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

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• 作者：Shashank R. Sirsi^&dagger ; ; Molly L. Flexman^&Dagger ; ; Fotois Vlachos^&Dagger ; ; Jianzhong Huang^§ ; ; Sonia L. Hernandez^鈥?/sup> ; Hyun Keol Kim^&Dagger ; ; Tessa B. Johung^§ ; ; Jeffrey W. Gander^§ ; ; Ari R. Reichstein^§ ; ; Brooke S. Lampl^¶ ; ; Antai Wang^# ; Andreas H. Hielscher^&Dagger ; ; ^¶ ; ; ^&lowast ; &lowast ; ; Jessica J. Kandel^§ ; ; ^{jjk47@columbia.edu} ; Darrell J. Yamashiro^§ ; ; ^鈥?/sup> ; ^{dy39@columbia.edu} ; Mark A. Borden^&dagger ; ; ^{mark.borden@colorado.edu}
• 关键词：Bevacizumab ; VEGF blockade ; Ewings family tumor ; Neuroblastoma ; Molecular imaging ; Blood volume ; Microbubble
• 刊名：Ultrasound in Medicine and Biology
• 出版年：2012
• 期刊代码：82_03015629
• 类别：ph
• 出版时间：June, 2012
• 卷：38
• 期：6
• 页码：1019-1029
• 文件大小：1212 K

摘要

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 伪_V尾₃ with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in 伪_V尾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.