Determinants of Response to ZD1839 (1 R01-CA104900-01)

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DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is deregulated in the majority of patients with epidermal cancers and has become an attractive target for the development of cancer therapeutics. ZD1839 is a small molecule inhibitor of the EGFR. Despite the significant knowledge acquired with regards to the clinical pharmacology, toxicity, and activity of this drug, the fundamental question regarding which factor (s) determine susceptibility to this class of agents remain poorly understood. Studies conducted thus far suggest that the expression of the EGFR is not a good predictor of the activity of these drugs. A better understanding of this question would facilitate targeting ZD1839 to patients more likely to benefit from the drug. The overall objective of this proposal is to rationally develop determinants of response to ZD1839. The central hypothesis of the proposed research is that ZD1839 will be particularly active in tumors with altered EGFR function in which the agent inhibits the activation and signaling of the receptor. The Specific Aims are to 1) develop a pharmacodiagnostic test for ZD1839; and, 2) develop and validate a pharmacodynamic test of ZD1839 effects in normal surrogate tissues. To accomplish this goal we will use a novel clinical trial design in which patients with stage II and III carcinoma of the rectum scheduled to undergo pre-operative chemoradiation in combination with ZD 1839 will receive single agent ZD1839 for a lead-in period of fifteen days prior to commencing the combined modality treatment segment. Biopsies of tumors tissues (easily accessible by endoscopic procedures), and normal skin tissues will be performed prior to treatment and after the lead-in treatment with ZD1839. Smears from oral mucosa will also be collected. The relationship between the expression and activation of the EGFR, polymorphisms in the intron 1 region of the EGFR gene and the effects of ZD1839 as measured by biological, metabolic, and toxicological response to ZD1839 will be determined. Correlations between the pharmacodynamic effects of the drug in normal and tumor tissues with measurements of biological and metabolic activity will be evaluated. These results will provide important information for the rationale clinical development of this class of novel agents based on biologic and mechanistic data.