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Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer
H Charles Manning1, Nipun B Merchant, A Coe Foutch
1Vanderbilt Institute of Imaging Science, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
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.
Insights
Noninvasive molecular imaging accurately assessed epidermal growth factor (EGF) receptor binding and apoptosis in colorectal cancer xenografts treated with cetuximab. This method shows promise for monitoring EGFR inhibition in preclinical and clinical settings.
Area of Science:
- Oncology
- Molecular Imaging
- Biomarker Development
Background:
- Cetuximab targets the epidermal growth factor receptor (EGFR) in colorectal cancer.
- Noninvasive biomarkers are needed to assess therapeutic efficacy and monitor EGFR inhibition.
- Molecular imaging offers a potential solution for serial assessment of treatment response.
Purpose of the Study:
- To evaluate noninvasive molecular imaging as a biomarker for cetuximab efficacy in colorectal cancer xenografts.
- To correlate imaging findings with immunohistochemical analysis of EGFR binding, apoptosis, and proliferation.
- To assess the potential for adapting these imaging assays for clinical use.
Main Methods:
- Synthesized optical imaging probes targeting EGFR (NIR800-EGF) and apoptosis (NIR700-Annexin V).
- Utilized [18F]FLT positron emission tomography for proliferation assessment.
- Conducted in vivo imaging in cetuximab-sensitive and insensitive colorectal cancer xenografts, validated by immunohistochemistry.
Main Results:
- NIR800-EGF accumulation correlated with EGFR expression and cetuximab occupancy.
- NIR700-Annexin V accumulation reflected cetuximab-induced apoptosis.
- No significant differences in proliferation were observed between treated and untreated groups via imaging or immunohistochemistry.
Conclusions:
- Molecular imaging can accurately assess EGF binding, apoptosis, and proliferation in colorectal cancer xenografts.
- These noninvasive imaging approaches are valuable for monitoring EGFR inhibition in preclinical studies.
- The developed assays are anticipated to be adaptable for clinical applications.
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