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（由申请人提供）：在过去的 3 年里，食管腺癌 (EAC) 的发病率在发达国家的上升速度比任何其他癌症都要快，随着肥胖和胃酸反流患病率的增加，这一趋势预计将持续下去。这种疾病被认为是由巴雷特食管引起的，目前早期癌症检测是通过白光内窥镜随机活检进行的。这种方法很容易出现抽样误差，因为高度不典型增生 (HGD) 和早期 EAC 形态平坦、分布不均匀且患病率低，很难在影像学上检测到。上皮生长因子受体基因 EGFR 和 ErbB2 在 EAC 中高频扩增，个体患者之间的重叠极小。相应的蛋白质靶标在细胞表面表达，并且可以使用高度特异性的肽进行体内成像。 我们将开发一种多聚体，将 EGFR 或 ErbB2 特异性的单个肽连接起来，并附加 Cy5.5（一种用于成像的明亮近红外 (NIR) 荧光团）。我们将使用结构模型优化肽与这些靶标的比对，并验证竞争和 siRNA 敲低研究的特异性结合。我们将在流式细胞仪上表征结合亲和力和快速结合，并使用多模态近红外内窥镜验证优化多聚体在离体食管肿瘤人类标本上的结合。荧光和反射图像将进行比例调整，以校正图像视场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值图像。轮廓将在白光图像上定义“红旗”区域，以帮助医生指导组织切除。这些实验将验证仪器对目标过度表达的敏感性。然后，我们将在动物身上进行药理学毒理学研究，以确定多聚体的安全性，并向 FDA 提交研究性新药申请 (IND)，以进行“首次人体”临床研究。首先将在患者中评估多聚体以确定安全性，然后进行成像研究以验证与早期肿瘤的结合。结果将与组织学进行比较。 成功完成这些目标将为医学界提供一种综合的多模态成像方法，该方法可检测过度表达的细胞表面靶标，以指导组织切除增加发展为癌症风险的病变，在尽可能早的阶段检测出癌症，减少过度诊断，并区分致命与非致命疾病。 这项合作工作将由密歇根大学的多学科团队进行，其中包括将开发肽多聚体的 TD Wang、将验证与 EGFR 和 ErbB2 的特异性多聚体结合的 DG Beer 以及将进行临床研究的 DK Turgeon。这个经验丰富的团队最近完成了 FDA 批准的食道单体肽的“人体首次”成像研究。