title: Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors: A
authors: A
authors: Lo Dico
authors: C
authors: C
authors: Martelli
authors: S
authors: S
authors: Valtorta
authors: I
authors: I
authors: Raccagni
authors: C
authors: C
authors: Diceglie
authors: S
authors: S
authors: Belloli
authors: U
authors: U
authors: Gianelli
authors: V
authors: V
authors: Vaira
authors: L S
authors: LS
authors: Politi
authors: S
authors: S
authors: Bosari
authors: G
authors: G
authors: Lucignani
authors: R M
authors: RM
authors: Moresco
authors: L
authors: L
authors: Ottobrini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D061848:Optical Imaging; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins; D003606:Dacarbazine; D002256:Carbonic Anhydrases; D000077204:Temozolomide