Improving breast ultrasound specificity through SFRP2 targeted molecular imaging

点击翻译按钮获取中文摘要

 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.