UNLABELLED: 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. CONCLUSION: Our findings suggest that imaging with (99m)Tc-scVEGF might be useful for monitoring VEGFR responses to antiangiogenic treatment regimens.
UNLABELLED: 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. CONCLUSION: Our findings suggest that imaging with (99m)Tc-scVEGF might be useful for monitoring VEGFR responses to antiangiogenic treatment regimens.
Authors: Jan-Philip Meyer; Kimberly J Edwards; Paul Kozlowski; Marina V Backer; Joseph M Backer; Jason S Lewis Journal: J Nucl Med Date: 2016-07-07 Impact factor: 10.057
Authors: Shuning He; Gerda Em Lamers; Jan-Willem M Beenakker; Chao Cui; Veerander Ps Ghotra; Erik Hj Danen; Annemarie H Meijer; Herman P Spaink; B Ewa Snaar-Jagalska Journal: J Pathol Date: 2012-07-03 Impact factor: 7.996
Authors: Monique R Bernsen; Klazina Kooiman; Marcel Segbers; Fijs W B van Leeuwen; Marion de Jong Journal: Eur J Nucl Med Mol Imaging Date: 2015-02-12 Impact factor: 9.236