Hernandez-Agudo, ElenaMondejar, TamaraSoto-Montenegro, Maria LuisaMegias Vazquez, DiegoMouron, Silvana AndreaSanchez, JesusHidalgo, ManuelLopez-Casas, Pedro PabloMulero Francisca, FranciscaDesco, ManuelQuintela Fandino, Miguel Angel2019-10-302019-10-302016-05Mol Oncol. 2016;10(5):704-18.15747891http://hdl.handle.net/20.500.12105/8537This work was supported by the following sources: Fondo de Investigacion Sanitaria (Ministry of Health, Spain; numbers FIS PI10/0288, FIS PI13/00430, FIS PI 11/00616, CPII14/00005 and FIS PI14/00860; the first two awarded to MQF and the last three to MD), and "Fondo Europeo de Desarrollo Regional (FEDER) - Una manera de hacer Europa". MQF is a recipient of a 2010 Beca-Retorno from the AECC Scientific Foundation. Rosae Foundation and AVON Espana S.A.U. contributed to this work with unrestricted donations. Dovitinib was kindly provided by Novartis.BACKGROUND: 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. METHODS: 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. RESULTS: [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. CONCLUSIONS: [18F]-FMISO accurately monitored vascular re-normalization and improved interstitial chemotherapy delivery.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/(18)F-misonidazole-PETAntiangiogenicsBiomarkerBreast cancerPancreatic cancerVascular normalizationAngiogenesis InhibitorsAnimalsAntimetabolites, AntineoplasticBenzimidazolesBreastBreast NeoplasmsCell HypoxiaCell Line, TumorDeoxycytidineFemaleFluorine RadioisotopesHumansMiceMice, NudeMisonidazoleNeovascularization, PathologicPancreasPancreatic NeoplasmsPositron-Emission TomographyQuinolonesAtribución-NoComercial-CompartirIgual 4.0 Internacional26778791105704-1810.1016/j.molonc.2015.12.0111878-0261Molecular oncologyopen access