Detecting epidermal growth factor receptor tumor activity in vivo during cetuximab therapy of murine gliomas.
OBJECTIVE
Noninvasive molecular imaging of glioma tumor receptor activity was assessed with diagnostic in vivo fluorescence monitoring during targeted therapy. The study goals were to assess the range of use for treatment monitoring and stratification of tumor types using epidermal growth factor (EGF) receptor (EGFR) status with administration of fluorescently labeled EGF and determine its utility for tumor detection compared to magnetic resonance imaging (MRI).


METHODS
EGFR+ and EGFR- glioma tumor lines (human glioma [U251-GFP] and rat gliosarcoma [9L-GFP], respectively) were used to assess these goals, having a 20-fold difference between their EGF uptakes.


RESULTS
Treatment with cetuximab in the EGFR+ tumor-bearing animals led to decreased EGF tumor uptake, whereas for the EGFR- tumors, no change in fluorescence signal followed treatment. This diagnostic difference in EGFR expression could be used to stratify the tumor-bearing animals into groups of potential responders and nonresponders, and receiver-operating characteristic curve analysis revealed an area under the curve (AUC) of 0.92 in separating these tumors. The nonlocalized growth pattern of U251-GFP tumors resulted in detection difficulty on standard MRI, but high EGFR expression made them detectable by fluorescence imaging (AUC = 1.0). The EGFR+ U251-GFP tumor-bearing animals could be noninvasively stratified into treated and untreated groups on the basis of fluorescence intensity difference (P = .035, AUC = 0.90).


CONCLUSIONS
EGFR expression was tracked in vivo with fluorescence and determined to be of use for the stratification of EGFR+ and EGFR- tumors, the detection of EGFR+ tumors, and monitoring of molecular therapy.
Gibbs-Strauss
Summer L
SL
Thayer School of Engineering, Dartmouth College, Hanover, NH, USA. sgibbs@bidmc.harvard.edu
Samkoe
Kimberley S
KS
O'Hara
Julia A
JA
Davis
Scott C
SC
Hoopes
P Jack
PJ
Hasan
Tayyaba
T
Pogue
Brian W
BW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000378:metabolism*; D005910:Glioma / Q000175:diagnosis* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000032:analysis; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013050:Spectrometry, Fluorescence / Q000379:methods*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab