⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

Abstract

Angiogenesis is a critical step in tumor development, in which vascular endothelial growth factor (VEGF) is a key growth aspect. Heat shock protein 90 (HSP90), a molecular chaperone, is essential for the activity of key proteins involved in VEGF transcription. Currently, no biomarkers to predict the effect of, or monitor, HSP90 inhibition therapy in individual patients exist. 89 Zr-bevacizumab PET provides a noninvasive tool to monitor tumor VEGF levels. The aim of this study was to investigate 89 Zr-bevacizumab PET for early antiangiogenic tumor response evaluation of treatment with the new HSP90 inhibitor NVP-AUY922. In xenografts of A2780 and its cisplatin-resistant CP70 human ovarian cancer subline, 89 Zr-bevacizumab smallanimal PET was performed before and after NVP-AUY922 treatment and verified with histologic response and ex vivo tumor VEGF levels. Compared with pretreatment values, 2 wk of NVP-AUY922 treatment decreased 89 Zr-bevacizumab uptake by 44.4% (P 5 0.0003) in A2780 xenografts, whereas tumor uptake was not affected in CP70 xenografts. The same pattern was observed in A2780 and CP70 tumor VEGF levels, measured with enzyme-linked immunosorbent assay, and mean vessel density after NVP-AUY922 treatment. These findings coincided with reduction in the proliferation rate, assessed by Ki67 staining, in A2780 tumor tissue only. Conclusion: 89 Zr-bevacizumab PET was in line with the antiangiogenic response and direct antitumor effects after NVP-AUY922 treatment, supporting the specificity of 89 Zr-bevacizumab PET as a sensitive technique to monitor the antiangiogenic response of HSP90 inhibition in vivo.

89Zr-Bevacizumab PET Imaging in Primary Breast Cancer

“…Thus, tracer dosages of radiolabeled bevacizumab can be used for tumor-specific, whole-body imaging of VEGF-A. In preclinical studies (6,7) and in a study in renal cell cancer patients (8), we have already shown an excellent tumor-to-background ratio with an optimum at 4 d after tracer injection when using 89 Zr-bevacizumab. In the present clinical feasibility study, we used 89 Zr-bevacizumab PET to provide proof of principle on whether VEGF-A imaging can be used for detection of primary breast tumors.…”

A Tyrosine Kinase Inhibitor–Based High-Affinity PET Radiopharmaceutical Targets Vascular Endothelial Growth Factor Receptor

“…VEGF/VEGFR antibodies have been labeled with various radioisotopes for the imaging of VEGFR expression in various disease models (20). For example, extracellular VEGF imaging was accomplished by coupling anti-VEGF monoclonal antibodies (bevacizumab, HuMV833) with 89 Zr (21,22), 111 In (23), and 124 I (24). Recombinant VEGF 165 was efficiently labeled with 123 I and VEGF 121 with both 99m Tc and 64 Cu for VEGF imaging in preclinical models (25)(26)(27)(28).…”

Development of a 124I-labeled version of the anti-PSMA monoclonal antibody capromab for immunoPET staging of prostate cancer: Aspects of labeling chemistry and biodistribution

“…PET provides better resolution (and, accordingly, lower influence of partial volume effect) and better registration efficiency, which improves imaging quality. Feasibility of antibody-mediated PET imaging (immunoPET) has been demonstrated in a number of preclinical studies using monoclonal antibodies targeting several tumor-associated antigens (6,(15)(16)(17)(18)(19)(20). Preliminary clinical data concerning immunoPET imaging of HER2-expressing breast cancer (21) and renal cell carcinoma (22) are very encouraging.…”