Molecular Spectroscopic Photoacoustic Imaging for Breast Lesion Characterization

用于乳腺病变表征的分子光谱光声成像

• 批准号: 9181200
• 负责人: Juergen Karl Willmann
• 金额: $ 19.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181200
• 关键词: Affinity; Age; Animals; Antibodies; Antibody Formation; Applications Grants; Benign; Binding; Binding Proteins; Biodistribution; Biological Assay; Biopsy; Blood Circulation; Breast Cancer Detection; Breast Cancer Early Detection; Breast Cancer Patient; Breast biopsy; Callback; Cancer Detection; Cells; Clinical; Clinical Trials; Confocal Microscopy; Contrast Media; Data; Development; Diagnosis; Disease; Dyes; FDA approved; Fibronectins; Flow Cytometry; Fluorescent Dyes; Foundations; Future; Goals; Half-Life; Health Care Costs; Healthcare Systems; Histamine H3 Receptors; Human; Human Cell Line; Hyperplasia; Image; Imaging Techniques; In Vitro; Indocyanine Green; Injection of therapeutic agent; Lesion; Life; Ligand Binding; Ligands; Light; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Ultrasonography; Mammography; Methodology; Modality; Modeling; Molecular; Molecular Target; Monitor; Mouse Mammary Tumor Virus; Mus; Noise; Noninfiltrating Intraductal Carcinoma; Operative Surgical Procedures; Optics; Patients; Predictive Value; Prospective Studies; Protein Engineering; Proteins; Proteolysis; Public Health; Receptor Cell; Research Proposals; Scaffolding Protein; Sensitivity and Specificity; Signal Transduction; Specificity; Spectrophotometry; Staging; Succinimides; Surface Plasmon Resonance; Testing; Time; Tissues; Transgenic Mice; Translating; Translations; Ultrasonography; United States; Woman; absorption; antibody conjugate; base; breast imaging; breast lesion; cancer biomarkers; cancer imaging; clinically actionable; clinically significant; contrast enhanced; cost; design; diagnostic accuracy; dosage; fluorescence imaging; follow-up; imaging modality; improved; in vivo; live cell imaging; malignant breast neoplasm; molecular imaging; mortality; mouse model; novel; overexpression; photoacoustic imaging; physical property; prevent; prototype; receptor mediated endocytosis; research study; scaffold; screening; sound; technique development; tool; tumor; uptake

Breast cancer is the second deadliest cancer in women, and will claim more than 40,000 lives in the United States in 2015 alone. Mammography is the first line imaging technique for early breast cancer detection, but the presence of dense breast tissue decreases its diagnostic accuracy. Due to its widespread availability and increased cancer detection rates, ultrasound is often performed as a second line test in women with dense breast tissue. However, ultrasound results in many false positive findings with unnecessary biopsies with increased associated health care costs. The goal of this research proposal is to develop an imaging approach that allows accurate, non-invasive characterization of focal breast lesions into clinically actionable (follow-up with biopsy or surgery is needed) and non-actionable lesions. We propose using spectroscopic photoacoustic (sPA) molecular imaging combined with a new clinically-translatable contrast agent that can be incorporated into the current clinical ultrasound imaging workflow. The new contrast agent will be developed by combining two clinically used components: First, a human fibronectin-based binding ligand (FN3-scaffolds), similar versions of which have been shown to be safe in patients; and second, the near-infrared fluorescent dye, indocyanine green (ICG), which is FDA approved for IV injection in patients. The ICG-FN3-scaffold will be targeted at a recently identified and validated breast cancer marker, B7-H3, which we have shown to be highly expressed in various types of human breast cancer compared to normal breast tissue and benign breast lesions in patients. It will be synthesized, tested, and optimized for its B7-H3 binding abilities in murine and human cell lines using flow cytometry. Since ICG can undergo significant shifts in optical absorption spectra based on its bound state to proteins, through live cell imaging experiments with confocal microscopy, we will assess whether B7-H3 receptor mediated endocytosis of the contrast agent results in intracellular release of ICG with consecutive spectral shift of its absorption spectrum. This shift could be leveraged to differentiate imaging signal from bound and non- bound contrast agent, thereby increasing tumor to background signal. Finally, to test the ability of B7-H3-targeted sPA molecular imaging to differentiate between clinically actionable and non-actionable lesions, a transgenic mouse model (FVB/N Tg(MMTV/PyMT634Mul) of breast cancer development will be used. Animals at varying ages, corresponding to different histopathological disease stages (normal, hyperplasia, DCIS, and breast cancer), will be imaged with sPA following IV injection of B7-H3-targeted ICG-FN3 and a sPA imaging signal threshold will be determined to allow differentiation of benign vs malignant lesions. This will be followed by a prospective study to assess the diagnostic accuracy of B7-H3-targeted sPA to differentiate clinically actionable from non-actionable lesions based on the sPA imaging signal in this model. Our study will lay the foundation for a significant change to current clinical breast imaging practice by improving non-invasive characterization of focal breast lesions, with the potential of substantially changing future management of breast cancer patients.

乳腺癌是女性第二个致命的癌症，将在联合夺取40,000多人生命 仅2015年的国家。乳房X线摄影是早期乳腺癌检测的第一行成像技术，但 致密的乳房组织的存在降低了其诊断准确性。由于其广泛的可用性和 癌症检测率提高，超声通常是在乳房密集的女性中作为第二线测试 组织。但是，超声导致许多虚假的阳性发现，并增加了不必要的活检 相关的医疗保健费用。该研究建议的目的是开发一种成像方法，以 将局灶性乳房病变的准确，无创的表征化为临床可行的（进行活检或随访） 需要手术）和不可动作的病变。我们建议使用光谱光声（SPA）分子 成像与可以掺入电流的新的临床转换对比剂结合 临床超声成像工作流程。新的对比剂将通过组合两个临床使用 组件：首先，一种基于人纤连蛋白的结合配体（FN3-Scaffolds），其类似版本具有 被证明在患者中是安全的；其次，近红外荧光染料，吲哚氰氨酸（ICG）， 这是FDA批准用于患者静脉注射的。 ICG-FN3-SCADGOLD将针对最近确定的 并经过验证的乳腺癌标记B7-H3，我们已证明在各种类型中表达了高度表达 与正常的乳腺组织和患者良性乳房病变相比，人类乳腺癌。这将是 使用流量合成，测试和优化了其在鼠和人类细胞系中的B7-H3结合能力 细胞仪。由于ICG可以根据其结合状态与 蛋白质，通过与共聚焦显微镜的活细胞成像实验，我们将评估B7-H3受体是否 对比剂的介导的内吞作用导致ICG的细胞内释放，并连续光谱移动 其吸收光谱。可以利用这种转变将成像信号与结合和非 - 结合对比剂，从而将肿瘤增加到背景信号。最后，测试B7-H3靶向的能力 SPA分子成像以区分临床可起作和不可动作的病变，转基因 将使用小鼠模型（FVB/N TG（MMTV/PYMT634MUL）乳腺癌发育。 年龄，对应于不同的组织病理学疾病阶段（正常，增生，DCI和乳房 癌症），将在静脉注射B7-H3靶向ICG-FN3和水疗成像信号后用水疗中心成像 将确定阈值允许良性与恶性病变的分化。接下来是 前瞻性研究，以评估B7-H3靶向水疗中心的诊断准确性，以区分临床可操作 从基于此模型中基于水疗成像信号的不可动作的病变。我们的研究将为 通过改善局灶性的非侵入性表征，对当前临床乳房成像实践的重大变化 乳房病变，可能会大大改变对乳腺癌患者的未来治疗。