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Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model

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Abstract

Purpose

Hypoxia-inducible factor 1α (HIF-1α) activity is one of the major players in hypoxia-mediated glioma progression and resistance to therapies, and therefore the focus of this study was the evaluation of HIF-1α modulation in relation to tumour response with the purpose of identifying imaging biomarkers able to document tumour response to treatment in a murine glioma model.

Methods

U251-HRE-mCherry cells expressing Luciferase under the control of a hypoxia responsive element (HRE) and mCherry under the control of a constitutive promoter were used to assess HIF-1α activity and cell survival after treatment, both in vitro and in vivo, by optical, MRI and positron emission tomography imaging.

Results

This cell model can be used to monitor HIF-1α activity after treatment with different drugs modulating transduction pathways involved in its regulation. After temozolomide (TMZ) treatment, HIF-1α activity is early reduced, preceding cell cytotoxicity. Optical imaging allowed monitoring of this process in vivo, and carbonic anhydrase IX (CAIX) expression was identified as a translatable non-invasive biomarker with potential clinical significance. A preliminary in vitro evaluation showed that reduction of HIF-1α activity after TMZ treatment was comparable to the effect of an Hsp90 inhibitor, opening the way for further elucidation of its mechanism of action.

Conclusion

The results of this study suggest that the U251-HRE-mCherry cell model can be used for the monitoring of HIF-1α activity through luciferase and CAIX expression. These cells can become a useful tool for the assessment and improvement of new targeted tracers for potential theranostic procedures.

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Acknowledgments

Raccagni I. was supported by a fellowship from the Doctorate in Biomedical Technologies, Department of Health Sciences, University of Milan-Bicocca, Milan, Italy. The authors wish to thank Dr. S. Todde for production and control quality of radiotracers. The authors thank Fondazione IRCCS Ca’ Granda for allowing the use of the imaging system IVIS Spectrum/CT. This work was supported in part by FP7 funded INSERT project (HEALTH-2012-INNOVATION-1, GA305311) and by Fondazione IRCCS Ca’ Granda - Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi” (INGM) grant in Molecular Medicine (2013 edition).

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    Authors and Affiliations

    1. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

      A. Lo Dico, C. Martelli, C. Diceglie, U. Gianelli, S. Bosari & L. Ottobrini

    2. Centre of Molecular and Cellular Imaging-IMAGO, University of Milan, Milan, Italy

      A. Lo Dico, C. Martelli, G. Lucignani & L. Ottobrini

    3. Institute of Molecular Bioimaging and Physiology (IBFM), National Researches Council (CNR), Segrate, MI, Italy

      S. Valtorta, S. Belloli & L. Ottobrini

    4. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy

      S. Valtorta, I. Raccagni, S. Belloli & R. M. Moresco

    5. Department of Health Sciences, University of Milano-Bicocca, Monza, Italy

      I. Raccagni & R. M. Moresco

    6. Doctorate School of Molecular Medicine, University of Milan, Milan, Italy

      C. Diceglie

    7. Division of Pathology, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy

      U. Gianelli, V. Vaira & S. Bosari

    8. Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi” (INGM), Milan, Italy

      V. Vaira

    9. Neuroradiology Department & Neuroradiology Research Group, IRCCS San Raffaele Scientific Institute, Milan, Italy

      L. S. Politi

    10. Department of Health Sciences, University of Milan, Milan, Italy

      G. Lucignani

    11. Department of Diagnostic Services, Unit of Nuclear Medicine, San Paolo Hospital, Milan, Italy

      G. Lucignani

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    1. A. Lo Dico
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    Correspondence to R. M. Moresco.

    Additional information

    R. M. Moresco and L. Ottobrini are joint senior authors.

    A. Lo Dico and C. Martelli contributed equally to this work.

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    Lo Dico, A., Martelli, C., Valtorta, S. et al. Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model. Eur J Nucl Med Mol Imaging 42, 1093–1105 (2015). https://doi.org/10.1007/s00259-015-3040-7

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