This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Manning, H. C. Articles by Coffey, R. J. Search for Related Content PubMed PubMed Citation Articles by Manning, H. C. Articles by Coffey, R. J.

Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer

Authors' Affiliations: ¹ Vanderbilt Institute of Imaging Science, Departments of ² Radiology and Radiological Sciences, ³ Neurological Surgery, ⁴ Surgery, ⁵ Pathology, and ⁶ Biostatistics, and ⁷ Program in Chemical and Physical Biology, Vanderbilt University Medical Center; Departments of ⁸ Biomedical Engineering, ⁹ Chemistry, and ¹⁰ Cell and Developmental Biology, Vanderbilt University; ¹¹ Department of Medicine, Vanderbilt University Medical School; ¹² Department of Veterans Affairs Medical Center, Nashville, Tennessee

Requests for reprints: Robert J. Coffey, Suite 4140, MRB III, 465 21st Avenue South, Vanderbilt University, Nashville, TN 37232. Phone: 615-343-6228; Fax: 615-343-1591; E-mail: robert.coffey{at}vanderbilt.edu.

Purpose: To evaluate noninvasive molecular imaging methods as correlative biomarkers of therapeutic efficacy of cetuximab in human colorectal cancer cell line xenografts grown in athymic nude mice. The correlation between molecular imaging and immunohistochemical analysis to quantify epidermal growth factor (EGF) binding, apoptosis, and proliferation was evaluated in treated and untreated tumor-bearing cohorts.

Experimental Design: Optical imaging probes targeting EGF receptor (EGFR) expression (NIR800-EGF) and apoptosis (NIR700-Annexin V) were synthesized and evaluated in vitro and in vivo. Proliferation was assessed by 3'-[¹⁸F]fluoro-3'-deoxythymidine ([¹⁸F]FLT) positron emission tomography. Assessment of inhibition of EGFR signaling by cetuximab was accomplished by concomitant imaging of NIR800-EGF, NIR700-Annexin V, and [¹⁸F]FLT in cetuximab-sensitive (DiFi) and insensitive (HCT-116) human colorectal cancer cell line xenografts. Imaging results were validated by measurement of tumor size and immunohistochemical analysis of total and phosphorylated EGFR, caspase-3, and Ki-67 immediately following in vivo imaging.

Results: NIR800-EGF accumulation in tumors reflected relative EGFR expression and EGFR occupancy by cetuximab. NIR700-Annexin V accumulation correlated with cetuximab-induced apoptosis as assessed by immunohistochemical staining of caspase-3. No significant difference in tumor proliferation was noted between treated and untreated animals by [¹⁸F]FLT positron emission tomography or Ki-67 immunohistochemistry.

Conclusions: Molecular imaging can accurately assess EGF binding, proliferation, and apoptosis in human colorectal cancer xenografts. These imaging approaches may prove useful for serial, noninvasive monitoring of the biological effects of EGFR inhibition in preclinical studies. It is anticipated that these assays can be adapted for clinical use.