18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma

Mette Kjoelhede Nedergaard; Signe Regner Michaelsen; Thomas Urup; Helle Broholm; Henrik El Ali; Hans Skovgaard Poulsen; Marie-Thérése Stockhausen; Andreas Kjaer; Ulrik Lassen

doi:10.1371/journal.pone.0115315

18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma

Mette Kjoelhede Nedergaard, Signe Regner Michaelsen, Thomas Urup, Helle Broholm, Henrik El Ali, Hans Skovgaard Poulsen, Marie-Thérése Stockhausen, Andreas Kjaer, Ulrik Lassen

6 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	e0115315
Tidsskrift	P L o S One
Vol/bind	10
Udgave nummer	2
Sider (fra-til)	1-16
Antal sider	16
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0115315
Status	Udgivet - 13 feb. 2015

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1371/journal.pone.0115315Licens: CC BY

Citationsformater

@article{7173b182f30d4fc6ac125d84856e6aa3,

title = "18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma",

abstract = "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.",

keywords = "Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Brain Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, Drug Synergism, Female, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Magnetic Resonance Imaging, Membrane Proteins, Mice, Microvessels, Multimodal Imaging, Optical Imaging, Positron-Emission Tomography, RNA, Messenger, Survival Analysis, Tomography, X-Ray Computed, Treatment Outcome, Tyrosine, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1",

author = "Nedergaard, {Mette Kjoelhede} and Michaelsen, {Signe Regner} and Thomas Urup and Helle Broholm and {El Ali}, Henrik and Poulsen, {Hans Skovgaard} and Marie-Th{\'e}r{\'e}se Stockhausen and Andreas Kjaer and Ulrik Lassen",

year = "2015",

month = feb,

day = "13",

doi = "10.1371/journal.pone.0115315",

language = "English",

volume = "10",

pages = "1--16",

journal = "P L o S One",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "2",

}

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 - 2015/2/13

Y1 - 2015/2/13

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

SN - 1932-6203

VL - 10

SP - 1

EP - 16

JO - P L o S One

JF - P L o S One

IS - 2

M1 - e0115315

ER -

18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater