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 αVβ3 with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in αVβ3 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 anti-angiogenic therapy.

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

“…UMI has also proven its ability to detect biomarkers of early response to chemotherapy in several cancer types by MBs targeted to single biomarker expressions (VEGFR2, a V b 3 , endoglin, Annexin V, or VEGF-VEGFR complex) [24,[166][167][168][169] and MBs targeted to two or more of these biomarker expressions [142]. Impressively, studies have shown that UMI using a v b 3 -tMBs is a consistent method that can classify a tumour as a responder or a non-responder as early as two days after treatment [170,171]. To establish the link to clinical oncology Flisikowska et al [172] have suggested the use of larger animal cancer models with more similarities to humans, such as genetically modified pigs.…”

Comparison of Photoacoustically Derived Hemoglobin and Oxygenation Measurements with Contrast-Enhanced Ultrasound Estimated Vascularity and Immunohistochemical Staining in a Breast Cancer Model

“…7 The size of these microbubbles (generally 1-8 µm) makes them excellent blood pool agents for visualization of blood flow in vessels within the tumor. [7][8][9] Ultrasound contrast agents (UCAs) have been widely used to monitor treatment response in both humans [9][10][11][12] and animal models of cancer, 13,14 but investigations have mainly focused on changes in either fractional blood volumes or blood flow kinetics as an indicator of treatment response relative to tumor size. Targeted UCAs have been described in which a targeting ligand is used to increase the affinity of the microbubble to the site of marker expression with promising results, but such UCAs are not currently approved for clinical use.…”

Molecular genetics of Ewing sarcoma, model systems and finding novel (immuno-) therapeutic targets

“…Not only new compounds are tested but also novel drug delivery methods, such as silk gel to effectuate a sustained release of chemotherapeutics locally [100] . Ultrasound visualization is being used for more accurate tissue implantation, as well as identifying early response to treatment [101,102] .…”