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

项目2：靶向STAT3预防遗传综合征和炎症性肠病中的结直肠癌（CRC）

基本信息

批准号：
10415969
负责人：
David John Tweardy
金额：
$ 43.72万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-20 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415969
关键词：
Acids Adenocarcinoma ApcMin/+ mice Apoptotic Archives Azoxymethane Binding Biological Markers Biopsy CLIA certified Cancer Center Carcinoma Cells Chemoprevention Chemopreventive Agent Chronic Clinical Research Clinical Trials Colitis Colitis associated colorectal cancer Collaborations Colon Colonic Adenoma Colorectal Cancer Crohn&apos s disease DNA Data Development Dextrans Diagnosis Disease Disease Progression Disease model Drug Targeting Enterocytes Epithelial Epithelial Cells Exposure to Familial Adenomatous Polyposis Syndrome Familial colorectal cancer Frequencies Genes Germ-Line Mutation Goals Growth Hereditary Nonpolyposis Colorectal Neoplasms High grade dysplasia Impairment Incidence Inflammation Inflammatory Inflammatory Bowel Diseases Inherited Intestinal Polyps Knowledge Ligands MLH1 gene MSH2 gene MSH3 gene MSH6 gene Malignant neoplasm of gastrointestinal tract Measures Mediating Messenger RNA Mismatch Repair Modeling Mucous Membrane Mus Mutation Nuclear Oral Organoids PMS2 gene Patients Peptides Persons Pharmacologic Substance Phase Phosphorylation Polyps Population Premalignant Cell Prevention Protein Isoforms RNA Splicing Risk STAT3 gene Safety Sampling Signal Transduction Sodium Sodium Chloride Stains Stat3 protein Stromal Cells Support System Syndrome Tissues Transgenic Mice Tyrosine Ulcerative Colitis Wild Type Mouse carcinogenesis colon cancer patients colon carcinogenesis colorectal cancer prevention colorectal cancer risk colorectal cancer treatment cytokine dextran sulfate sodium induced colitis gene repair high risk inhibitor intestinal epithelium mouse model novel strategies patient population patient subsets pre-clinical prevent prospective repair enzyme screening small molecule src Homology Region 2 Domain stem tumor villin

项目摘要

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.

项目2：摘要/摘要尽管采用了多种筛查方法，但估计有135,000人被诊断出有结直肠 2017年的癌症（CRC），大约有50,000人将死亡。证据正在增加信号传感器和转录激活剂（Stat）3有助于CRC风险增加的患者，例如患有CRC的患者炎症性肠病（IBD）和遗传综合征患者，例如家族性腺瘤息肉病（FAP）和林奇综合征（LS）。 STAT3在这些环境中对CRC的贡献的重要性靶向STAT3对CRC发育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小鼠的结肠炎。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]是与野生型小鼠相比，在仅表达STAT3α的转基因小鼠，促炎和抗凋亡的同工型的转基因小鼠中，CRC的进展更加严重。与我们的合作药物合作伙伴（STEMMED，Ltd。），我们开发了一个小分子C188-9，可能会抑制STAT3 激活[酪氨酸（Y）707，PY-STAT3上的磷酸化]，它阻止了由DSS和DSS引起的IBD 小鼠中的TNB。其他人则表明，肠上皮细胞中缺乏STAT3的小鼠减少了在结肠炎相关的CRC [氮甲烷（AOM）加DSS]模型中，肿瘤大小和肿瘤发病率降低。同样，在APCMIN/+鼠标（APCMIN/+STAT3 +/-）中，通常降低了STAT3的水平与APCMIN/+STAT3+/+小鼠相比，肠道息肉，而STAT3激活导致核外隔离 HMSH3可能会进一步损害LS患者的肠球细胞中的DMMR，从而增加 CRC。该项目的长期目标是确定C188-9是否对预防有益和/或 CRC的处理。中心假设是STAT3有助于有风险患者的CRC发展对于CRC，可以通过C188-9成功将其靶向。目标是确定目标的影响使用C188-9的STAT3防止IBD，FAP和LS的鼠标模型中的CRC并确定贡献在相应的患者子集中向CRC发育的STAT3信号传导。我们已经表达了3个紧密集中具体的目的是检查这些假设并实现这些目标。在AIM 1中，我们将确定 C188-9预防IBD小鼠模型和遗传性CRC中CRC的能力。在AIM 2中，我们将审核 STAT3信号对FAP，LS和IBD患者的CRC发育的贡献，包括在可行的患者衍生的结肠器官中。最后，在AIM 3中，我们将确定对PY-STAT3和慢性安全的影响通过IBD，LS诊断的高危大肠癌患者的C188-9作为化学预防剂并在IB期化学预防临床试验的背景下处理的FAP。这些研究的结果将提供有关STAT3对CRC开发的贡献并支持进一步临床的关键信息研究C188-9预防CRC的研究。