Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET

Elena Hernández-Agudo, Tamara Mondejar, Maria Luisa Soto-Montenegro, Diego Megías, Silvana Mouron, Jesus Sanchez, Manuel Hidalgo, Pedro Pablo Lopez-Casas, Francisca Mulero, Manuel Desco, Miguel Quintela-Fandino

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
JournalMolecular Oncology
DOIs
StateAccepted/In press - Oct 13 2015
Externally publishedYes

Fingerprint

gemcitabine
Blood Vessels
Pets
Dextrans
Pancreas
Neoplasms
Therapeutics
Growth
Misonidazole
Fluorodeoxyglucose F18
Microvessels
Heterografts
Caspase 3
Doxorubicin
fluoromisonidazole
Breast
Necrosis
Biomarkers
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Staining and Labeling

Keywords

  • F-misonidazole-PET
  • Antiangiogenics
  • Biomarker
  • Breast cancer
  • Pancreatic cancer
  • Vascular normalization

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Hernández-Agudo, E., Mondejar, T., Soto-Montenegro, M. L., Megías, D., Mouron, S., Sanchez, J., ... Quintela-Fandino, M. (Accepted/In press). Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET. Molecular Oncology. https://doi.org/10.1016/j.molonc.2015.12.011

Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET. / Hernández-Agudo, Elena; Mondejar, Tamara; Soto-Montenegro, Maria Luisa; Megías, Diego; Mouron, Silvana; Sanchez, Jesus; Hidalgo, Manuel; Lopez-Casas, Pedro Pablo; Mulero, Francisca; Desco, Manuel; Quintela-Fandino, Miguel.

In: Molecular Oncology, 13.10.2015.

Research output: Contribution to journalArticle

Hernández-Agudo, E, Mondejar, T, Soto-Montenegro, ML, Megías, D, Mouron, S, Sanchez, J, Hidalgo, M, Lopez-Casas, PP, Mulero, F, Desco, M & Quintela-Fandino, M 2015, 'Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET', Molecular Oncology. https://doi.org/10.1016/j.molonc.2015.12.011
Hernández-Agudo, Elena ; Mondejar, Tamara ; Soto-Montenegro, Maria Luisa ; Megías, Diego ; Mouron, Silvana ; Sanchez, Jesus ; Hidalgo, Manuel ; Lopez-Casas, Pedro Pablo ; Mulero, Francisca ; Desco, Manuel ; Quintela-Fandino, Miguel. / Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET. In: Molecular Oncology. 2015.
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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

PY - 2015/10/13

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