title: Detection of rapalog-mediated therapeutic response in renal cancer xenografts using ⁶⁴Cu-bevacizumab immunoPET.
abstract: The importance of neovascularization for primary and metastatic tumor growth fostered numerous clinical trials of angiogenesis inhibitors either alone or in combination with conventional antineoplastic therapies. One challenge with the use of molecularly targeted agents has been the disconnection between size reduction and tumor biologic behavior, either when the drug is efficacious or when tumor resistance emerges. Here, we report the synthesis and characterization of (64)Cu-NOTA-bevacizumab as a PET imaging agent for imaging intratumoral VEGF content in vivo. (64)Cu-NOTA-bevacizumab avidly accumulated in 786-O renal carcinoma xenografts with lower levels in host organs. RAD001 (everolimus) markedly attenuated (64)Cu-NOTA-bevacizumab accumulation within 786-O renal carcinoma xenografts. Tumor tissue and cellular molecular analysis validated PET imaging, demonstrating decreases in total and secreted VEGF content and VEGFR2 activation. Notably, (64)Cu-NOTA-bevacizumab PET imaging was concordant with the growth arrest of RAD001 tumors. These data suggest that immunoPET targeting of angiogenic factors such as VEGF could be a new class of surrogate markers complementing the RECIST criteria in patients receiving molecularly targeted therapies.
authors.affiliation: Department of Radiation Oncology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Chang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sohn
authors.forename: Zhi Hong
authors.initials: ZH
authors.lastname: Lu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Lapi
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003301:Copper Radioisotopes; D000068338:Everolimus; D006571:Heterocyclic Compounds / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D018796:Immunoconjugates; D007680:Kidney Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy; D051379:Mice; D009389:Neovascularization, Pathologic; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography; D020123:Sirolimus / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D000068338:Everolimus; D020123:Sirolimus