Novel Molecular Functions of WEE1 in Esophageal Adenocarcinoma

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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.