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

PLoS One. 2015 Feb 13;10(2):e0115315. doi: 10.1371/journal.pone.0115315. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / diagnosis
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics
  • Glioblastoma / pathology
  • Humans
  • Magnetic Resonance Imaging
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics
  • Mice
  • Microvessels / drug effects
  • Multimodal Imaging*
  • Optical Imaging
  • Positron-Emission Tomography
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Survival Analysis
  • Tomography, X-Ray Computed
  • Treatment Outcome
  • Tyrosine / analogs & derivatives*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics

Substances

  • Antineoplastic Agents
  • Membrane Proteins
  • PIGF protein, human
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • (18F)fluoroethyltyrosine
  • Tyrosine
  • Vascular Endothelial Growth Factor Receptor-1

Grant support

Danish Cancer Research Foundation; The Danish Cancer Society; Danish National Advanced Technology Foundation; AP Møller Foundation; The Lundbeck Foundation; Novo Nordisk Foundation; Svend Andersen Foundation; The John and Birgitte Meyer Foundation; Danish Research Council; Rigshospitalets Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.