In Viro Detection of Neoplasia in the Digestive Tract

描述(申请人提供)：本研究计划的最终目标是建立一个多学科、多机构的翻译研究网络，以开发、标准化、验证和优化一个有针对性的、多模式的光学/核成像平台，该平台使用标记的探针来识别消化道发育不良的粘膜，以便早期发现高危患者的癌症。初级项目的目标是建立网络基础设施，标准化成像协议，并在三个临床中心之间验证性能指标，以检测荧光标记的多肽与直径5 mm的固有性结肠腺瘤的优先结合，并将其用作异型增生的模型。广域内窥镜用于定位提示多肽黏附的区域，共聚焦显微镜提供与发育不良的结肠细胞结合的确认，而不是被困在粘液或碎片中，以提高检测特异性。在常规筛查结肠镜检查过程中，将通过喷雾导管将多肽局部应用于局部粘膜，以证明这种新的成像方法在未来通过灌肠提供输送的应用的概念证明。我们整合了学术界和工业界的力量和资源，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级调查团队，以实现这些目标。将进行试验性临床研究，为该中心未来的多中心临床试验做好准备，在资助期结束时。此外，还提出了四个具体任务项目，以支持初级项目的进展。这些措施包括研究使用放射性标记多肽在SPECT/CT成像上定位异型增生，最终用于高危人群，以确定结肠镜检查的筛查间隔。此外，将开发一种新型光学仪器，使用双轴共聚焦结构成像到粘膜下层，以用于未来评估肿瘤侵袭和微转移。此外，使用噬菌体展示和基因表达谱技术提供功能靶点，将发现新的多肽与扁平异型增生结合，这在标准的白光内窥镜下是无法识别的。多肽因其克隆多样性、体积小、免疫原性低等优点而被选作分子探针，并因其结合动力学快、组织穿透性深、无毒性而适合临床应用。在这一资助期结束时，我们将准备在一项多中心临床试验中验证这一综合战略。公共卫生：拟议的研究将导致一种新颖的多模式成像平台的标准化和验证，该平台使用标记的多肽来靶向早期发现和预防癌症的风险较高的人的消化道中癌前粘膜的存在。

DESCRIPTION (provided by applicant): 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.