COMBINED ULTRASOUND/MOLECULAR ANALYSIS OF TUMOR RESPONSE TO VEGF BLOCKADE

描述(申请人提供)：组织学不良的儿童肾母细胞瘤(WT)和转移性疾病继续经历高死亡率。这些患者迫切需要新的治疗方法。我们最近报告的I期数据显示，在儿童难治性肿瘤中，抗血管内皮生长因子(VEGF)抗体贝伐单抗(BV)具有良好的耐受性。由于这种疗法已经在成人癌症中得到验证，它可能为侵袭性WT患者提供了一个有吸引力的选择；然而，临床上缺乏评估肿瘤反应的方法。对于儿科癌症患者来说，这是一个特别关键的问题，他们的目标是长期控制肿瘤。在我们以前的研究中，我们报道了实验性WT最初被血管内皮生长因子抑制剂显著抑制。然而，与临床观察一致的是，接受BV治疗的成年人几乎都取得了进展，我们发现，如果持续治疗，即使是高度敏感的异种移植物也会恢复生长。对血管内皮生长因子拮抗剂的耐药机制尚不清楚，临床耐药终点尚不明确。我们实验室和其他实验室的新数据表明，受到血管内皮生长因子抑制的肿瘤表现出缺血性损伤的特征，包括诱导损伤反应途径和血管重塑。此外，基因表达、血管组装和血流灌注的明显变化在急性和慢性两种情况下都会发生。例如，我们之前已经报道，抑制血管内皮生长因子可以导致24小时内分支血管的显著丧失和缺血，而长期的阻断会导致血管重塑、血流恢复和肿瘤进展。血管损伤反应的关键分子标志物包括与血管生成有关的基因家族成员，包括整合素(αVbeta3)、血管内皮生长因子受体(VEGFR-1和-2)和Notch家族成员(Jagge-1)，以及缺氧反应的介体(如COX-2)。高频超声是一种新兴的技术，可以快速和纵向地评估血管内皮生长因子抑制剂对WT血管系统的解剖、功能和生理反应。此外，新上市的商用扫描仪对超声造影剂(微泡)回声特征具有极高的敏感度，有助于实体肿瘤中血管结构的可视化、血流的量化以及内皮生物标志物的分子成像。然而，这项技术仍处于初级阶段，进一步开发长期循环的靶向微泡对于充分发挥其作为评估血管结构和功能动态变化的手段的潜力至关重要。特别是，开发一种适合临床护理点使用的平台是至关重要的。在这些研究中，我们将使用高频超声，在实验WT的特定背景下，使用新型微泡工具和超声成像技术来研究血管重构。我们在这些研究中的目标是将WT血管生成的急性和慢性分子变化与超声揭示的高度定量和敏感的结构和流动特征以及血管生物标记物的表达模式联系起来。与公共卫生相关：我们的最终目标是开发一种创新的超声技术，以监测和指导临床侵袭性肾母细胞瘤(WT)儿童的抗血管生成治疗。我们将开发这项技术，同时探索血管内皮生长因子(VEGF)最初阻断和慢性阻断期间肿瘤血管的变化。我们假设WT血管生成的分子变化可以与非侵入性超声揭示的血管变化相关。

DESCRIPTION (provided by applicant): 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.