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)
Pages (from-to)704-718
Number of pages15
JournalMolecular oncology
Volume10
Issue number5
DOIs
StatePublished - May 1 2016

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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  • Cite this

    Hernández-Agudo, E., Mondejar, T., Soto-Montenegro, M. L., Megías, D., Mouron, S., Sanchez, J., Hidalgo, M., Lopez-Casas, P. P., Mulero, F., Desco, M., & Quintela-Fandino, M. (2016). Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET. Molecular oncology, 10(5), 704-718. https://doi.org/10.1016/j.molonc.2015.12.011