Molecular Flourescent Imaging for the Early Detection of Colorectal Neoplasia

早期发现结直肠癌，5年生存率超过95%。虽然 结肠镜检查是一种很好的筛查工具，被认为是目前的黄金标准，对于 息肉高达22%。特别是，结肠中的“扁平病变”更容易被漏掉，而且可能更容易被忽略。 可能含有异型增生的区域。溃疡性结肠炎(UC)的问题进一步加剧，在这种情况下 异型增生可发生在肉眼看起来正常的粘膜上。因此，有必要发展小说 允许早期发现和原位描述早期结肠癌的技术 病变具有较高的敏感性和特异性。这项建议的总体目标是临床翻译小说 我们已经开发了成像剂和设备来满足这一未得到满足的需求。具体来说，我们将利用 一类可增强近红外(NIR)荧光的“智能”试剂，它们在与一种 靶蛋白(组织蛋白酶)，在结肠腺瘤和腺癌中过度表达。利用这一点 技术，我们的初步研究已经证明了优越的内窥镜检测癌前病变 与传统的白光检查相比，小鼠结肠癌模型中的病变。 此外，我们观察到这项技术对肿瘤的诊断具有类似的敏感性和特异性。 在慢性UC的背景下。我们试图在新的小鼠模型中优化和表征这种药物 自发性地发展为结肠局灶性腺瘤和已知年龄和位置的腺癌。 在这些小鼠模型中，组织蛋白水解酶的表达将与病变进展相关，以及 在广泛的体外人类肿瘤损伤中..这一努力的顶峰将是一项试点临床 这项新技术的可行性和诊断性能将在患者身上进行评估的试验 散发性侵袭性结直肠癌、息肉综合征患者和异型增生患者 加州大学。

When colorectal cancer (CRC) is detected at an early stage, the 5-year survival exceeds 95%. Although colonoscopy is an excellent screening tool and considered the current gold standard, there is a miss rate for polyps as high as 22%. In particular, "flat lesions" in the colon are more commonly missed and may be more likely to contain areas of dysplasia. The problem is further exacerbated in ulcerative colitis (UC), in which dysplasia can develop in macroscopically normal-appearing mucosa. Thus, there is a need to develop novel technologies that would permit the early detection and in situ characterization of early neoplastic colonic lesions with high sensitivity and specificity. The overall goal of this proposal is to clinically translate novel imaging agents and devices we have developed to address this unmet need. Specifically, we will utilize a class of "smart" agents that increase their near infrared (NIR) fluorescence after selective interaction with a target protease (cathepsin) that is overexpressed in colonic adenomas and adenocarcinomas. Utilizing this technology, our preliminary studies have demonstrated superior endoscopic detection of preneoplastic lesions in mouse models of colon cancer when compared to conventional white light examinations. Moreover, we have observed comparable sensitivity and specificity of this technique for neoplasia that arises in the background of chronic UC. We seek to optimize and characterize this agent in new mouse models that spontaneously develop focal colonic adenomas and adenocarcinomas of known age and location. Cathepsin protease expression will be correlated with lesion progression in these mouse models as well as in a broad spectrum of ex vivo human neoplastic lesions.. The culmination of this effort will be a pilot clinical trial in which the feasibility and diagnostic performance of this novel technology will be evaluated in patients with sporadic invasive CRC, patients with polyposis syndromes, and patients with dysplasia in the setting of UC.