Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8537
Title
Monitoring vascular normalization induced by antiangiogenic treatment with (18)F-fluoromisonidazole-PET
Author(s)
Hernandez-Agudo, Elena CNIO | Mondejar, Tamara | Soto-Montenegro, Maria Luisa | Megias Vazquez, Diego CNIO | Mouron, Silvana Andrea CNIO | Sanchez, Jesus | Hidalgo, Manuel | Lopez-Casas, Pedro Pablo | Mulero Francisca, Francisca CNIO | Desco, Manuel CNIC | Quintela Fandino, Miguel Angel CNIO
Date issued
2016-05
Citation
Mol Oncol. 2016;10(5):704-18.
Language
Inglés
Document type
journal article
Abstract
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.
Subject
(18)F-misonidazole-PET | Antiangiogenics | Biomarker | Breast cancer | Pancreatic cancer | Vascular normalization
MESH
Angiogenesis Inhibitors | Animals | Antimetabolites, Antineoplastic | Benzimidazoles | Breast | Breast Neoplasms | Cell Hypoxia | Cell Line, Tumor | Deoxycytidine | Female | Fluorine Radioisotopes | Humans | Mice | Mice, Nude | Misonidazole | Neovascularization, Pathologic | Pancreas | Pancreatic Neoplasms | Positron-Emission Tomography | Quinolones
Description
This 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.
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