Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Children with unfavorable histology Wilms tumor (WT) and metastatic disease continue to experience high mortality rates. These patients urgently require new therapies. We have recently reported Phase I data indicating excellent tolerance of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (BV) in refractory pediatric tumors. Because this therapy has been validated in adult cancers, it may provide an attractive option for patients with aggressive WT;however, methods of assessing tumor response clinically are lacking. This is a particularly critical issue for pediatric cancer patients, in whom long-term tumor control is the goal. In our previous studies, we reported that experimental WT were initially strikingly suppressed by VEGF inhibitors. Yet consistent with clinical observations that adults treated with BV virtually all progress, we found that even highly responsive xenografts resumed growth if treatment was sustained. The mechanism of resistance to VEGF blockade is poorly understood, and clinical endpoints of resistance remain undefined. Emerging data from our lab and others suggests that tumors subjected to VEGF inhibition exhibit features of ischemic injury, including induction of damage response pathways and vessel remodeling. Further, distinct changes in gene expression, vascular assembly, and perfusion occur both acutely and chronically. For example, we have previously reported that VEGF inhibition can cause striking loss of branching vasculature and ischemia by 24 hours, whereas long-term blockade results in vessel remodeling, recovery of flow, and tumor progression. Key molecular markers of the response to vessel injury include members of gene families that are essential to angiogenesis, including integrins (alphaVbeta3), VEGF receptors (VEGFR-1 and -2), and Notch family members (Jagged-1), and mediators of the response to hypoxia (such as COX-2). High frequency ultrasound is an emerging technology that can provide rapid and longitudinal assessment of the anatomic, functional, and physiological response of WT vasculature to VEGF inhibitors. Further, the excellent sensitivity of newly available commercial scanners to sonographic contrast agents (microbubble) echo-signatures facilitates visualization of vessel architecture, quantification of blood flow, and molecular imaging of endothelial biomarkers in solid tumors. Yet this technology is still in its infancy, and further development of long-circulating and targeted microbubbles is critical for realizing its full potential as a means of evaluating dynamic changes in vessel structure and function. In particular, it is essential to develop a platform suitable for clinical point-of-care use. In these studies, we will investigate vascular remodeling during VEGF blockade using high frequency ultrasound, in the specific context of experimental WT, and using novel microbubble tools and ultrasound imaging techniques. Our goal in these studies is to relate acute and chronic molecular changes in WT angiogenesis with highly quantitative and sensitive architectural and flow characteristics and vascular biomarker expression patterns revealed by ultrasound. PUBLIC HEALTH RELEVANCE: Our ultimate goal is to develop an innovative ultrasound technique to monitor and guide anti-angiogenic therapy for children with clinically aggressive Wilms tumors (WT). We will develop this technology while exploring tumor vascular changes during initial and chronic blockade of vascular endothelial growth factor (VEGF). We hypothesize that molecular changes in WT angiogenesis can be correlated with vascular changes revealed by noninvasive ultrasound.

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