title: Monitoring vascular normalization induced by antiangiogenic treatment with (18)F-fluoromisonidazole-PET.
abstract: Rationalization of antiangiogenics requires biomarkers. Vascular re-normalization is one widely accepted mechanism of action for this drug class. The interstitium of tumors with abnormal vasculature is hypoxic. We sought to track vascular normalization with (18)F-misonidazole ([18F]-FMISO, a probe that detects hypoxia) PET, in response to window-of-opportunity (WoO) treatment with the antiangiogenic dovitinib.
  
  
  
  Two patient-derived pancreas xenografts (PDXs; Panc215 and Panc286) and the spontaneous breast cancer model MMTV-PyMT were used. Animals were treated during 1 week of WoO treatment with vehicle or dovitinib, preceded and followed by [18F]-FMISO-PET, [18F]-FDG-PET, and histologic assessment (dextran extravasation, hypoxia and microvessel staining, and necrosis, cleaved caspase-3 and Ki67 measurements). After WoO treatment, gemcitabine (pancreas)/adriamycin (breast) or vehicle was added and animals were treated until the humane endpoint. Tumor growth inhibition (TGI) and survival were the parameters studied.
  
  
  
  [18F]-FMISO SUV did not change after dovitinib-WoO treatment compared to vehicle-WoO (0.54 vs. 0.6) treatment in Panc215, but it decreased significantly in Panc286 (0.58 vs. 1.18; P < 0.05). In parallel, 10-KDa perivascular dextran extravasation was not reduced with dovitinib or vehicle-WoO treatment in Panc215, but it was reduced in Panc286. Whereas the addition of dovitinib to gemcitabine was indifferent in Panc215, it increased TGI in Panc286 (TGI switched from -59% to +49%). [18F]-FMISO SUV changes were accompanied by an almost 100% increase in interstitial gemcitabine delivery (665-1260 ng/mL). The results were validated in the PyMT model.
  
  
  
  [18F]-FMISO accurately monitored vascular re-normalization and improved interstitial chemotherapy delivery.
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Hernández-Agudo
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Tamara
authors.initials: T
authors.lastname: Mondejar
authors.affiliation: Unidad de Medicina y Cirugía Experimental, Instituto de Investigación Sanitaria Gregorio Marañon, Doctor Esquerdo, 46, Madrid, 28007, Spain; CIBER de Salud Mental, Monforte de Lemos 3-5, Pabellón 11, Madrid, 28029, Spain.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Soto-Montenegro
authors.affiliation: Confocal Microscopy Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Megías
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Silvana
authors.initials: S
authors.lastname: Mouron
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Sanchez
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Gastrointestinal Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Pedro Pablo
authors.initials: PP
authors.lastname: Lopez-Casas
authors.affiliation: Molecular Imaging Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.affiliation: Unidad de Medicina y Cirugía Experimental, Instituto de Investigación Sanitaria Gregorio Marañon, Doctor Esquerdo, 46, Madrid, 28007, Spain; CIBER de Salud Mental, Monforte de Lemos 3-5, Pabellón 11, Madrid, 28029, Spain; Aerospace Engineering and Bioengineering Department, Universidad Carlos III, Avenida de la Universidad, 30. Leganés, Madrid, 28911, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Desco
authors.affiliation: Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain. Electronic address: mquintela@cnio.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintela-Fandino
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use*; D001940:Breast / Q000098:blood supply / Q000000981:diagnostic imaging; D001943:Breast Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000188:drug therapy; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005462:Fluorine Radioisotopes / Q000032:analysis*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000032:analysis; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D010179:Pancreas / Q000098:blood supply / Q000000981:diagnostic imaging; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000188:drug therapy; D049268:Positron-Emission Tomography; D015363:Quinolones / Q000627:therapeutic use*; D000093542:Gemcitabine
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D001562:Benzimidazoles; D005462:Fluorine Radioisotopes; D015363:Quinolones; C031843:fluoromisonidazole; D003841:Deoxycytidine; D008920:Misonidazole; D000093542:Gemcitabine
keywords: (18)F-misonidazole-PET; Antiangiogenics; Biomarker; Breast cancer; Pancreatic cancer; Vascular normalization