In Viro Detection of Neoplasia in the Digestive Tract

该研究计划的最终目标是建立一个多学科、多机构的转化研究网络，以开发、标准化、验证和优化一个有针对性的、多模态的光学/核成像平台，该平台使用标记探针来识别消化道中的异型增生粘膜，以早期检测风险增加的患者的癌症。主要项目的目标是建立网络基础设施，标准化成像方案，并验证三个临床中心的性能指标，用于检测荧光标记肽与直径> 5 mm的无蒂结肠腺瘤的优先结合，用作异型增生模型。广域内窥镜用于定位暗示肽粘附的区域，并且共聚焦显微镜提供了与发育异常的结肠细胞结合的确认，而不是被困在粘液或碎片中以增加检测特异性。肽将在常规筛查结肠镜检查期间通过喷雾导管局部应用于局部粘膜，以证明这种新型成像方法的概念证明，用于通过灌肠剂提供递送的未来应用。我们结合了学术界和工业界的优势和资源，建立了一支由密歇根大学、斯坦福大学、马约诊所、奥林巴斯医疗系统公司和STI医疗系统公司组成的世界级研究团队，以实现这些目标。将进行初步临床研究，以便在资助期结束前为该中心未来的多中心临床试验做好准备。此外，还提出了四个具体任务项目，以支持主要项目的进展。他们包括研究使用放射性标记的肽来定位SPECT/CT成像上的异型增生，以最终用于高风险个体，以确定结肠镜检查的筛查间隔。此外，新的光学仪器将开发使用双轴共聚焦架构的图像到粘膜下层，用于未来评估肿瘤浸润和微转移。此外，将发现新的肽，其结合到在标准白色光内窥镜检查中不能识别的平坦发育不良，使用噬菌体展示和基因表达谱技术来提供功能靶标。肽由于其克隆多样性、小尺寸和最小免疫原性而被选择用作分子探针，并且由于其快速结合动力学、深组织渗透和无毒性而非常适合于临床使用。在本资助期结束时，我们将准备在多中心临床试验中验证这一综合策略。公共卫生：拟议的研究将导致一种新型的多模态成像平台的标准化和验证，该平台使用标记的肽来靶向个体消化道中癌前粘膜的存在，从而增加早期检测和预防癌症的风险。

The ultimate objective of this research plan is to establish a multi-disciplinary, multi-institutional Network for Translational Research to develop, standardize, validate, and optimize a targeted, multi-modal optical/nuclear imaging platform that uses labeled probes to identify dysplastic mucosa in the digestive tract for the early detection of cancer in patients at increased risk. The goal of the Primary Project is to establish network infrastructure, standardize imaging protocols and validate performance measures among three clinical centers for detecting preferential binding of fluorescent-labeled peptides to sessile colonic adenomas > 5 mm in diameter used as a model for dysplasia. Wide area endoscopy is used to localize regions suggestive of peptide adherence and confocal microscopy provides confirmation of binding to dysplastic colonocytes rather than being trapped in mucus or debris for increased detection specificity. Peptides will be topically applied to the local mucosa via a spray catheter during routine screening colonoscopy to demonstrate the proof of concept of this novel imaging methodology for future applications that provide delivery via an enema. We have combined the strengths and resources from academia and industry to establish a world class team of investigators from the University of Michigan, Stanford University, Mayo Clinic, Olympus Medical Systems Corp, and STI Medical Systems Inc to pursue these aims. Pilot clinical studies will be performed to prepare this Center for a future multi-center clinical trial by the end of the funding period. In addition, four Task-Specific Projects have been proposed to support the progress of the Primary Project. They include investigating the use of radio-labeled peptides to localize dysplasia on imaging with SPECT/CT for ultimate use in high risk individuals to determine the screening interval for colonoscopy. Furthermore, novel optical instrumentation will be developed using a dual axes confocal architecture to image into the submucosa for future use in assessing tumor invasion and micrometastases. In addition, new peptides will be discovered that bind to flat dysplasia that cannot be appreciated on standard white light endoscopy using techniques of phage display and gene expression profiles to provide functional targets. Peptides have been chosen for use as molecular probes because of their clonal diversity, small size, and minimal immunogenicity, and are well-suited for clinical use because of their rapid binding kinetics, deep tissue penetration and lack of toxicity. At the end of this funding period, we will be prepared to validate this integrated strategy in a multi-center clinical trial. Public Health: The proposed studies will result in the standardization and validation of a novel, multi-modal imaging platform that uses labeled peptides to target the presence of pre-malignant mucosa in the digestive tract of individuals at increased risk for the early detection and prevention of cancer.