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）食管腺癌（EAC）的发生率急剧增加在美国过去的三十年。大约80％的患者在高级阶段（III）被诊断出或iv）五年生存率小于5％。 EAC的治疗选择有限，通常无效由于缺乏基于生物学的靶向治疗。根据美国癌症协会的说法，吸烟是 EAC的主要和重要危险因素。我们的新型初步数据表明WEE1表达水平通过在EAC细胞中吸烟和WEE1的异常过表达引起的诱导在EAC组织样品和体外细胞模型中定位。该提议的长期目标是评估 WEE1在EAC中的分子，生物学和治疗潜力。目标，这是通往长期目标是研究分子机制，通过激活吸烟-wee1-stat3信号传导靶向WEE1在人类EAC中的途径以及靶向WEE1的有效性和临床结果。中心假设是吸烟引起的WEE1异常过表达为癌细胞提供了潜在的促生存优势通过激活STAT3信号通路。靶向WEE1-STAT3轴可能是一种新的疗法 EAC中的方法。该假设主要是由申请人的工作。将实现三个特定目标来检验这一假设。目标1。调查机制 WEE1在EAC中引起的吸烟。 AIM 2。确定WEE1-STAT3信号的分子函数轴。 AIM 3。研究EAC中WEE1-STAT3轴的临床意义。该提案的创新包括创新的假设，即1）吸烟在人EAC中引起的胞质WEE1过表达激活STAT3信号传导，2）一种针对WEE1的新型热方法，以改善EAC的结果， 3）实验设计，利用一般设计的TET诱导细胞模型，双病毒表达， CRISPR基因敲低系统，患者衍生的Xenographictics（PDXS）和SynergySeq分析使用 NIH基于集成网络的蜂窝签名（LINCS）项目资源的库。该提议是显着，不仅可以通过揭示新的分子WEE1-STAT3信号轴产生积极影响而且还因为其翻译成分。翻译研究包括1）确定潜力使用RNA-Seq在3最佳与3个最差WEE1抑制剂（MK1775）PDX中使用RNA-Seq进行热响应的生物标志物响应者和2）确定MK1775作为单个代理或组合的潜在治疗效率通过FDA批准的抗癌药物在复杂计算治疗预测的临床前环境中使用SynergySeq的方法。在此中的综合分子，功能和翻译方法预计建议将对EAC的生物学和分子基础提供新的理解。结果可以为循证治疗奠定基础，并迅速翻译以改善治疗和 EAC患者的预后。