In Viro Detection of Neoplasia in the Digestive Tract

本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、多模态光学/核成像平台，该平台使用标记探针识别消化道发育不良粘膜，以便在风险增加的患者中早期发现癌症。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，以检测荧光标记肽与直径为50mm的无基结腺瘤的优先结合，作为不典型增生的模型。广域内窥镜用于定位提示肽粘附的区域，共聚焦显微镜可确认与发育不良的结肠细胞结合，而不是被困在粘液或碎片中，从而提高检测特异性。在常规结肠镜筛查期间，多肽将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，为未来通过灌肠提供递送的应用提供了证据。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、梅奥诊所、奥林巴斯医疗系统公司和STI医疗系统公司组成的世界一流的研究团队，以实现这些目标。将进行试点临床研究，为该中心在资助期结束前进行未来的多中心临床试验做准备。此外，已提出四个具体工作项目，以支持初级项目的进展。其中包括研究使用放射性标记肽在SPECT/CT成像上定位不典型增生，最终用于高风险人群，以确定结肠镜检查的筛查间隔。此外，将开发新型光学仪器，使用双轴共聚焦结构成像粘膜下层，以便将来用于评估肿瘤侵袭和微转移。此外，利用噬菌体展示和基因表达谱技术提供功能靶点，将发现与标准白光内窥镜无法识别的扁平发育不良结合的新肽。多肽由于其克隆多样性、小尺寸和最小的免疫原性而被选择作为分子探针，并且由于其快速的结合动力学、深入组织渗透和缺乏毒性而非常适合临床应用。在融资期结束时，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的多模式成像平台的标准化和验证，该平台使用标记肽靶向早期发现和预防癌症风险增加的个体消化道中存在的癌前粘膜。

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.