Molecular Mechanisms of Blockage of ErbB receptors

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DESCRIPTION (provided by applicant): The rationale for using EGFR-targeted approaches in cancer treatment is now firmly established, and numerous clinical trials are in progress. Improved understanding of EGFR's role in cancer has raised the question of whether EGFR-targeted agents are active against the deletion mutant EGFRvIII. This mutant form is expressed in several types of cancer, including breast cancer, in which it enhances tumorigenicity and is often associated with an aggressive tumor phenotype. EGFR-TKIs remain a remarkable advance in targeted therapy for solid tumors. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene of patients with non-small cell lung cancer treated with gefitinib (Iressa) has inaugurated a new era of integrated diagnostics and therapeutics --- new anticancer drugs are taking advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatments. Despite the encouraging results, not all tumors that overexpress EGFR or with EGFR mutant (EGFRvIII) respond to these treatments. In a phase II trial, gefitinib has not elicited clinical responses in patients with gliomas, despite the high frequency of amplification and rearrangement of the EGFR gene in such patients. The response to TKIs was not correlated with EGFR expression. The sensitivity of tumor cells to EGFR inhibition is likely to be influenced by other factors such as activating mutations in EGFR, levels of EGFR ligands, and expression of other ErbB family members that may form heterodimers and allow continued signal amplification. Furthermore, we have detected co-expression of wild-type EGFR with EGFRvIII, as well as co-expression of ErbB-2 with EGFRvIII, in breast cancer. It is important to evaluate the impact of EGFRvIII expression on responses to these EGFR-TKIs. To achieve this goal, we propose the following Specific Aims. 1): To assess whether sensitivity and resistance to tyrosine kinase inhibitors are dependent upon the expression levels and activities of EGFR and its variants as well as other members of the EGFR family of receptors. 2): To evaluate the therapeutic efficacy and pharmacologic effect of EGFR-targeted therapies on xenograft model systems expressing EGFR and its variants. We believe that these studies will provide valuable information, which may help optimize the current available drugs and promote the development of novel agents.