TY - JOUR
T1 - Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET
AU - Hernández-Agudo, Elena
AU - Mondejar, Tamara
AU - Soto-Montenegro, Maria Luisa
AU - Megías, Diego
AU - Mouron, Silvana
AU - Sanchez, Jesus
AU - Hidalgo, Manuel
AU - Lopez-Casas, Pedro Pablo
AU - Mulero, Francisca
AU - Desco, Manuel
AU - Quintela-Fandino, Miguel
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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 18F-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.
AB - 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 18F-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.
KW - Antiangiogenics
KW - Biomarker
KW - Breast cancer
KW - F-misonidazole-PET
KW - Pancreatic cancer
KW - Vascular normalization
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UR - http://www.scopus.com/inward/citedby.url?scp=84953438859&partnerID=8YFLogxK
U2 - 10.1016/j.molonc.2015.12.011
DO - 10.1016/j.molonc.2015.12.011
M3 - Article
C2 - 26778791
AN - SCOPUS:84953438859
SN - 1574-7891
VL - 10
SP - 704
EP - 718
JO - Molecular oncology
JF - Molecular oncology
IS - 5
ER -