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：总结/摘要尽管有多种筛查方法，但估计仍有 135,000 人被诊断出患有结直肠癌 2017 年，大约有 50,000 人将死于癌症（CRC），越来越多的证据表明信号转换器和转录激活因子 (STAT) 3 会导致罹患 CRC 风险增加的患者，例如患有以下疾病的患者炎症性肠病 (IBD) 和患有遗传综合征的患者，例如家族性腺瘤息肉病 (FAP) 和林奇综合征 (LS) 在这些情况下 STAT3 对 CRC 的重要性。靶向 STAT3 对 CRC 发生和疾病进展的影响是目前研究中的显着差距我们和其他人已经证明，两种葡聚糖均可诱发小鼠结肠炎。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] 与野生型小鼠相比，仅表达 STAT3α（STAT3 的促炎和抗凋亡亚型）的转基因小鼠中结直肠癌的进展更为严重且进展更快。与制药合作伙伴 (StemMed, Ltd.) 合作，我们开发了一种小分子 C188-9，可有效抑制 STAT3 激活 [酪氨酸 (Y) 707 磷酸化，pY-STAT3]，可预防由 DSS 和其他研究表明，小鼠肠上皮细胞中缺乏 Stat3 的 TNBS 有所减少。结肠炎相关 CRC 模型中的肿瘤大小和肿瘤发生率降低 [氧化偶氮甲烷 (AOM) 加 DSS]。此外，通过基因方法降低 ApcMin/+ 小鼠 (ApcMin/+Stat3+/-) 的 STAT3 水平也减少了与 ApcMin/+Stat3+/+ 小鼠相比，肠息肉增加，而 STAT3 激活导致核外隔离 hMSH3，这可能会进一步损害 LS 患者肠细胞中的 dMMR，从而导致风险增加该项目的长期目标是确定 C188-9 是否有益于预防和/或 CRC 的治疗的中心假设是 STAT3 有助于高危患者的 CRC 发展。用于 CRC，并且可以使用 C188-9 成功靶向目标是确定靶向效果。 STAT3 使用 C188-9 预防 IBD、FAP 和 LS 小鼠模型中的 CRC 并确定其贡献我们制定了 3 个密切关注的 STAT3 信号传导与相应患者亚群中 CRC 发展的关系。具体目标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，我们将审核 STAT3 信号传导对 FAP、LS 和 IBD 患者 CRC 发展的贡献，包括来自患者的可行结肠类器官。最后，在目标 3 中，我们将确定对 pY-STAT3 的影响和慢性病的安全性。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中治疗的 FAP 这些研究的结果将。提供有关 STAT3 对 CRC 发展的贡献的关键信息并支持进一步的临床研究检查 C188-9 在预防 CRC 中的作用。