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

基本信息

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
项目类别：
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

项目摘要

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.

原始项目摘要最近，食管（EAC）和胃食管连接（GEJAC）的事件腺癌的增长幅度急剧增加，5年生存率较低 15％。早期检测到，这些患者可以在手术后有良好的临床结局。这些观察结果强调了早期癌症检测的重要性。患者众所周知，巴雷特的食管（BE）的风险增加。我们的总体目标是推进成像的新方法，以可视化空间的影响通过使用新型成像方法评估BE中遗传改变的分布在向EAC进展的异质性。我们提出了一个多机构的，跨的巴雷特食管转化研究中的纪律，转化研究中心网络（betrnet）。我们的使命是基于我们在基因组表征方面的专业知识，肽生物化学和临床翻译以实现我们提早执行的最终目标在热干预最有效的早期阶段的癌症检测。我们将识别一个在细胞表面过表达的基因的完整基因面板，将用于开发和验证新的肽成像剂。选择的目标将解决3 重要的临床需求：1）实时内窥镜治疗病变和早期癌症指导内窥镜切除； 2）定时患者的风险分层内窥镜监测； 3）检测胃食管连接腺癌没有内窥镜外观的患者。我们将使用最先进的基因组工具来识别早期表达过度过表达的基因靶标的通过提供基因表达的全面分析，出现在BE向EAC的发展中改变，DNA拷贝数变化和遗传突变。我们将选择候选基因在细胞表面表达，可以在体内对其进行内镜下成像。我们将用定量的RT-PCR严格验证候选目标面板和使用人类食管的独立队列在组织微阵列上的免疫组织化学标本。我们将使用这些目标首先识别和验证单体Petides 高度具体。然后，我们将在二聚体配置中排列单体petides以产生多价配体目标相互作用以提高结合性能并允许早期在表达较低的情况下要检测到的靶标。我们将使用灵活的纤维多光谱可以通过标准医疗内窥镜的工作渠道的内窥镜同时检测多个目标。这些目标的成功完成将提供集成的多光谱成像纵向可视化驱动进展的分子靶标的方法巴雷特的食管食管腺癌。这种创新的方法可以作为验证预防措施改善患者管理的基础。

项目成果

期刊论文数量（52）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Joshi,BishnuP;Wang,ThomasD
通讯作者：
Wang,ThomasD

DOI：
10.18632/oncotarget.10253
发表时间：
2016-08-23
期刊：
Oncotarget
影响因子：
0
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

Use of Appropriate Surveillance for Patients With Nondysplastic Barrett's Esophagus.

DOI：
10.1016/j.cgh.2018.01.052
发表时间：
2018-06
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
0
作者：
Tavakkoli A;Appelman HD;Beer DG;Madiyal C;Khodadost M;Nofz K;Metko V;Elta G;Wang T;Rubenstein JH
通讯作者：
Rubenstein JH