The epidermal growth factor receptor (EGFR) is a transmembrane receptor involved in the transduction of proliferative and survival signals which is overexpressed in up to 50 % of patients with colon cancer. Preclinical data suggest that pharmacological inhibition of the EGFR results in tumor growth inhibition and, therefore, the EGFR represents a potential target for cancer therapy. ZD1839 is a novel, orally available, small molecule inhibitor of the EGFR in clinical development. Important questions in the development of this agent, as well as other mechanistic based compounds are the definition of patient populations more likely to respond to the drug based on the presence and functionality of the target pathway in tumor tissues and the assessment of target inhibition in clinical trials. This proposal outlines a series of clinical, pharmacological and biological studies of ZD1839 in patients with colon cancer. Our long term goal is to develop ZD1839 for the treatment of patients with colon cancer, as well as with other EGFR-driven tumors, utilizing rationally derived biological concepts based on the putative mechanism of action of the agent.
The specific aims of this proposal are:
Specific Aim # 1: to determine the relationship between expression and activation of the EGFR receptor in malignant tissues and the activity of ZD1839 in patients with colon cancer, Specific Aim # 2: to characterize the effects of ZD1839 on the activation and signaling of the EGFR in tumor and normal tissues of patients with colon cancer who are treated with ZD1839; and, Specific Aim # 3: to relate the pharmacodynamic effects of ZD 1839 to relevant indices of clinical activity. Patients with advanced, measurable, colon cancer will be treated with ZD1839 at a dose of 500 mg/day on a protracted oral dosing schedule. Tumor tissues, normal skin tissues, and plasma will be collected at baseline and 28 days post-treatment. The expression and activation of the EGFR will be determined using validated immunohistochemical methods developed at our institutions. The result from the biological studies will be correlated with indices of drug activity. These results will provide hypothesis-generating data regarding the subset of colon cancer patients more likely to benefit from treatment with this agent as well as information regarding the biological activity of ZD1839 in colon cancer. Collectively, these data will impact in the future development of ZD1839 in patients with colon cancer as well as other tumor types.
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