title: Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Vanderbilt Institute of Imaging Science, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
authors.forename: Nipun B
authors.initials: NB
authors.lastname: Merchant
authors.forename: A Coe
authors.initials: AC
authors.lastname: Foutch
authors.forename: John M
authors.initials: JM
authors.lastname: Virostko
authors.forename: Shelby K
authors.initials: SK
authors.lastname: Wyatt
authors.forename: Chirayu
authors.initials: C
authors.lastname: Shah
authors.forename: Eliot T
authors.initials: ET
authors.lastname: McKinley
authors.forename: Jingping
authors.initials: J
authors.lastname: Xie
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Mutic
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Bonnie
authors.initials: B
authors.lastname: LaFleur
authors.forename: Mohammed Noor
authors.initials: MN
authors.lastname: Tantawy
authors.forename: Todd E
authors.initials: TE
authors.lastname: Peterson
authors.forename: M Sib
authors.initials: MS
authors.lastname: Ansari
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Bornhop
authors.forename: John C
authors.initials: JC
authors.lastname: Gore
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D003952:Diagnostic Imaging / Q000379:methods*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D019265:Spectroscopy, Near-Infrared; D013936:Thymidine; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D066246:ErbB Receptors; D000068818:Cetuximab; D013936:Thymidine