18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma
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18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma. / Nedergaard, Mette Kjoelhede; Michaelsen, Signe Regner; Urup, Thomas; Broholm, Helle; El Ali, Henrik; Poulsen, Hans Skovgaard; Stockhausen, Marie-Thérése; Kjaer, Andreas; Lassen, Ulrik.
I: P L o S One, Bind 10, Nr. 2, e0115315, 2015, s. 1-16.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - 18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma
AU - Nedergaard, Mette Kjoelhede
AU - Michaelsen, Signe Regner
AU - Urup, Thomas
AU - Broholm, Helle
AU - El Ali, Henrik
AU - Poulsen, Hans Skovgaard
AU - Stockhausen, Marie-Thérése
AU - Kjaer, Andreas
AU - Lassen, Ulrik
PY - 2015
Y1 - 2015
N2 - BACKGROUND: Conflicting data exist for anti-cancer effects of anti-placental growth factor (anti-PlGF) in combination with anti-VEGF. Still, this treatment combination has not been evaluated in intracranial glioblastoma (GBM) xenografts. In clinical studies, position emission tomography (PET) using the radiolabeled amino acid O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) and magnetic resonance imaging (MRI) add complementary but distinct information about glioma growth; however, the value of 18F-FET MicroPET combined with MicroMRI has not been investigated preclinically. Here we examined the use of 18F-FET MicroPET and MicroMRI for evaluation of anti-VEGF and anti-PlGF treatment response in GBM xenografts.METHODS: Mice with intracranial GBM were treated with anti-VEGF, anti-PlGF + anti-VEGF or saline. Bioluminescence imaging (BLI), 18F-FET MicroPET and T2-weighted (T2w)-MRI were used to follow tumour development. Primary end-point was survival, and tumours were subsequently analysed for Ki67 proliferation index and micro-vessel density (MVD). Further, PlGF and VEGFR-1 expression were examined in a subset of the xenograft tumours and in 13 GBM patient tumours.RESULTS: Anti-VEGF monotherapy increased survival and decreased 18F-FET uptake, BLI and MVD, while no additive effect of anti-PlGF was observed. 18F-FET SUV max tumour-to-brain (T/B) ratio was significantly lower after one week (114 ± 6%, n = 11 vs. 143 ± 8%, n = 13; p = 0.02) and two weeks of treatment (116 ± 12%, n = 8 vs. 190 ± 24%, n = 5; p = 0.02) in the anti-VEGF group as compared with the control group. In contrast, T2w-MRI volume was unaffected by anti-VEGF. Gene expression of PlGF and VEGFR-1 in xenografts was significantly lower than in patient tumours.CONCLUSION: 18F-FET PET was feasible for anti-angiogenic response evaluation and superior to T2w-MRI; however, no additive anti-cancer effect of anti-PlGF and anti-VEGF was observed. Thus, this study supports use of 18F-FET PET for response evaluation in future studies.
AB - BACKGROUND: Conflicting data exist for anti-cancer effects of anti-placental growth factor (anti-PlGF) in combination with anti-VEGF. Still, this treatment combination has not been evaluated in intracranial glioblastoma (GBM) xenografts. In clinical studies, position emission tomography (PET) using the radiolabeled amino acid O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) and magnetic resonance imaging (MRI) add complementary but distinct information about glioma growth; however, the value of 18F-FET MicroPET combined with MicroMRI has not been investigated preclinically. Here we examined the use of 18F-FET MicroPET and MicroMRI for evaluation of anti-VEGF and anti-PlGF treatment response in GBM xenografts.METHODS: Mice with intracranial GBM were treated with anti-VEGF, anti-PlGF + anti-VEGF or saline. Bioluminescence imaging (BLI), 18F-FET MicroPET and T2-weighted (T2w)-MRI were used to follow tumour development. Primary end-point was survival, and tumours were subsequently analysed for Ki67 proliferation index and micro-vessel density (MVD). Further, PlGF and VEGFR-1 expression were examined in a subset of the xenograft tumours and in 13 GBM patient tumours.RESULTS: Anti-VEGF monotherapy increased survival and decreased 18F-FET uptake, BLI and MVD, while no additive effect of anti-PlGF was observed. 18F-FET SUV max tumour-to-brain (T/B) ratio was significantly lower after one week (114 ± 6%, n = 11 vs. 143 ± 8%, n = 13; p = 0.02) and two weeks of treatment (116 ± 12%, n = 8 vs. 190 ± 24%, n = 5; p = 0.02) in the anti-VEGF group as compared with the control group. In contrast, T2w-MRI volume was unaffected by anti-VEGF. Gene expression of PlGF and VEGFR-1 in xenografts was significantly lower than in patient tumours.CONCLUSION: 18F-FET PET was feasible for anti-angiogenic response evaluation and superior to T2w-MRI; however, no additive anti-cancer effect of anti-PlGF and anti-VEGF was observed. Thus, this study supports use of 18F-FET PET for response evaluation in future studies.
KW - Animals
KW - Antineoplastic Agents
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Brain Neoplasms
KW - Cell Line, Tumor
KW - Cell Transformation, Neoplastic
KW - Drug Synergism
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Glioblastoma
KW - Humans
KW - Magnetic Resonance Imaging
KW - Membrane Proteins
KW - Mice
KW - Microvessels
KW - Multimodal Imaging
KW - Optical Imaging
KW - Positron-Emission Tomography
KW - RNA, Messenger
KW - Survival Analysis
KW - Tomography, X-Ray Computed
KW - Treatment Outcome
KW - Tyrosine
KW - Vascular Endothelial Growth Factor A
KW - Vascular Endothelial Growth Factor Receptor-1
U2 - 10.1371/journal.pone.0115315
DO - 10.1371/journal.pone.0115315
M3 - Journal article
C2 - 25680186
VL - 10
SP - 1
EP - 16
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 2
M1 - e0115315
ER -
ID: 162374026