title: Contrast ultrasound imaging for identification of early responder tumor models to anti-angiogenic therapy.
abstract: Agents targeting vascular endothelial growth factor (VEGF) have been validated as cancer therapeutics, yet efficacy can differ widely between tumor types and individual patients. In addition, such agents are costly and can have significant toxicities. Rapid noninvasive determination of response could provide significant benefits. We tested if response to the anti-VEGF antibody bevacizumab (BV) could be detected using contrast-enhanced ultrasound imaging (CEUS). We used two xenograft model systems with previously well-characterized responses to VEGF inhibition, a responder (SK-NEP-1) and a non-responder (NGP), and examined perfusion-related parameters. CEUS demonstrated that BV treatment arrested the increase in blood volume in the SK-NEP-1 tumor group only. Molecular imaging of α(V)β(3) with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in α(V)β(3) vasculature following BV treatment in SK-NEP-1 tumors. Paralleling these findings, lectin perfusion assays detected a disproportionate pruning of smaller, branch vessels. Therefore, we conclude that the response to BV can be identified soon after initiation of treatment, often within 3 days, by use of CEUS molecular imaging techniques. The use of a noninvasive ultrasound approach may allow for earlier and more effective determination of efficacy of antiangiogenic therapy.
authors.affiliation: Department of Mechanical Engineering, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Shashank R
authors.initials: SR
authors.lastname: Sirsi
authors.forename: Molly L
authors.initials: ML
authors.lastname: Flexman
authors.forename: Fotois
authors.initials: F
authors.lastname: Vlachos
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Hernandez
authors.forename: Hyun Keol
authors.initials: HK
authors.lastname: Kim
authors.forename: Tessa B
authors.initials: TB
authors.lastname: Johung
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Gander
authors.forename: Ari R
authors.initials: AR
authors.lastname: Reichstein
authors.forename: Brooke S
authors.initials: BS
authors.lastname: Lampl
authors.forename: Antai
authors.initials: A
authors.lastname: Wang
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Hielscher
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
authors.forename: Mark A
authors.initials: MA
authors.lastname: Borden
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D001810:Blood Volume; D003287:Contrast Media; D018450:Disease Progression; D051379:Mice; D008819:Mice, Nude; D045423:Microbubbles; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D009447:Neuroblastoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D011379:Prognosis; D012044:Regression Analysis; D012512:Sarcoma, Ewing / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003287:Contrast Media; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab