Molecular Ultrasound Imaging of Cancer Response to Antiangiogenic Therapy

描述（由申请人提供）：根据患者对治疗的个人反应治疗个体患者的目标非常接近。无效的治疗可能导致不必要的发病率和高成本而无益处。对于该项目来说，重要的是，抗血管生成疗法的广泛临床引入刺激了对用于监测治疗反应的替代成像生物标志物的搜索。一种有前景的方法利用超声（US）造影剂靶向位于肿瘤血管内的特定生物标志物的能力。这些造影剂可以被设计为选择性地结合与血管生成过程相关的过度丰富的生物标志物，以允许在细胞和分子水平上对肿瘤血管生成进行体内US成像。分子超声成像是一种新兴技术，具有超声的所有优点，包括广泛的临床可用性、无电离辐射、便携性和相对低的成本。优选地，使用造影剂破坏/补充技术和图像处理来确定分子成像信号，以区分附着的和自由循环的造影剂。虽然我们的研究小组已经证明这种方法是稳健的，但是造影剂破坏所需的US压力对于不同的造影剂类型并不标准化，并且用于诊断目的的高功率破坏性脉冲可能会引起不必要的生物效应，这些生物效应仍然没有完全表征。因此，需要能够在不使用破坏技术的情况下隔离目标造影剂信号的新的图像处理算法。虽然US成像传统上是二维空间成像模式，但我们小组最近开创了用于监测整个肿瘤对药物治疗反应的三维对比增强US成像策略。为了充分认识分子US成像在癌症中的应用，需要开发和验证通过实时体积策略的整个肿瘤血管生成成像和治疗监测。为此，拟议的研究项目将解决这些局限性，并通过以下具体目标进行定义：（1）开发图像处理算法和软件，用于从未结合（全身自由流动）的造影剂中分离与US图像中的肿瘤血管生物标志物结合的靶向US造影剂。使用体外血流体模测试新的US图像处理方法。(2)使用已建立的肾癌动物评估肿瘤靶向造影剂的体积分子US成像。放射性标记超声造影剂，通过体内生物分布测定确定生物标记物结合的造影剂水平，并与分子超声成像结果相关。(3)评价肾细胞癌对抗血管生成药物索拉非尼反应的体积分子US成像。确定肿瘤生物标志物密度的基线US测量值是否与肿瘤对抗血管生成治疗的反应相关。该研究项目的成功完成将引入一种全肿瘤分子US成像技术，用于在药物给药后的关键早期阶段监测抗血管生成治疗。

DESCRIPTION (provided by applicant): The goal of treating an individual patient based on their personal response to therapy is tantalizingly close. Therapy that is not efficacious may result in unnecessary morbidity and a high cost without benefit. Of importance to this project, the widespread clinical introduction of anti-angiogenic therapies is stimulating the search for surrogate imaging biomarkers for monitoring treatment response. One promising approach takes advantage of the ability of ultrasound (US) contrast agents to be targeted to specific biomarkers located inside the tumor vascularity. These contrast agents can be engineered to selectively bind to overly abundant biomarkers associated with the angiogenic process to permit in vivo US imaging of tumor angiogenesis at the cellular and molecular level. Molecular US imaging is an emerging technology that exhibits all the advantages of US including broad clinical availability, lack of ionizing radiation, portability, and relatively low costs. Traditionlly, the molecular imaging signal is determined using a contrast agent destruction/replenishment technique and image processing to differentiate attached from freely circulating contrast agents. While our group has shown that this approach is robust, the US pressure necessary for contrast agent destruction is not standardized for different agent types and high-powered destructive pulses for diagnostic purposes may cause unwarranted biological effects that are still not fully characterized. Therefore, new image processing algorithms that can isolate the targeted contrast agent signal without use of destruction techniques are needed. While US imaging has traditionally been a 2-dimensional spatial imaging modality, 3-dimensional contrast-enhanced US imaging strategies for monitoring whole tumor response to drug therapy have recently been pioneered by our group. In order to fully appreciate molecular US imaging for cancer applications, whole tumor angiogenesis imaging and treatment monitoring through real-time volumetric strategies need to be developed and validated. To that end, the proposed research project will address these limitations and is defined by the following specific aims (1) Develop image processing algorithms and software for isolating targeted US contrast agents that have bound to tumor vascularity biomarkers in US images from the unbound (systemically free flowing) contrast agents. Test new US image processing methods using an in vitro flow phantom. (2) Assess volumetric molecular US imaging of a tumor-targeted contrast agent using an established animal of renal cancer. Radiolabel US contrast agents to determine biomarker bound contrast agent levels via in vivo biodistribution assays and correlate to molecular US imaging results. (3) Evaluate volumetric molecular US imaging of renal cell carcinoma response to the anti-angiogenic drug sorafenib. Determine if baseline US measurements of tumor biomarker density correlate to tumor response to anti-angiogenic therapy. Successful completion of this research project will introduce a whole tumor molecular US imaging technique for monitoring anti-angiogenic therapy during the critical early phase after drug dosing.