Contrast Ultrasound Imaging for Identification of Early Responder Tumor Models to Anti-Angiogenic Therapy

• Published in: Ultrasound in medicine & biology Vol. 38; no. 6; pp. 1019 - 1029
• Main Authors: Sirsi, Shashank R, Flexman, Molly L, Vlachos, Fotois, Huang, Jianzhong, Hernandez, Sonia L, Kim, Hyun Keol, Johung, Tessa B, Gander, Jeffrey W, Reichstein, Ari R, Lampl, Brooke S, Wang, Antai, Hielscher, Andreas H, Kandel, Jessica J, Yamashiro, Darrell J, Borden, Mark A
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2012; Elsevier
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Antibodies; Antibodies, Monoclonal, Humanized - pharmacology; Bevacizumab; Biological and medical sciences; Blood; Blood Volume; Cancer; Contrast Media; Contrast media. Radiopharmaceuticals; Disease Progression; Ewings family tumor; imaging; Investigative techniques, diagnostic techniques (general aspects); Lectins; Medical sciences; Mice; Mice, Nude; Microbubble; Microbubbles; Miscellaneous. Technology; Molecular imaging; Neovascularization, Pathologic - diagnostic imaging; Neovascularization, Pathologic - drug therapy; Neuroblastoma; Neuroblastoma - diagnostic imaging; Neuroblastoma - drug therapy; Perfusion; Pharmacology. Drug treatments; Prognosis; Pruning; Radiology; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Regression Analysis; Sarcoma, Ewing - diagnostic imaging; Sarcoma, Ewing - drug therapy; Toxicity; Tumors; Ultrasonic investigative techniques; Ultrasonography; Ultrasound; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; VEGF blockade; Xenografts; Molecular imaging; Microbubble; Blood volume; Ewings family tumor; Neuroblastoma; VEGF blockade; Bevacizumab; Antineoplastic agent; Nuclear medicine; Ewing sarcoma; Ultrasound imaging; Diseases of the osteoarticular system; Monoclonal antibody; Antiangiogenic agent; Contrast media; Biomedical engineering; Nervous system diseases; Malignant tumor; Immunomodulator; Vascular endothelium growth factor; Treatment; Radiology; Medical imagery; Models; Autonomic neuropathy; Cancer; Functional imaging
• ISSN: 0301-5629; 1879-291X
• DOI: 10.1016/j.ultrasmedbio.2012.01.014

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 αV β3 with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in αV β3 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.