Disruption of Transcription Networks in Esophageal Adenocarcinoma Tumorigenesis

总结/摘要：食管腺癌（EAC）的发病率增加超过 在过去的三十年里翻了六倍EAC患者的5年生存率低于15%，强调了 需要了解潜在的生物学，以确定新的治疗方法。慢性胃食管 反流病（GERD），其中酸性胆汁盐（ABS）异常反流到食管，影响更多 超过美国人口的20%。在这个项目中，我们假设APE 1氧化还原 功能和异evuglandins（IsoLGs）蛋白加合物促进关键致癌基因的激活和稳定性 转录网络介导食管肿瘤发生中的细胞存活和扩增。这个程序 该项目利用主要研究人员的独特专业知识，并利用先进的遗传和 手术动物模型、三维体外模型、人体组织、患者来源的异种移植物（PDX），以及 创新技术。项目1研究APE 1-氧化还原功能促进 在回流条件下EAC中SOX 9转录因子的活化。机制和功能研究将 探索APE 1氧化还原功能和IsoLGs加合物在调节SOX 9促进癌细胞存活中的作用 和扩张。转化研究将使用体内小鼠来确定APE 1氧化还原抑制剂的功效。 模型项目2通过IsoLG蛋白加合物研究STAT 3作为细胞反应的新机制 由回流条件引起的氧化应激。翻译实验包括使用异LG 抑制剂，以抑制致癌蛋白加合物的形成和发展为EAC的动物模型 巴雷特的肿瘤形成。项目3研究SOX 4在EAC开发中的作用。20世纪的翻译研究 项目3包括测试FDA批准的抑制SOX 4的药物，作为开发新药物的概念验证。 治疗EAC的策略。该项目中的集成数据交换将使我们能够共同 研究APE 1氧化还原功能和IsoLG蛋白加合物在食管肿瘤发生中的作用。的 三个拟议核心为所有项目提供关键服务。管理核心（核心A）将管理 所有科学和财政问题，并促进研究互动。分子病理学核心（核心B） 将为动物和人体组织提供组织病理学和免疫组织化学服务。的 生物统计学和生物信息学核心（CORE C）将在提供计算， 统计和生物信息服务。通过这些项目和核心的互动，我们将确定生物学相关的 致癌分子的脆弱性，可以治疗靶向受益EAC患者

SUMMARY/ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades. EAC patients' 5-year survival rate is less than 15%, underscoring the need to understand the underlying biology to identify new therapeutic approaches. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts (ABS) abnormally refluxate into the esophagus, affects more than 20% of the US population. In this program project, we hypothesize that interactions between APE1 redox functions and isolevuglandins (IsoLGs) protein adducts promote activation and stability of critical oncogenic transcription networks to mediate cell survival and expansion in esophageal tumorigenesis. This program project leverages unique expertise of the principal investigators and takes advantage of advanced genetic and surgical animal models, 3-dimensional in vitro models, human tissues, patient-derived xenografts (PDXs), and innovative technologies. Project 1 investigates mechanisms by which APE1-redox function promotes activation of SOX9 transcription factor in EACs under reflux conditions. Mechanistic and functional studies will explore the role of APE1 redox function and IsoLGs adducts in regulating SOX9 to promote cancer cell survival and expansion. Translational studies will determine the efficacy APE1 redox inhibitors using in vivo mouse models. Project 2 investigates novel mechanisms of STAT3 by IsoLG protein adducts, as a cellular response to oxidative stress induced by reflux conditions. The translational experiments include the use of isoLG inhibitors to suppress formation of oncogenic protein adducts and progression to EAC in animal models of Barrett’s tumorigenesis. Project 3 investigates the role SOX4 in EAC development. The translation studies in Project 3 include testing FDA-approved drugs that inhibit SOX4, as a proof of concept to develop a novel strategy to treat EACs. The integrated data exchange in this program project will enable us to collectively investigate the role of APE1 redox functions and IsoLG protein adducts in esophageal tumorigenesis. The three proposed cores deliver key services for all the projects. The Administrative Core (Core A) will manage all scientific and fiscal issues and facilitate research interactions. The Molecular Pathology Core (CORE B) will provide histopathology and immunohistochemistry services for animal and human tissues. The Biostatistics and Bioinformatics Core (CORE C) will play a central role in providing computational, statistical, and bioinformatics services. Via these Project and Core interactions we will identify biology-relevant oncogenic molecular vulnerabilities that can be therapeutically targeted to benefit EAC patients