Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer

H. Charles Manning, Nipun B. Merchant, A. Coe Foutch, John M. Virostko, Shelby K. Wyatt, Chirayu Shah, Eliot T. McKinley, Jingping Xie, Nathan J. Mutic, M. Kay Washington, Bonnie LaFleur, Mohammed Noor Tantawy, Todd E. Peterson, M. Sib Ansari, Ronald M. Baldwin, Mace L. Rothenberg, Darryl J. Bornhop, John C. Gore, Robert J. Coffey

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

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-AnnexinV, and [18F] FLT incetuximab-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 Vac cumulation 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.

Original languageEnglish (US)
Pages (from-to)7413-7422
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number22
DOIs
StatePublished - Nov 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Manning, H. C., Merchant, N. B., Foutch, A. C., Virostko, J. M., Wyatt, S. K., Shah, C., McKinley, E. T., Xie, J., Mutic, N. J., Washington, M. K., LaFleur, B., Tantawy, M. N., Peterson, T. E., Ansari, M. S., Baldwin, R. M., Rothenberg, M. L., Bornhop, D. J., Gore, J. C., & Coffey, R. J. (2008). Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer. Clinical Cancer Research, 14(22), 7413-7422. https://doi.org/10.1158/1078-0432.CCR-08-0239