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

项目2：摘要/摘要 尽管有各种各样的筛查方法，估计仍有135,000人将被诊断为结直肠癌 2017年将死于癌症(CRC)，约有5万人将死于此病。越来越多的证据表明信号换能器和 转录激活子(STAT)3有助于增加结直肠癌风险的患者，例如那些患有 炎症性肠病(IBD)和遗传性综合征患者，如家族性腺瘤 息肉病(FAP)和林奇综合征(LS)。S在这些背景下对中国铁路局的重要贡献 靶向STAT3对结直肠癌发展和疾病进展的影响是 这个项目的知识。我们和其他人已经证明了由右旋糖苷或右旋糖苷引起的小鼠结肠炎 钠盐[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STAT3α的转基因小鼠中，越严重，进展越快， 与野生型小鼠相比，STAT3的炎症和抗凋亡亚型。与我们的 我们开发了一种小分子C188-9，它能有效地抑制STAT3 激活[酪氨酸(Y)707上的磷酸化，Py-STAT3]，防止DSS和DSS引起的IBD 小鼠的TNBS。其他研究表明，肠道上皮细胞中STAT3基因缺陷的小鼠数量减少 在结肠炎相关CRC[偶氮甲烷(AOM)+DSS]模型中，肿瘤大小和肿瘤发病率降低。 此外，通过降低ApcMin/小鼠(ApcMin/STAT3/−)中STAT3的基因水平，减少了 肠息肉与ApcMin/STAT3/小鼠的比较，而STAT3激活导致核外隔离 HMSH3的表达，可能会进一步损害LS患者肠细胞的dMMR，从而增加发生 CRC。该项目的长期目标是确定C188-9是否在预防和/或 结直肠癌的治疗。核心假设是STAT3有助于高危患者发生结直肠癌 用于CRC，并可以成功地与C188-9对准。目标是确定目标的效果 STAT3使用C188-9预防IBD、FAP和LS小鼠模型中的CRC并确定其作用 STAT3信号在相应的患者亚群中对CRC发生的影响。我们制定了三个紧密结合的方案 具体目的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预防IBD小鼠模型和遗传性结直肠癌的能力。在目标2中，我们将审计 STAT3信号在FAP、LS和IBD患者(包括存活患者)CRC发展中的作用 派生的结肠类器官。最后，在目标3中，我们将确定对Py-STAT3的影响和慢性药物的安全性 诊断为IBD、LS的高危结直肠癌患者暴露于C188-9作为化学预防药物 和FAP在Ib期化学预防临床试验的背景下治疗。这些研究的结果将 提供有关STAT3对结直肠癌发展的贡献的关键信息并支持进一步的临床 检测C188-9预防结直肠癌的研究。

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.