title: Evaluation of novel combined carbogen USPIO (CUSPIO) imaging biomarkers in assessing the antiangiogenic effects of cediranib (AZD2171) in rat C6 gliomas.
abstract: The recently described combined carbogen USPIO (CUSPIO) magnetic resonance imaging (MRI) method uses spatial correlations in independent imaging biomarkers to assess specific components of tumor vascular structure and function. Our study aimed to evaluate CUSPIO biomarkers for the assessment of tumor response to antiangiogenic therapy. CUSPIO imaging was performed in subcutaneous rat C6 gliomas before and 2 days after treatment with the potent VEGF-signaling inhibitor cediranib (n = 12), or vehicle (n = 12). Histological validation of Hoechst 33342 uptake (perfusion), smooth muscle actin staining (maturation), pimonidazole adduct formation (hypoxia) and necrosis were sought. Following treatment, there was a significant decrease in fractional blood volume (-43%, p < 0.01) and a significant increase in hemodynamic vascular functionality (treatment altered ΔR(2) *(carbogen)  from 1.2 to -0.2 s(-1) , p < 0.05). CUSPIO imaging revealed an overall significant decrease in plasma perfusion (-27%, p < 0.05) following cediranib treatment, that was associated with selective effects on immature blood vessels. The CUSPIO responses were associated with a significant 15% reduction in Hoechst 33342 uptake (p < 0.05), but no significant difference in vascular maturation or necrosis. Additionally, treatment with cediranib resulted in a significant 40% increase in tumor hypoxia (p < 0.05). The CUSPIO imaging method provides novel and more specific biomarkers of tumor vessel maturity and vascular hemodynamics, and their response to VEGF-signaling inhibition, compared to current MR imaging biomarkers utilized in the clinic. Such biomarkers may prove effective in longitudinally monitoring tumor vascular remodeling and/or evasive resistance in response to antiangiogenic therapy.
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Jake S
authors.initials: JS
authors.lastname: Burrell
authors.forename: Simon
authors.initials: S
authors.lastname: Walker-Samuel
authors.forename: Lauren C J
authors.initials: LC
authors.lastname: Baker
authors.forename: Jessica K R
authors.initials: JK
authors.lastname: Boult
authors.forename: Yann
authors.initials: Y
authors.lastname: Jamin
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
authors.forename: Jane
authors.initials: J
authors.lastname: Halliday
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003287:Contrast Media; D003911:Dextrans; D005456:Fluorescent Dyes / Q000494:pharmacology; D005910:Glioma / Q000098:blood supply* / Q000175:diagnosis / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D008297:Male; D009593:Nitroimidazoles / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D003287:Contrast Media; D003911:Dextrans; D005456:Fluorescent Dyes; D058185:Magnetite Nanoparticles; D009593:Nitroimidazoles; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C097921:ferumoxtran-10; C033815:pimonidazole; C500926:cediranib; D007211:Indoles; C017807:bisbenzimide ethoxide trihydrochloride