Early Targets in Progression of Barrett's Esophagus to Esophageal Adenocarcinoma

巴雷特食管进展为食管腺癌的早期目标

• 批准号: 10613011
• 负责人: JOEL H RUBENSTEIN
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-04-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10613011
• 关键词: Address; Adenocarcinoma; Appearance; Barrett Esophagus; Binding; Biochemistry; Candidate Disease Gene; Cell surface; Center for Translational Science Activities; Clinical; Copy Number Polymorphism; DNA Sequence Alteration; DNA copy number; Detection; Developed Countries; Disease; Endoscopes; Endoscopy; Esophageal Adenocarcinoma; Esophagogastric Junction; Esophagus; Excision; Fiber; Foundations; Gene Expression Alteration; Gene Expression Profiling; Gene Targeting; Genes; Genomics; Goals; Human; Image; Immunohistochemistry; Incidence; Lesion; Ligands; Light; Malignant Neoplasms; Malignant neoplasm of esophagus; Medical; Methodology; Mission; Molecular Target; Mutation; Operative Surgical Procedures; Outcome; Patients; Peptides; Performance; Preventive measure; Reverse Transcriptase Polymerase Chain Reaction; Risk; Screening for cancer; Spatial Distribution; Specimen; Survival Rate; Therapeutic Intervention; Time; Tissue Microarray; Tissues; Translational Research; clinical translation; cohort; dimer; flexibility; gastroesophageal junction adenocarcinoma; genomic tools; imaging agent; imaging modality; improved; in vivo imaging; innovation; monomer; novel; overexpression; premalignant; risk stratification; spectrograph; tumor heterogeneity

Original Project Abstract Recently, the incidence of esophageal (EAC) and gastro-esophageal junction (GEJAC) adenocarcinoma has increased dramatically, and have a poor 5-year survival rate of less than 15%. When detected early, these patients can have a good clinical outcome following surgery. These observations underscore the importance of early cancer detection. Patients with Barrett’s esophagus (BE) are known to be at increased risk. Our overarching goal is to advance new methods of imaging to visualize the effects of spatial distribution of genetic alterations in BE by using novel imaging methods to evaluate tumor heterogeneity on the progression toward EAC. We propose a multi-institutional, trans- disciplinary, translational Research Center in the Barrett’s Esophagus Translational Research Network (BETRNet). Our mission is to build on our expertise in genomic characterization, peptide biochemistry, and clinical translation to achieve our ultimate goal to perform early cancer detection at an early stage where therapeutic intervention can be most effective. We will identify a complementary panel of genes that are overexpressed on the cell surface and will be used to develop and validate new peptide imaging agents. The targets chosen will address 3 important clinical needs: 1) Real-time endoscopic identification of pre-malignant lesions and early stage cancer to guide endoscopic resection; 2) Risk stratification of BE patients for timing of endoscopic surveillance; and 3) Detection of gastro-esophageal junction adenocarcinomas in patients without endoscopic appearance of BE. We will use state-of-the-art genomic tools to to identify early overexpressed gene targets that arise in progression of BE to EAC by providing comprehensive analyses of gene expression alterations, DNA copy number variation, and genetic mutations. We will select candidate genes that are expressed on the cell surface where they can be endoscopically imaged in vivo. We will rigorously validate the panel of candidate targets with quantitative RT-PCR and immunohistochemistry on tissue microarrays using an independent cohort of human esophagus specimens. We will use these targets to first identify and validate monomer peptides that are highly specific. We will then arrange monomer peptides in a dimer configuration to produce multivalent ligand target interactions to improve binding performance and allow for early targets to be detected at low levels of expression. We will use a flexible fiber multi-spectral endoscope that can pass through the working channel of a standard medical endoscope to detect multiple targets at the same time. Successful completion of these aims will provide an integrated multi-spectral imaging methodology to longitudinally visualize overexpressed molecular targets that drive progression of Barrett’s esophagus to esophageal adenocarcinoma. This innovative approach can serve as the foundation for validated preventive measures to improve patient management.

原始项目摘要 近年来，食道(EAC)和胃-食道交界处(GEJAC)的发病率 腺癌急剧增加，五年存活率不到 15%。如果及早发现，这些患者在手术后可以获得良好的临床结果。 这些观察结果强调了癌症早期检测的重要性。患有疾病的患者 众所周知，巴雷特食道(BE)的风险增加。 我们的首要目标是提出新的成像方法来可视化空间效应 应用新的影像方法评估肿瘤基因改变在BE中的分布 EAC进程中的异质性。我们提出了一个多机构的，跨- 巴雷特食道翻译研究中的学科翻译研究中心 网络(BETRNet)。我们的使命是建立我们在基因组特征方面的专业知识， 多肽生化，临床翻译，实现我们的终极目标，及早执行 在治疗干预最有效的早期阶段发现癌症。我们 将识别一组在细胞表面过度表达的互补基因，并将 用于开发和验证新的多肽显像剂。选定的目标将解决3个问题 重要的临床需求：1)实时内窥镜识别癌前病变和 早期癌症指导内窥镜切除；2)BE患者的风险分层时机 3)胃-食道交界部腺癌的检测 无BE内窥镜表现的患者。 我们将使用最先进的基因组工具来识别早期过度表达的基因靶点 通过提供全面的基因表达分析，在BE到EAC的进展中出现 突变、DNA拷贝数变异和基因突变。我们将选择候选基因 它们表达在细胞表面，在那里它们可以在体内内窥镜下成像。我们会 严格验证候选靶标的定量RT-PCR和 利用独立的人食道队列对组织芯片的免疫组织化学研究 标本。我们将使用这些目标首先识别和验证以下单体多肽 非常具体。然后我们将把单体多肽排列成二聚体构型，以产生 多价配体靶向相互作用以提高结合性能并允许早期 低表达水平的待检测靶点。我们将使用灵活的光纤多光谱 可通过标准医用内窥镜的工作通道 同时检测多个目标。 这些目标的成功完成将提供综合的多光谱成像 纵向可视化推动进展的过度表达分子靶点的方法 从巴雷特食道到食管腺癌。这种创新的方法可以作为 有效的预防措施的基础，以改善患者管理。

项目成果

Computational modelling suggests that Barrett's oesophagus may be the precursor of all oesophageal adenocarcinomas.

• DOI: 10.1136/gutjnl-2020-321598
• 发表时间: 2020-11-24
• 期刊: Gut
• 影响因子: 24.5
• 作者: Curtius K;Rubenstein JH;Chak A;Inadomi JM
• 通讯作者: Inadomi JM

Design and Synthesis of Near-Infrared Peptide for in Vivo Molecular Imaging of HER2.

• DOI: 10.1021/acs.bioconjchem.5b00565
• 发表时间: 2016-02-17
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Joshi BP;Zhou J;Pant A;Duan X;Zhou Q;Kuick R;Owens SR;Appelman H;Wang TD
• 通讯作者: Wang TD

Imaging: Dynamic imaging of gut function--allowing the blind to see.

成像：肠道功能的动态成像——让盲人也能看见。

• DOI: 10.1038/nrgastro.2014.149
• 发表时间: 2014
• 期刊: Nature reviews. Gastroenterology & hepatology
• 作者: Joshi,BishnuP;Wang,ThomasD
• 通讯作者: Wang,ThomasD

Genomic similarity between gastroesophageal junction and esophageal Barrett's adenocarcinomas.

• DOI: 10.18632/oncotarget.10253
• 发表时间: 2016-08-23
• 期刊: Oncotarget
• 作者: Ferrer-Torres D;Nancarrow DJ;Kuick R;Thomas DG;Nadal E;Lin J;Chang AC;Reddy RM;Orringer MB;Taylor JM;Wang TD;Beer DG
• 通讯作者: Beer DG

Yield of Higher-Grade Neoplasia in Barrett's Esophagus With Low-Grade Dysplasia Is Double in the First Year Following Diagnosis.

巴雷特食管中伴有低度不典型增生的高级别肿瘤的发生率在诊断后的第一年内翻倍。

• DOI: 10.1016/j.cgh.2018.01.002
• 发表时间: 2018
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• 作者: Rubenstein,JoelH;Waljee,AkbarK;Dwamena,Ben;Bergman,Jacques;Vieth,Michael;Wani,Sachin
• 通讯作者: Wani,Sachin