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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