Molecular imaging of changes in the prevalence of vascular endothelial growth factor receptor in sunitinib-treated murine mammary tumors.
Several drugs targeting vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) are approved for cancer treatment. However, these drugs induce relatively modest and frequently unpredictable tumor responses. In this work, we explored whether noninvasive imaging of VEGFR, a direct target of antiangiogenic drugs, can provide real-time information on responses to the treatment with sunitinib, a small-molecule VEGFR inhibitor approved by the Food and Drug Administration.


METHODS
We imaged VEGFR in an orthotopic mammary tumor model during the course of treatment with sunitinib using a recently developed SPECT tracer, a (99m)Tc-labeled single-chain VEGF (scVEGF), that binds to and is internalized by VEGFR. Tumors from imaged mice were harvested and cryosectioned, and alternating sections were analyzed by autoradiography and immunohistochemistry to determine the expression of endothelial cell markers VEGFR-2 and CD31.


RESULTS
In vitro assays with endothelial cells overexpressing VEGFR-2 established that sunitinib does not inhibit VEGFR-2-mediated uptake of scVEGF-based tracers. SPECT and autoradiography with (99m)Tc-scVEGF of tumor cryosections revealed a 2.2- to 2.6-fold decrease in tracer uptake after 4 daily doses of sunitinib. However, once treatment was discontinued, tracer uptake rapidly (3 d) increased, particularly at the tumor edges. Immunohistochemical analysis of VEGFR-2 and CD31 supported SPECT and autoradiographic imaging findings, revealing the corresponding depletion of VEGFR-2- and CD31-positive endothelial cells from tumor vasculature during therapy and the rapid reemergence of VEGFR-2- and CD31-positive vasculature at the tumor edges after discontinuation of treatment.


CONCLUSIONS
Our findings suggest that imaging with (99m)Tc-scVEGF might be useful for monitoring VEGFR responses to antiangiogenic treatment regimens.
Levashova
Zoia
Z
Department of Radiology/MIPS, Stanford University, Palo Alto, California, USA.
Backer
Marina
M
Hamby
Carl V
CV
Pizzonia
John
J
Backer
Joseph M
JM
Blankenberg
Francis G
FG
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015202:Protein Engineering; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D000077210:Sunitinib; D013667:Technetium; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D007211:Indoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D013667:Technetium; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib