Molecular Ultrasound for Early Breast Cancer Detection

描述(申请人提供)：乳腺癌早期发现可以显著提高患者的存活率。超声是诊断乳腺疾病的主要成像方法之一，并满足作为乳腺癌早期检测的理想成像和筛查工具的许多先决条件：它是非侵入性的，与其他成像方式相比相对便宜；它不使用电离辐射；它具有高空间和时间分辨率，并且在全球大多数临床成像部门常规提供。然而，超声往往缺乏在早期发现乳腺癌的敏感性和特异性。在这项拟议的研究中，我们将通过使用分子靶向超声造影剂微泡将超声的优势与分子成像的优势结合起来。这种改进的靶向超声造影成像策略(分子超声成像)，可能为乳腺癌的早期检测提供一种定量和客观的成像方法。我们将测试新开发的临床可翻译微泡，这些微泡针对人类激酶插入结构域受体(KDR)，已被证明在乳腺癌血管生成的血管上过度表达。在乳腺从正常乳腺组织发展为浸润性乳腺癌的转基因小鼠的纵向筛查中，将在体内评估使用KDR靶向对比微泡筛查超声的诊断准确性。分子超声成像数据将与KDR在肿瘤血管中的表达和肿瘤组织学定量相关。继正在进行的KDR靶向微泡对患者的毒性研究之后，我们将以组织学为金标准，对患有各种乳腺病变的女性进行KDR靶向分子超声成像的首次临床可行性和有效性试验。最后，我们将通过设计针对乳腺癌特定分子靶点的下一代造影剂微泡，进一步开发和完善用于乳腺癌早期检测的分子超声成像。根据成功的研究结果，我们预计这项技术将迅速应用于临床，通过早期诊断乳腺癌来改善患者生存和患者护理。 公共卫生相关性：目前诊断早期乳腺癌的策略存在重大局限性，导致延误或漏诊。在这项研究计划中，我们将测试一种新的靶向超声成像方法的准确性，该方法可以检测早期乳腺癌肿瘤血管中的分子变化。我们的目标的成功完成将导致一种新的成像方法的开发，这种方法可以用于在早期、仍可治愈的阶段更准确地诊断乳腺癌。

DESCRIPTION (provided by applicant): Breast cancer early detection can substantially improve patient survival. Ultrasound is one of the primary imaging approaches to diagnose breast diseases and fulfills many prerequisites as an ideal imaging and screening tool for breast cancer early detection: It is non-invasive and relatively cheap compared to other imaging modalities; it does not use ionizing irradiation; it has a high spatial and temporal resolution and is routinely available in most clinical imaging departments worldwide. However, ultrasound often lacks the sensitivity and specificity to detect breast cancer at an early stage. In this proposed study, we will combine the advantages of ultrasound with the advantages of molecular imaging through use of molecularly targeted ultrasound contrast microbubbles. This modified targeted contrast-enhanced ultrasound imaging strategy (molecular ultrasound imaging), may provide a quantitative and objective imaging approach for earlier detection of breast cancer. We will test newly developed clinically translatable micro bubbles that are targeted to the human kinase insert domain receptor (KDR), which has been shown to be over expressed on angiogenic vessels in breast cancer. In longitudinal screening exams in transgenic mice with mammary glands progressing from normal breast tissue to invasive breast cancer, diagnostic accuracy of screening ultrasound using KDR-targeted contrast micro bubbles will be assessed in vivo. Molecular ultrasound imaging data will be quantitatively correlated with KDR expression in tumor vessels and with tumor histology. Following ongoing toxicity studies on KDR-targeted micro bubbles in patients, we will perform a first ever clinical feasibility and efficacy trial on KDR-targeted molecular ultrasound imaging in women with various breast pathologies, using histology as the gold standard. Finally, we will further develop and refine molecular ultrasound imaging for early breast cancer detection by designing next generation contrast micro bubbles targeted to breast cancer specific molecular targets. Based on successful study results, we anticipate rapid translation of this technique into the clinic to improve patient survival and patient care by diagnosing breast cancer at an earlier stage. PUBLIC HEALTH RELEVANCE: Current strategies for the diagnosis of early breast cancer have major limitations leading to delayed or missed diagnoses. In this research proposal, we will test the accuracy of a new targeted ultrasound imaging approach that allows detection of molecular alterations in tumor vessels of early stage breast cancer. The successful completion of our aims will lead to the development of a new imaging approach that can be used to more accurately diagnose breast cancer at an early, still curable stage.