89Zr-bevacizumab PET of early antiangiogenic tumor response to treatment with HSP90 inhibitor NVP-AUY922.
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 small-animal 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 = 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.


CONCLUSIONS
(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.
Nagengast
Wouter B
WB
Department of Medical Oncology, University of Groningen, Groningen, The Netherlands.
de Korte
Maarten A
MA
Oude Munnink
Thijs H
TH
Timmer-Bosscha
Hetty
H
den Dunnen
Wifred F
WF
Hollema
Harry
H
de Jong
Johan R
JR
Jensen
Michael R
MR
Quadt
Cornelia
C
Garcia-Echeverria
Carlos
C
van Dongen
Guus A M S
GA
Lub-de Hooge
Marjolijn N
MN
Schröder
Carolien P
CP
de Vries
Elisabeth G E
EG
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D000068258:Bevacizumab; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011868:Radioisotopes; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012118:Resorcinols / Q000627:therapeutic use*; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015040:Zirconium
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D019394:Ki-67 Antigen; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D012118:Resorcinols; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C580636:89Zr-bevacizumab; D015040:Zirconium; D002945:Cisplatin