Project 2: Targeting STAT3 to Prevent Colorectal Cancer (CRC) in Hereditary Syndromes and Inflammatory Bowel Disease

项目2：总结/摘要 尽管有各种筛查方法，估计仍有135，000人将被诊断为结直肠癌。 癌症（CRC）在2017年，约50，000人将死于它。越来越多的证据表明，信号转导和 转录激活因子（STAT）3导致CRC风险增加的患者，如患有 炎症性肠病（IBD）和遗传性综合征患者，如家族性腺瘤性 息肉病（FAP）和Lynch综合征（LS）。STAT 3在这些环境中对CRC的贡献的重要性 以及靶向STAT 3对CRC发展和疾病进展的影响是目前研究中的重大空白。 了解这个项目。我们和其他人已经证明，无论是右旋糖酐诱导的小鼠结肠炎， 钠盐[DSS;溃疡性结肠炎（UC）模型]或三硝基苯甲酸[TNBS;克罗恩病（CD）模型]， 在仅表达STAT 3 α的转基因小鼠中， 与野生型小鼠相比，STAT 3的炎症和抗凋亡同种型。在与我们的合作中， 制药合作伙伴（StemMed，Ltd.），我们开发了一种小分子C188-9，它可以有效抑制STAT 3， 激活[酪氨酸（Y）707，pY-STAT 3上的磷酸化]，其预防由DSS和 小鼠中的TNBS。其他研究表明，在肠上皮细胞中缺乏Stat 3的小鼠， 结肠炎相关CRC模型中肿瘤大小和肿瘤发病率降低[氧化偶氮甲烷（AOM）加DSS]。 此外，在ApcMin/+小鼠（ApcMin/+ Stat 3 +/−）中，基因降低的STAT 3水平减少了 与ApcMin/+ Stat 3 +/+小鼠相比， 的hMSH 3，这可能进一步损害来自LS患者的肠细胞中的dMMR，从而导致 《儿童权利公约》。本项目的长期目标是确定C188-9是否有助于预防和/或 CRC的治疗。中心假设是STAT 3有助于有风险患者的CRC发展 对于CRC，可以用C188-9成功靶向。目标是确定目标选择的效果 STAT 3使用C188-9预防IBD、FAP和LS小鼠模型中的CRC并确定其贡献 STAT 3信号传导与相应患者亚群中CRC发展的关系。我们制定了3个紧紧围绕 具体目标是检验这些假设并实现这些目标。在目标1中，我们将确定 C188-9在IBD和遗传性CRC小鼠模型中预防CRC的能力。在目标2中，我们将审计 STAT 3信号传导对FAP、LS和IBD患者（包括存活患者）中CRC发展的贡献- 结肠类器官。最后，在目标3中，我们将确定对pY-STAT 3的影响和慢性免疫的安全性。 在诊断为IBD、LS的高危结直肠癌患者中暴露于C188-9作为化学预防剂 和在Ib期化学预防临床试验的背景下治疗的FAP。这些研究的结果将 提供关于STAT 3对CRC发展的贡献的关键信息，并支持进一步的临床研究。 研究C188-9在预防CRC中的作用。

PROJECT 2: Summary/Abstract Despite a variety of screening approaches, an estimated 135,000 persons will be diagnosed with colorectal cancer (CRC) in 2017, and about 50,000 will die from it. Evidence is increasing that signal transducer and activator of transcription (STAT) 3 contributes to patients at increased risk for CRC, such as those with inflammatory bowel disease (IBD) and patients with hereditary syndromes, such as familial adenomatous polyposis (FAP) and Lynch syndrome (LS). The importance of STAT3's contribution to CRC in these settings and the effects of targeting STAT3 on CRC development and disease progression are the significant gaps in knowledge for this project. We and others have demonstrated that colitis in mice induced by either dextran sodium salt [DSS; ulcerative colitis (UC) model] or trinitrobenzoic acid [TNBS; Crohn's disease (CD) model] is more severe and progresses more rapidly to CRC in transgenic mice expressing only STAT3α, the pro- inflammatory and anti-apoptotic isoform of STAT3, compared to wild type mice. In collaboration with our pharmaceutical partner (StemMed, Ltd.), we developed a small-molecule, C188-9, that potently inhibits STAT3 activation [phosphorylation on tyrosine (Y) 707, pY-STAT3], which prevented IBD caused by both DSS and TNBS in mice. Others have shown that mice deficient in Stat3 in their intestinal epithelial cells have reduced tumor size and reduced tumor incidence in a model of colitis-associated CRC [azoxymethane (AOM) plus DSS]. Also, genetically reducing levels of STAT3 in the ApcMin/+ mouse (ApcMin/+Stat3+/−) reduced the number of intestinal polyps compared to ApcMin/+Stat3+/+ mice while STAT3 activation resulted in extra-nuclear sequestration of hMSH3, which may further impair dMMR in enterocytes from LS patients thereby resulting in increased risk of CRC. The long-term goal of this project is to determine if C188-9 will be of benefit in the prevention and/or treatment of CRC. The central hypotheses are that STAT3 contributes to CRC development in patients at risk for CRC and can be targeted successfully with C188-9. The objectives are to determine the effects of targeting STAT3 using C188-9 to prevent CRC in mouse models of IBD, FAP, and LS and to determine the contribution of STAT3 signaling to CRC development in corresponding patient subsets. We have formulated 3 tightly focused Specific Aims to examine these hypotheses and to achieve these objectives. In Aim 1, we will determine the ability of C188-9 to prevent CRC in mouse models of IBD and hereditary CRC. In Aim 2, we will audit the contribution of STAT3 signaling to CRC development in FAP, LS and IBD patients, including in viable patient- derived colonic organoids. Lastly, in Aim 3, we will determine the effect on pY-STAT3 and safety of chronic exposure to C188-9 as chemopreventive agent in high-risk colorectal cancer patients diagnosed with IBD, LS and FAP treated in the context of a Phase Ib chemopreventive clinical trial. The results of these studies will provide critical information regarding the contribution of STAT3 to CRC development and support further clinical studies examining C188-9 in the prevention of CRC.