Abstract 1493: 18F-misonidazole PET (FMISO-PET) monitors vascular normalization (VN) and predicts benefit from antiangiogenic treatment plus chemotherapy in pancreas cancer
Authors: Mondejar Tamara , Hernadez-Agudo Elena , Soto-Montenegro Marisa , Megias Diego , Cebrian David , Sanchez Jesus , Mulero Francisca , Colomer Ramon , Hidalgo Manuel , Desco Manuel , Quintela-Fandino Miguel 
Published: August 2015

Abstract
Antiangiogenic agents’ effects are elicited by VN, a process that improves tumor oxygenation and chemotherapy delivery, factors implicated in chemo-sensitivity. A biomarker that allowed monitoring this process non-invasively could help guiding individual therapeutic decisions. As hypoxia can be tracked with FMISO-PET, and hypoxia is influenced by vessel abnormality, we reasoned that a dynamic FMISO-PET monitoring of tumors treated with antiangiogenics at early timepoints could be informative of VN.
Three pancreas cancer PDXs, (Panc215, Panc 286 and Panc219) were studied. Animals (athymic nude mice) were randomized to a window-of-opportunity (WOP) short course (4 days) of the multikinase inhibitor antiangiogenic agent dovitinib (DOV, a VEGFR1-3, PDGFRA/B and FGFR inhibitor) or vehicle. The WOP was preceded and followed by FMISO-PET and FDG-PET, as well as tumor sampling in order to assess vessel architecture and density (CD31 and confocal acquisition), 10Kda-dextran extravasation (vessel abnormality), tumor necrosis (H&E), and hypoxia staining (pimomidazole immunohistochemistry, in order to study the correspondence between FMISO-PET and tissue hypoxia evolution). After the WOP, animals were randomized to the addition of GEM or vehicle to their treatment. Tumor growth inhibition (TGI) was the parameter under study, comparing for each PDX the TGI of GEM, DOV or the combination versus vehicle.
DOV did not exert significant TGI in any of the three models. FMISO-PET SUV levels evolved during the WOP: the SUV increased 53% and 72% for Panc286 and Panc219 when treated with vehicle, but remained unchanged during WOP for Panc215. The SUV changes were modulated by DOV: administered during the WOP, FMISO-PET SUV in Panc215 remained stable, but abrogated the increase in Panc219, and induced a 10% decrease in Panc285. FDG-PET showed that the areas that turned FMISO-PET-negative with DOV were still viable in the three models, confirmed by histologic examination (no significant change in the percentage of necrotic area surface). DOV did not add TGI effect to GEM in Panc215 but it improved TGI an additional &gt;80% and 75% compared to GEM alone in Panc286 and Panc219 (p = 0.02 and 0.001). Dovitinib reduced vessel tortuosity and dextran extravasation in Panc286 and Panc219, whereas did not change these parameters in Panc215 during the WOP. FMISO-PET mirrored pimomidazole staining evolution during the WOP. Intratumor gemcitabine concentration increased &gt;2fold after DOV vs. vehicle during the WOP in Panc286 and Panc219, whereas did not change in Panc215.
In conclusion, FMISO-PET accurately monitors the changes following VN induced by DOV: hypoxia and vessel leakage reversal, and increased interstitial concentration of GEM. FMISO-PET monitoring during the WOP detect in which tumors antiangiogenic treatment exerts positive effects added to chemotherapy.
Citation Format: Tamara Mondejar, Elena Hernadez-Agudo, Marisa Soto-Montenegro, Diego Megias, David Cebrian, Jesus Sanchez, Francisca Mulero, Ramon Colomer, Manuel Hidalgo, Manuel Desco, Miguel Quintela-Fandino. 18F-misonidazole PET (FMISO-PET) monitors vascular normalization (VN) and predicts benefit from antiangiogenic treatment plus chemotherapy in pancreas cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1493. doi:10.1158/1538-7445.AM2015-1493