we hypothesize that a combined treatment with PPE and EGFR-TKI can additively/synergistically inhibit carcinogenesis as reflected in biomarkers in patients with premalignant lesions of the head and neck. To test these hypotheses we propose the following specific aims: (1) To understand the underlying mechanisms of the effect of the combined treatment with EGCG (and PPE) and Erlotinib (EGFR-TKIs) on signal transduction pathways, i.e. EGFR and IGF-1R mediated pathways and their common down stream mediators AKT and ERK, which are responsible for SCCHN progression and survival; (2) To conduct a phase I/II trial of the combined treatment with PPE and EGFR-TKI (Erlotinib) in patients with premalignant lesions of the head and neck; (3) To identify the biomarkers relevant to this treatment by using patient specimens and correlate alteration of the proposed biomarker with clinical and pathological endpoints. In Specific Aim 1, SCCHN cell lines will be used to study effect of the combined treatment on the proposed biomarkers which will be applied to a clinical trial using this combined regimen with toxicology, pharmacokinetic, and sophisticated statistical analyses in Specific Aim 2 and 3.
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Last update: June 21st, 2007 |
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