Improving breast ultrasound specificity through SFRP2 targeted molecular imaging

 描述（由申请方提供）：目前用于高风险患者乳腺癌筛查的方式是每年筛查乳房X线检查联合乳腺MRI。虽然乳腺MRI提高了高危患者乳腺癌的检测，但MRI具有高假阳性率，导致不必要的乳腺活检和增加患者焦虑，并且是一种昂贵的测试，限制了未投保患者的使用。乳腺MRI假阳性率高的一个原因是，当病变血流增加时，MRI增强，但不能区分肿瘤和正常血管。迫切需要能够区分肿瘤血管和正常血管的造影剂，因为这可以提高目前成像模式的特异性。通过对恶性肿瘤内皮细胞的基因组分析，DeMore实验室发现了一种新的血管生成因子，分泌型卷曲相关蛋白2（SFRP 2），与正常血管相比，它在乳腺肿瘤血管中高度过表达。我们已经产生了一种小鼠和人源化的单克隆抗体SFRP 2抑制乳腺癌的生长在体内。由此，我们产生了一种可以用超声可视化的SFRP 2分子靶向微泡造影剂，我们的初步数据显示，造影剂选择性地积聚在小鼠皮下植入的乳腺肿瘤的脉管系统中，在正常血管中没有摄取。鉴于这种分子靶向造影剂对肿瘤血管的高度特异性，这种造影剂有可能提高乳腺超声的灵敏度和特异性-增加乳腺癌的检测并减少不必要的乳腺活检。此外，造影剂通过超声可视化，与MRI相比，超声是更便宜的成像模式。我们假设1。SFRP 2导向成像将允许肿瘤脉管系统的成像，并且将是通过超声增强乳腺癌的早期非侵入性检测的有用工具; 2. SFRP定向成像对肿瘤脉管系统（与正常血管相比）的特异性高于其他靶向成像模式，例如血管内皮生长因子（VEGF）和av β 3定向成像。我们的目标是开发一种SFRP 2靶向微泡造影剂，以可视化乳腺肿瘤血管;定量肿瘤体积，以可视化肿瘤血管与SFRP 2靶向成像;并比较特异性SFRP 2靶向微泡造影剂肿瘤血管（与正常血管相比）VEGF靶向微泡造影剂。

 DESCRIPTION (provided by applicant): Current modalities used for breast cancer screening in high risk patients are annual screening mammogram in conjunction with breast MRI. Although breast MRI improves the detection of breast cancer in high risk patients, MRI has a high false positive rate leading to unnecessary breast biopsies and increased patient anxiety, and is an expensive test which limits access to uninsured patients. One reason for the high false positive rate of breast MRI is that MRI enhances when there is increased blood flow to lesions, but it does not differentiate between tumor and normal vessels. There is a critical need for contrast agents that can distinguish between tumor vessels and normal blood vessels, as this could improve specificity of present imaging modalities. Through genomic profiling of malignant tumor endothelium, the DeMore laboratory has discovered a novel angiogenesis factor, secreted frizzled related protein 2 (SFRP2) that is highly overexpressed in breast tumor vasculature compared to normal vessels. We have generated both a mouse and humanized monoclonal antibody to SFRP2 that inhibits the breast carcinoma growth in vivo. From this we have generated an SFRP2 molecularly targeted microbubble contrast agent that can be visualized with ultrasound, and our preliminary data shows that the contrast agent selectively accumulates in the vasculature of breast tumors implanted subcutaneously in mice, with no uptake in normal vessels. Given the high specificity of the this molecularly targeted contrast agent to tumor vessels, this agent has the potential to improve the sensitivity and specificity of breast ultrasound - increasing the detection of breast cancer and reducing unnecessary breast biopsies. Furthermore the contrast agent is visualized by ultrasound, which is a less expensive imaging modality compared to MRI. We hypothesize that 1. SFRP2-directed imaging will allow for imaging of the tumor vasculature, and will be a useful tool to enhance early non-invasive detection of breast cancer by ultrasound; 2. SFRP-directed imaging is more specific for tumor vasculature (compared to normal vessels) then other targeted imaging modalities such as vascular endothelial growth factor (VEGF) and avß3-directed imaging. Our aims are to develop an SFRP2-targeted microbubble contrast agent to visualize breast tumor vasculature; to quantitate the tumor volume required to visualize tumor vascularization with SFRP2-targeted imaging; and to compare the specificity of SFRP2-targeted microbubble contrast for tumor vessels (compared with normal vessels) to VEGF-targeted microbubble contrast.