Novel Molecular Functions of WEE1 in Esophageal Adenocarcinoma

WEE1 在食管腺癌中的新分子功能

基本信息

批准号：
10439574
负责人：
Zheng Chen
金额：
$ 19.16万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439574
关键词：
Address Adenocarcinoma Cell American Cancer Society Antineoplastic Agents Attention Automobile Driving Barrett Esophagus Biological Biological Response Modifier Therapy Biology CDC2 gene Cell Cycle Cell Shape Cell model Cells Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Cyclin B Data Development Diagnosis Esophageal Adenocarcinoma Esophagus Experimental Designs FDA approved Foundations Future Genes Genetic Engineering Genetic Transcription Goals Human In Vitro Incidence Ketones Libraries Malignant neoplasm of esophagus Mediating MicroRNAs Molecular Network-based Nicotine Nitrosamines Nuclear Oncogenic Outcome Pathway interactions Patients Phosphorylation Phosphotransferases Play Prognosis Proteins Resistance Resources Risk Risk Factors Role STAT3 gene Signal Pathway Signal Transduction Smoking Solid Stat3 Signaling Pathway Survival Rate System Testing Tetanus Helper Peptide Therapeutic Time Tissue Sample Tissues Translating Treatment Efficacy Tumor-Derived Tyrosine Phosphorylation United States United States National Institutes of Health Work angiogenesis base cancer cell carcinogenicity cigarette smoking clinically significant evidence base improved improved outcome in vitro Model in vivo inhibitor innovation knock-down new therapeutic target non-smoker novel novel therapeutic intervention overexpression patient derived xenograft model potential biomarker pre-clinical protein expression response smoking cessation smoking exposure targeted treatment transcriptome sequencing translational approach translational study treatment response tumor growth tumor xenograft tumorigenesis

项目摘要

Project summary/abstract (30 lines) A sharp increase in the incidence of esophageal adenocarcinoma (EAC) has been documented over the past three decades in the United States. Approximately 80% of patients are diagnosed at advanced stages (III or IV) with a five-year survival rate less than 5%. Therapeutic options for EAC are limited and often ineffective due to the lack of biology based targeted therapeutics. According to the American Cancer Society, smoking is a major and important risk factor of EAC. Our novel preliminary data demonstrate that WEE1 expression level is induced by smoking in EAC cells and a frequent aberrant overexpression of WEE1 with surprising cytosolic localization in EAC tissue samples and in vitro cell models. The long-term goal of this proposal is to evaluate the molecular, biological, and therapeutic potential of WEE1 in EAC. The objective, which is a bridge to the long-term goal, is to investigate molecular mechanisms by which activate smoking-WEE1-STAT3 signaling pathway and the efficacy and clinical outcome of targeting WEE1 in human EAC. The central hypothesis is that smoking induced aberrant overexpression of WEE1 provides potent pro-survival advantage to cancer cells through activation of STAT3 signaling pathway. Targeting the WEE1-STAT3 axis could be a novel therapeutic approach in EAC. This hypothesis has been generated primarily from the preliminary studies conducted by the applicant’s work. Three specific aims will be achieved to test this hypothesis. Aim 1. Investigate mechanisms by which smoking induces WEE1 in EAC. Aim 2. Determine the molecular functions of WEE1-STAT3 signaling axis. Aim 3. Investigate the clinical significance of WEE1-STAT3 axis in EAC. The innovations in this proposal include innovative hypothesis that 1) smoking induced cytosolic WEE1 overexpression in human EAC activates STAT3 signaling, 2) a novel therapeutic approach targeting WEE1 for improving outcome of EAC, and 3) experimental design that utilizes genetically engineered tet-inducible cell models, lenti-viral expression, CRISPR gene knockdown systems, patient-derived xenografts (PDXs) and SynergySeq analysis utilizing the NIH Library of Integrated Network-Based Cellular Signatures (LINCS) project resources. This proposal is significant and can have a positive impact not only by revealing a novel molecular WEE1-STAT3 signaling axis but also because of its translational components. The translational studies include 1) identify potential biomarkers for therapeutic response using RNA-seq in 3 best versus 3 worst WEE1 inhibitor (MK1775) PDX responders and 2) determine the potential therapeutic efficacy of MK1775 as a single agent or in combination with FDA approved anti-cancer drugs in pre-clinical settings predicted by complex computational therapeutics approach using SynergySeq. The integrated molecular, functional, and translational approaches in this proposal are expected to provide a novel understanding of the biology and molecular basis of EAC. The results can lay the foundation for evidence-based therapy and swiftly be translated for improving therapy and prognosis in EAC patients.

项目摘要/摘要（30 行）据记录，食管腺癌（EAC）的发病率在过去几年中急剧增加过去三十年，美国大约 80% 的患者确诊时已处于晚期（III 期）。或 IV），EAC 的五年生存率低于 5%，且治疗选择有限且通常无效。根据美国癌症协会的说法，由于缺乏基于生物学的靶向治疗，吸烟是导致癌症的原因之一。我们的新初步数据表明，WEE1 表达水平是 EAC 的一个主要且重要的风险因素。是由 EAC 细胞中吸烟和 WEE1 频繁异常过度表达引起的，并具有令人惊讶的胞质该提案的长期目标是评估 EAC 组织样本和体外细胞模型中的定位。 WEE1 在 EAC 中的分子、生物学和治疗潜力目标是通向 EAC 的桥梁。长期目标是研究激活吸烟-WEE1-STAT3信号传导的分子机制人类 EAC 中靶向 WEE1 的途径以及功效和临床结果中心假设是：吸烟诱导的 WEE1 异常过度表达为癌细胞提供了强大的促生存优势通过激活 STAT3 信号通路，靶向 WEE1-STAT3 轴可能是一种新的治疗方法。 EAC 的方法主要来自于 EAC 进行的初步研究。申请人的工作将实现三个具体目标来检验这一假设。目标 1. 研究机制。吸烟通过 EAC 诱导 WEE1 目标 2. 确定 WEE1-STAT3 信号传导的分子功能。目的 3. 研究 WEE1-STAT3 轴在 EAC 中的临床意义。包括以下创新假设：1) 吸烟诱导人类 EAC 中胞质 WEE1 过度表达激活 STAT3 信号传导，2) 一种针对 WEE1 的新型治疗方法，用于改善 EAC 的结果， 3）利用基因工程tet诱导细胞模型、慢病毒表达的实验设计， CRISPR 基因敲除系统、患者来源的异种移植物 (PDX) 和 SynergySeq 分析 NIH 基于网络的集成蜂窝签名库 (LINCS) 项目资源该提案是。意义重大，不仅可以通过揭示新的分子 WEE1-STAT3 信号传导轴产生积极影响还因为其转化成分，转化研究包括 1) 识别潜力。使用 RNA-seq 检测 3 种最佳与 3 种最差 WEE1 抑制剂 (MK1775) PDX 的治疗反应生物标志物反应者和 2) 确定 MK1775 作为单一药物或组合的潜在治疗功效通过复杂的计算疗法预测，在临床前环境中使用 FDA 批准的抗癌药物使用 SynergySeq 的方法，其中集成了分子、功能和翻译方法。预计提案将为 EAC 的生物学和分子基础提供新的理解。可以为循证治疗奠定基础，并迅速转化为改善治疗和 EAC 患者的预后。