Molecular Imaging for the Detection of High-Grade Dysplasia in Barrett's Esophagus

分子成像检测巴雷特食管高度不典型增生

• 批准号: 9112887
• 负责人: Andrew T Chan
• 金额: $ 31.38万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-31 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9112887
• 关键词: Ablation; Allelic Imbalance; Area; Barrett Esophagus; Biopsy; Cathepsins; Cathepsins B; Characteristics; Clinical; Clinical Trials; Colon Carcinoma; Colonic Adenoma; Colorectal Neoplasms; Columnar Epithelium; Dana-Farber Cancer Institute; Detection; Development; Devices; Diagnosis; Disease; Dysplasia; Dysplasia in Barrett' s Esophagus; Early Diagnosis; Endoscopy; Esophageal; Esophageal Adenocarcinoma; Esophageal Tissue; Esophageal mucous membrane; Esophagoscopy; Evaluation; Excision; Fluorescent Probes; Funding; General Population; Genomic Instability; Goals; Guidelines; Histologic; Human; Image; Image Analysis; In Situ; Incidence; Individual; Inflammation; Lesion; Light; Malignant Neoplasms; Metaplastic; Molecular Profiling; Mucous Membrane; Optics; Patient risk; Patients; Peptide Hydrolases; Phase; Population; Prevention; Recording of previous events; Resolution; Role; Signal Transduction; Specificity; Specimen; Staging; Technology; Time; Tissue Sample; Tissues; Translating; Up-Regulation; Woman; Work; colon dysplasia; differential expression; fluorescence imaging; high risk; human disease; imaging modality; imaging platform; imaging probe; imaging system; improved; in vivo; in vivo imaging; innovation; men; molecular imaging; mouse model; multidisciplinary; new technology; novel; novel marker; novel strategies; open label; pre-clinical

In the U.S., the incidence of esophageal adenocarcinoma (EAC) is rising more rapidly than other cancer, increasing 350% in the last 30 years. Most cases of EAC are preceded by Barrett's esophagus (BE), observed in 2-5% of the population. Although only 0.5% of individuals with BE develop EAC annually, it is widely agreed that the rate of EAC for BE patients with high-grade dysplasia (HGD) approaches 5-8%. Thus, current guidelines recommend routine endoscopic surveillance for HGD followed by eradication of HGD lesions. A major challenge is that current white light (WL) endoscopic surveillance requires invasive and cumbersome random biopsies since HGD arising within BE is often patchy and indistinguishable from non-dysplastic mucosa. Thus, the vast majority of patients with non-dysplastic BE undergo unnecessary surveillance with biopsies. Moreover, this strategy is insensitive, with up to 40% of patients with HGD harboring additional foci of undetected EAC and does not permit real-time identification of dysplasia for immediate treatment. These inherent limitations of our current surveillance approach underscores the need for novel endosopic imaging methods which can detect, in real time and in situ, HGD with high sensitivity. Our overall goal is to advance technologies that we have developed utilizing near infrared fluorescent (NIRF) endoscopic imaging of novel optical probes activated selectively in dysplasia by cathepsin B (CTSB) proteases. In the prior funding period, we have made considerable progress in the development of this approach for more sensitive, real time detection of colorectal neoplasia. We have also demonstrated selective upregulation of CTSB in small HGD lesions within background, CTSB-negative non-dysplastic BE. Thus, we now propose to translate these innovative CTSB-selective probes for the detection of HGD in BE using mouse models which closely mimic human disease and human BE tissue samples which have been histologically and genomically characterized. We will leverage this preclinical work into a Phase l/ll clinical trial in patients with BE. If successful, this technology could fundamentally change our approach to the early detection and real time localization of HGD in BE, a critical area of unmet need for the prevention of EAC.

在美国，食管腺癌（EAC）的发病率比其他癌症迅速升高，在过去30年中增长了350％。在2-5％的人口中观察到的大多数EAC病例之前是Barrett的食管（BE）。尽管每年只有0.5％的患有EAC的患者，但人们普遍认为，高级发育不良（HGD）患者的EAC率为5-8％。因此，当前的指南建议对HGD进行常规内窥镜监测，然后消除HGD病变。一个主要的挑战是，当前的白光（WL）内窥镜监测需要侵入性且繁琐的随机活检，因为在Be内产生的HGD通常与非塑性粘膜相差且无法区分。因此，绝大多数非塑性患者对活检进行了不必要的监视。此外，该策略不敏感，高达40％的HGD患者携带了未发现的EAC的额外焦点，并且不允许实时鉴定发育不良以立即治疗。我们当前的监视方法的这些固有局限性强调了对新型内体成像方法的需求，这些方法可以实时和原位以高灵敏度检测HGD。 我们的总体目标是推进我们利用近红外荧光（NIRF）内窥镜成像对新型光学探针的内窥镜成像进行选择，从而在发育不良B（CTSB）蛋白酶中选择性地激活的新型光学探针。在以前的资金期间，我们在这种方法的开发方面取得了长足的进步，以实时检测结直肠肿瘤。我们还证明了CTSB在背景中的小型HGD病变中的选择性上调，CTSB阴性非塑性BE。因此，我们现在建议翻译这些创新的CTSB选择性探针，以检测HGD在使用小鼠模型中，这些模型紧密模仿了已经过去的人类疾病和人类组织样本 组织学和基因组的特征。我们将把这项临床前的工作利用为BE患者的L/LL临床试验。如果成功的话，这项技术从根本上可以改变我们对HGD的早期检测和实时定位的方法，这是预防EAC的关键领域。