Multiplexed Multi-Modal Endoscopic Imaging of Cancer Biomarkers

癌症生物标志物的多重多模态内窥镜成像

• 批准号: 8890458
• 负责人: Thomas D Wang
• 金额: $ 35.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890458
• 关键词: Acids; Affinity; Animals; Antibodies; Appearance; Architecture; Area; Barrett Esophagus; Base Ratios; Beer; Binding; Biological Markers; Biopsy; Cell surface; Cells; Clinical Research; Communities; Detection; Developed Countries; Disease; Dissociation; Dysplasia; Endoscopes; Endoscopy; Epidermal Growth Factor Receptor; Epithelial; Esophageal; Esophageal Adenocarcinoma; Esophageal mucous membrane; Esophagus; Excision; FDA approved; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluorescence; Frequencies; Gene Amplification; Genes; Geometry; Growth Factor Receptors; Hemoglobin; Histology; Human; Image; Immunofluorescence Immunologic; In Vitro; Incidence; Individual; Investigational New Drug Application; Kinetics; Label; Lesion; Light; Link; Low Prevalence; Malignant Neoplasms; Malignant neoplasm of esophagus; Medical; Methodology; Methods; Michigan; Molecular; Morphology; Near-infrared optical imaging; Neoplasms; Obesity; Patients; Peptides; Pharmacology and Toxicology; Physicians; Premalignant; Prevalence; Proteins; Reflux; Research; Risk; Safety; Sampling Errors; Screening for cancer; Signal Transduction; Small Interfering RNA; Specificity; Specimen; Staging; Structural Models; Surface; Time; Tissues; Topical application; Universities; Work; absorption; cancer diagnosis; cancer imaging; clinically relevant; experience; fluorophore; human subject; imaging biomarker; improved; in vivo imaging; instrument; monomer; novel; overexpression; public health relevance; research study; response; trend; validation studies

 DESCRIPTION (provided by applicant): Over the past 3 decades, the incidence of esophageal adenocarcinoma (EAC) has risen faster than any other cancer in developed countries, a trend that is expected to continue with increasing prevalence of obesity and acid reflux. This disease is believed to arise from Barrett's esophagus, where early cancer detection is currently performed on white light endoscopy with random biopsies. This approach is prone to sampling error because high-grade dysplasia (HGD) and early EAC are difficult to detect on imaging because of flat morphology, patchy distribution, and low prevalence. The genes for epithelial growth factor receptors, EGFR and ErbB2, are amplified in high frequency in EAC with minimal overlap among individual patients. The corresponding protein targets are expressed on the cell surface and accessible to in vivo imaging with use of highly specific peptides. We will develop a multimer that links individual peptides specific for either EGFR or ErbB2, and attach Cy5.5, a bright near-infrared (NIR) fluorophore for imaging. We will optimize the peptides on alignment to these targets using a structural model, and validate specific binding on competition and siRNA knockdown studies. We will characterize binding affinity and rapid binding on flow cytometry, and validate binding of the optimized multimer on human specimens of esophageal neoplasia ex vivo using a multi-modal NIR endoscope. Fluorescence and reflectance images will be ratioed to correct for difference in distance and geometry over the image field-of-view. The threshold that maximizes variance will be used to create a binary image. The contour will define a "red-flag" region on the white light image to help physicians guide tissue resection. These experiments will verify instrument sensitivity to target overexpression. We will then perform a pharmacology toxicology study in animals to establish multimer safety, and submit an Investigational New Drug Application (IND) to the FDA to perform a "first-in-human" clinical study. The multimer will first be evaluated in patients to establish safety and then studied on imaging to validate binding to early neoplasia. The results will be compared with histology. Successful completion of these aims will provide the medical community with an integrated multi modal imaging methodology that detects overexpressed cell surface targets to guide tissue resection of lesions that have increased risk for progressing onto cancer, detect cancer at the earliest stages possible, reduce overdiagnosis, and distinguish lethal from non-lethal disease. This collaborative work will be performed by a multi-disciplinary team at the University of Michigan, including TD Wang who will develop the peptide multimer, DG Beer who will validate specific multimer binding to EGFR and ErbB2, and DK Turgeon who will perform the clinical studies. This experienced team has recently completed an FDA-approved "first-in-human" imaging study of a monomer peptide in esophagus.

 描述（由适用提供）：在过去的三十年中，食管腺癌（EAC）的事件的增长速度比发达国家的任何其他癌症都快，这种趋势预计将继续增加肥胖症和酸反射率。据信这种疾病是由巴雷特的食道引起的，该疾病目前在白光内窥镜检查中进行了早期癌症检测，随机活检。这种方法容易出现抽样误差，因为高级别的发育异常（HGD）和早期EAC由于具有平坦的形态，斑点分布和较低的患病率而难以检测到成像。在EAC中，上皮生长因子受体EGFR和ERBB2的基因在单个患者之间的重叠最小的EAC中被扩增。相应的蛋白质靶标在细胞表面表达，并使用高度特异性的肽访问体内成像。我们将开发一个多聚体，该多聚体将特定于EGFR或ERBB2的单个肽连接，并附上CY5.5，这是一种明亮的近红外（NIR）荧光团进行成像。我们将使用结构模型对与这些靶标的对准进行优化，并验证对竞争和siRNA敲低研究的特定结合。我们将表征结合亲和力和对流式细胞术的快速结合，并使用多模式NIR内窥镜验证优化多聚体对食管肿瘤的人类样本的结合。荧光和反射率图像将被比率比较，以纠正图像视野视野上的距离和几何形状的差异。最大化方差的阈值将用于创建二进制图像。轮廓将在白光图像上定义一个“红色标记”区域，以帮助医师指导组织切除。这些实验将验证仪器对目标过表达的敏感性。然后，我们将在动物中进行药理学毒理学研究，以建立多膜安全性，并向FDA提交研究新药物应用（IND），以进行“人类第一”临床研究。该多动物将首先在患者中进行评估以建立安全，然后在成像上进行研究以验证与早期肿瘤的结合。结果将与组织学进行比较。这些目标的成功完成将为医学界提供一种集成的多模态成像方法，该方法可检测过表达的细胞表面靶标，以指导病变的组织切除，这些病变会增加患癌症的风险，在最早的阶段检测到癌症，减少过度诊断，并区分致命的疾病。这项合作工作将由密歇根大学的一个多学科团队进行，包括TD Wang，他们将开发肽多聚机，DG啤酒，他们将验证特定的多聚体与EGFR和ERBB2的约束，以及DK Turgeon，他们将进行临床研究。这支经验丰富的团队最近完成了一项对食管中单体肽的FDA批准的“人类的第一名”成像研究。