The long-term goal of this research program is to develop and validate a novel microfluidic method to capture and characterize circulating tumor cells (CTCs) from the peripheral blood of cancer patients. CellPoint Diagnostics has developed a high-speed microfluidic platform that uses size- based separation and immunoaffinity capture to selectively recover rare cells from blood with frequencies as low as 10-7. Preliminary studies demonstrated that model cell lines and patient CTCs can be recovered and analyzed by immunocytochemistry and fluorescence in situ hybridization. This Fast-Track SBIR application proposes to optimize and validate this microfluidic system to analyze CTCs from patients with advanced non- small cell (NSC) lung cancer. CTC analysis would be valuable for assessing prognosis, monitoring therapeutic efficacy, and detecting mutations in endothelial growth factor receptor (EGFR) that affect tumor response to the EGFR-targeted drug gefitinib (Iressa, AstraZeneca). The objectives of this Phase I project are to optimize the microfluidic cell analysis platform for CTCs and demonstrate its feasibility for lung cancer. Aim 1 will create and test new designs for the internal geometry of the microfabricated chips to obtain an optimal balance among yield, purity, cell integrity and throughput. Aim 2 will demonstrate that the captured CTCs can be used to detect EGFR mutations that have been associated with response to gefitinib, by either conventional gene sequencing or, preferably, a novel multiplexed RT-PCR assay. Successful completion of this work will lead to a Phase II project, described in the accompanying proposal, to conduct clinical studies to correlate CTC levels with clinical outcomes in patients with advanced lung cancer. Relevance. CTCs are believed to be an early harbinger of tumor expansion and metastasis. CTC analysis may be useful in monitoring cancer patients for response to treatment, disease progression and early evidence of relapse. In addition, molecular analysis of certain genetic markers in CTCs may help identify patients who are more likely to respond to targeted cancer therapies. A rapid and minimally invasive method to measure and analyze CTCs would be especially valuable in the clinical management of lung cancer if it could detect early responses to therapy and identify patients whose tumors carry clinically relevant EGFR gene mutations that affect their response to targeted cancer drugs such as gefitinib.
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