Multimodality therapy for esophageal cancer patients with locally advanced resectable tumors involving chemotherapy and/or radiation followed by surgery promises to be a substantial improvement over treatment with surgery alone. However, only patients whose tumors respond well to chemotherapy/radiation have a clear survival benefit. Therefore, the ability to predict whether response to the neoadjuvant treatment can be expected would give patients with unfavorable prognosis the option of avoiding the acute toxicities associated with radiation and chemotherapy and the risk of delaying definitive treatment. In this application, the applicant describes a molecular approach toward this goal based on identifying and measuring biochemical determinants of tumor sensitivity to drugs and radiation in tumor biopsy specimens prior to therapy. Quantitative RT-PCR technology for precisely and reproducibly measuring gene expressions (relative mRNA levels) in small tissue specimens has been developed and refined in this laboratory. The applicant will investigate the association between intratumoral expressions of thymidylate synthase, ERCC1, thymidine phosphorylase, bcl-2, bax and the p53 mutational status in esophageal squamous cell carcinoma and adenocarcinoma treated with neoadjuvant protocols involving 5-fluorouracil, cisplatin, taxol, and radiation and the degree of tumor response to the treatments. The hypothesis will be tested that tumors that achieve a pathological complete response to radio/chemotherapy can be distinguished on the basis of molecular determinants from non-responding tumors. Molecular differences between esophageal adenocarcinoma and squamous cell carcinoma histological types will be characterized, especially thymidylate synthase expression and p53 mutational spectrum. In vitro studies with adenocarcinoma and squamous cell carcinoma cell lines will be used to investigate the effect of p53 status on the chemo-and radiosensitivity of esophageal cancer cells and to study the role of the bcl-2 family of proteins in determining the activity of taxol. Transfection experiments will be done to test the hypothesis that gain-of-function p53 mutants up-regulate thymidylate synthase expression.
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