4.7 Article

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

Journal

Publisher

SPRINGER
DOI: 10.1007/s00259-015-3040-7

Keywords

Temozolomide; HIF-1alpha; Optical imaging; Biomarker; CAIX

Funding

  1. Doctorate in Biomedical Technologies, Department of Health Sciences, University of Milan-Bicocca, Milan, Italy
  2. INSERT project [HEALTH-2012-INNOVATION-1, GA305311]
  3. Fondazione IRCCS Ca' Granda - Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi (INGM) grant in Molecular Medicine

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Purpose Hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha 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-1 alpha activity after treatment with different drugs modulating transduction pathways involved in its regulation. After temozolomide (TMZ) treatment, HIF-1 alpha 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-1 alpha 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-1 alpha 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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