Improving breast ultrasound specificity through SFRP2 targeted molecular imaging

通过 SFRP2 靶向分子成像提高乳腺超声特异性

• 批准号: 9112966
• 负责人: Paul A Dayton
• 金额: $ 48.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-17 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112966
• 关键词: Angiogenic Factor; Animals; Antibodies; Anxiety; Benign; Binding; Biomedical Engineering; Blinded; Blood Vessels; Blood flow; Breast; Breast Angiosarcoma; Breast Cancer Detection; Breast Carcinoma; Breast biopsy; Clinical; Clinical Trials; Complex; Contrast Media; Data; Detection; Diagnostic; Disadvantaged; ERBB2 gene; Early treatment; Endothelium; Equipment; Estrogen receptor positive; Europe; Genetic Engineering; Gold; Growth; Health; Hemangiosarcoma; Human; Image; Image Enhancement; Immunocompetent; Immunohistochemistry; Implant; KDR gene; Kidney; Laboratories; Lesion; Ligands; Liver; Location; MDA MB 231; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Neoplasms; Mammography; Mass in breast; Measurement; Medicine; Methods; Microbubbles; Modality; Molecular Target; Monitor; Monoclonal Antibodies; Motivation; Mus; Non-Invasive Cancer Detection; Noninfiltrating Intraductal Carcinoma; Normal tissue morphology; Patients; Proteins; Reader; Rural Population; Safety; Sensitivity and Specificity; Specificity; Spleen; System; Testing; Time; Tumor Volume; Ultrasonography; Underserved Population; Uninsured; Vascular Endothelial Growth Factors; Vascularization; Woman; Work; Xenograft Model; antibody conjugate; cancer imaging; chemotherapy; contrast enhanced; cost; density; design; genomic profiles; high risk; humanized monoclonal antibodies; imaging modality; improved; in vivo; infiltrating duct carcinoma; malignant breast neoplasm; molecular imaging; novel; overexpression; portability; prototype; radiologist; research study; response; screening; soft tissue; targeted agent; targeted imaging; tool; tumor; tumor xenograft; uptake

 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.

 描述（由适用提供）：高风险患者进行乳腺癌筛查的当前方式是与乳房MRI结合的年度筛查乳房X线照片。尽管乳房MRI改善了高风险患者对乳腺癌的检测，但MRI的假阳性率很高，导致不必要的乳房活检并增加患者焦虑，并且是一项昂贵的测试，限制了获得未保险患者的机会。高乳房MRI的假阳性率很高的原因之一是，当病变流动增加时，MRI会增强，但没有区分肿瘤和正常血管。对对比剂的迫切需要可以区分肿瘤血管和正常血管，因为这可以提高当前成像方式的特异性。通过对恶性肿瘤内皮细胞的基因组分析，遣散的实验室发现了一种新型的血管生成因子，分泌的毛躁相关蛋白2（SFRP2）与正常血管相比在乳腺肿瘤的血管中高表达。我们已经产生了与SFRP2的小鼠和人源化的单克隆抗体，该抗体抑制了体内乳腺癌的生长。由此，我们产生了一个可以用超声检查可视化的SFRP2分子微生物对比剂，我们的初步数据表明，对比剂在小鼠中植入的乳腺肿瘤的脉管系统中选择性积累，在正常容器中没有摄取。鉴于分子靶向对比剂对肿瘤血管的高特异性，该药物具有提高乳房超声的敏感性和特异性的潜力 - 增加了乳腺癌的检测并减少了不必要的乳房活检。此外，对比剂可以通过超声观察到，这是一种比MRI廉价的成像方式。我们假设1。SFRP2定向的成像将允许对肿瘤脉管系统进行成像，并且将是通过超声检查增强早期非侵入性检测乳腺癌的有用工具。 2。SFRP指导的成像比肿瘤脉管​​系统（与正常血管相比）更具体，而不是其他有针对性的成像方式，例如血管内皮生长因子（VEGF）和AVß3导向的成像。我们的目的是开发一个针对SFRP2的微泡对比剂，以可视化乳腺肿瘤脉管系统。用SFRP2靶向成像可视化肿瘤血管化所需的肿瘤体积；并比较SFRP2靶向的微泡对比度对肿瘤血管（与正常血管相比）的特异性与靶向VEGF的微泡对比度的特异性。