title: DCE and DW-MRI monitoring of vascular disruption following VEGF-Trap treatment of a rat glioma model.
abstract: Vascular-targeted therapies have shown promise as adjuvant cancer treatment. As these agents undergo clinical evaluation, sensitive imaging biomarkers are needed to assess drug target interaction and treatment response. In this study, dynamic contrast enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI) were evaluated for detecting response of intracerebral 9 L gliosarcomas to the antivascular agent VEGF-Trap, a fusion protein designed to bind all forms of Vascular Endothelial Growth Factor-A (VEGF-A) and Placental Growth Factor (PGF). Rats with 9 L tumors were treated twice weekly for two weeks with vehicle or VEGF-Trap. DCE- and DW-MRI were performed one day prior to treatment initiation and one day following each administered dose. Kinetic parameters (K(trans), volume transfer constant; k(ep), efflux rate constant from extravascular/extracellular space to plasma; and v(p), blood plasma volume fraction) and the apparent diffusion coefficient (ADC) over the tumor volumes were compared between groups. A significant decrease in kinetic parameters was observed 24 hours following the first dose of VEGF-Trap in treated versus control animals (p < 0.05) and was accompanied by a decline in ADC values. In addition to the significant hemodynamic effect, VEGF-Trap treated animals exhibited significantly longer tumor doubling times (p < 0.05) compared to the controls. Histological findings were found to support imaging response metrics. In conclusion, kinetic MRI parameters and change in ADC have been found to serve as sensitive and early biomarkers of VEGF-Trap anti-vascular targeted therapy.
authors.affiliation: Department of Radiology, University of Michigan, Center for Molecular Imaging, Ann Arbor, MI 48109, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hoff
authors.forename: Mahaveer S
authors.initials: MS
authors.lastname: Bhojani
authors.forename: John
authors.initials: J
authors.lastname: Rudge
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Chenevert
authors.forename: Charles R
authors.initials: CR
authors.lastname: Meyer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Johnson
authors.forename: Judith Sebolt
authors.initials: JS
authors.lastname: Leopold
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Galbán
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D003287:Contrast Media; D004058:Diffusion; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005910:Glioma / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D006439:Hemodynamics; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor