Efficacy of an Electrophile Scavenger in the Prevention of Gastrointestinal Inflammatory Carcinogenesis

亲电子清除剂在预防胃肠道炎症癌发生中的功效

• 批准号: 10257862
• 负责人: John A Rathmacher
• 金额: $ 40万
• 依托单位: MTI BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257862
• 关键词: Academic Medical Centers; Acrolein; Aldehydes; Alzheimer' s Disease; Animal Experiments; Animal Model; Animals; Automobile Driving; Azoxymethane; Bacterial Infections; Bioavailable; Biological Availability; Biotechnology; Buckwheat; Cancer Etiology; Cancer Model; Carcinoma; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Colitis; Collaborations; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; DNA; DNA Damage; Data; Development; Disease; Dysplasia; Enzymes; Epithelial; Epithelial Cells; Etiology; Future; Gastric Intraepithelial Neoplasia; Gastric Tissue; Gastrins; Gastritis; Gastrointestinal tract structure; Genes; Genomics; Gerbils; Helicobacter Infections; Helicobacter pylori; Histologic; Histones; Human; Hydrogen Peroxide; Hypertension; Immune; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Insulin; Lead; Lesion; Lipid Peroxidation; Lymphoma; Lysine; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malondialdehyde; Mediating; Modeling; Molecular; Molecular Target; Mucositis; Mus; N-methylacetamide-oxotremorine M; NADP; Natural Products; Neoplastic Cell Transformation; Nucleic Acids; Organoids; Outcome; Oxides; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Polyunsaturated Fatty Acids; Prevention; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Publishing; Risk; Rodent; Rodent Model; Role; Seeds; Small Business Technology Transfer Research; Sodium Dextran Sulfate; Spermine; Stomach; Stomach Carcinoma; Testing; Therapeutic; Toxic effect; Transgenic Organisms; adduct; analog; base; cancer prevention; carcinogenesis; colitis associated cancer; colon carcinogenesis; enzyme activity; gastric carcinogenesis; gastrointestinal; high risk; lifetime risk; macromolecule; malignant stomach neoplasm; mouse model; novel; novel strategies; novel therapeutic intervention; oxidative damage; pathogenic bacteria; phase 2 study; pre-clinical; premalignant; prevent; primary endpoint; protective effect; prototype; secondary endpoint; tumor; tumorigenesis

SUMMARY: Many cancers are recognized to have an inflammatory etiology. Gastric cancer, the third leading cause of cancer deaths worldwide, is the prototype- it is caused by infection with the bacterial pathogen Helicobacter pylori in 90% of cases. For colorectal cancer (CRC), the second leading cause of cancer deaths, inflammatory bowel disease (IBD) is a frequent precursor lesion. This STTR Phase I proposal is a partnership between the Wilson Lab at Vanderbilt University Medical Center (VUMC), which is focused on gastrointestinal inflammation- associated carcinogenesis, and MTI BioTech, Inc. (MTI), who are together developing a new therapeutic strategy to prevent cancer. Under conditions of chronic mucosal inflammation, increased enzyme activities result in formation of dicarbonyl electrophiles, products of lipid peroxidation that include isolevuglandins (isoLGs), malondialdehyde, 4-oxo-nonenal, and acrolein, all of which can form adducts with DNA, histones, and proteins. This adduct formation may lead to somatic genomic abnormalities and risk for neoplastic transformation. The compound 2-hydroxybenzylamine (2-HOBA) can serve as a scavenger of all electrophiles, thus preventing adduct formation. 2-HOBA is a natural product derived from buckwheat seeds. It has been shown to be highly bioavailable, with no toxicity, in rodents and in recent human Phase I clinical trials. 2-HOBA protects mice from oxidative damage in models of hypertension and Alzheimer’s disease. The Wilson Lab has discovered that isoLG adducts are increased i) in gastric tissues of patients and mice infected with H. pylori; ii) in the colon of humans with chronic colitis from inflammatory bowel disease, and colitis-associated cancer (CAC), and mice treated with azoxymethane-dextran sulfate sodium (AOM-DSS), a model of CAC. The Lab has found that a 2-HOBA analog, EtHOBA, which also scavenges electrophiles, markedly reduces gastric dysplasia and carcinoma in two models of H. pylori-induced gastric carcinoma, transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils, and reduces colonic tumorigenesis in the AOM-DSS CAC model. However, unlike 2-HOBA, EtHOBA has not reached development for human use. We hypothesize that electrophiles have a key role in inflammation-driven gastrointestinal carcinogenesis via formation of adducts to macromolecules and are new molecular targets for cancer prevention by 2-HOBA. We will determine the protective effect of 2-HOBA on H. pylori-induced gastric carcinogenesis in INS-GAS mice and gerbils (Aim 1) and on colitis-associated carcinogenesis in the AOM-DSS mouse model (Aim 2). Primary endpoints will be reduction in dysplasia, carcinoma, and tumor formation, and secondary endpoints will be effects on DNA damage and isoLG adducts. A successful STTR Phase I outcome will be a protective effect of 2-HOBA on gastric and colon carcinogenesis and will be the primary go/no go endpoint to a Phase II STTR project. We envision future studies testing 2-HOBA in animals in which disease is already fully established; further assessment of molecular mechanisms underlying protective effects, including in human organoids; and human clinical trials in patients with precancerous gastric and colon lesions.

总结： 许多癌症被认为具有炎性病因。胃癌，第三大癌症病因 世界范围内的死亡，是原型-它是由细菌病原体幽门螺杆菌感染引起的， 90%的案件。对于结肠直肠癌（CRC），癌症死亡的第二大原因，炎症性肠病， IBD是一种常见的前驱病变。这STTR第一阶段的建议是一个合作伙伴之间的威尔逊 范德比尔特大学医学中心（VUMC）的实验室专注于胃肠道炎症- 相关的致癌作用，和MTI BioTech，Inc. (MTI)他们正在共同开发一种新的治疗策略， 来预防癌症在慢性粘膜炎症的条件下，增加的酶活性导致 形成二羰基亲电体，脂质过氧化产物，包括异evuglandins（isoLG）， 丙二醛、4-氧代-壬烯醛和丙烯醛，所有这些都可以与DNA、组蛋白和蛋白质形成加合物。 这种加合物的形成可能导致体细胞基因组异常和肿瘤转化的风险。的 化合物2-羟基苄胺（2-HOBA）可以作为所有亲电体的清除剂，从而防止 加合物形成2-HOBA是从荞麦种子中提取的天然产物。它已经被证明是高度 在啮齿类动物和最近的人类I期临床试验中生物可利用，无毒性。2-HOBA保护小鼠免受 高血压和阿尔茨海默病模型中的氧化损伤。威尔逊实验室发现， i）在感染H.幽门螺杆菌; ii）在人的结肠中 患有炎症性肠病引起的慢性结肠炎和结肠炎相关癌症（CAC）的小鼠， 氧化偶氮甲烷-葡聚糖硫酸钠（AOM-DSS），CAC模型。实验室发现2-HOBA类似物， EtHOBA也能清除亲电体，在两种模型中显著减少胃异型增生和胃癌 阁下于pylori诱导的胃癌，转基因FVB/N胰岛素-胃泌素（INS-GAS）小鼠和蒙古沙鼠， 并减少AOM-DSS CAC模型中的结肠肿瘤发生。然而，与2-HOBA不同，EtHOBA没有 发展为人类所用。我们假设亲电体在炎症驱动的 通过形成大分子加合物的胃肠道致癌作用，是新的分子靶点， 2-HOBA预防癌症我们将确定2-HOBA对H.幽门诱发性胃 INS-GAS小鼠和沙鼠中的致癌作用（目的1）以及AOM-DSS中结肠炎相关的致癌作用 小鼠模型（Aim 2）。主要终点将是异型增生、癌和肿瘤形成的减少， 次要终点是对DNA损伤和异LG加合物的影响。成功的STTR第一阶段结果 将是2-HOBA对胃和结肠癌发生的保护作用，并且将是主要的go/no go 第二阶段STTR项目的终点。我们设想未来的研究测试2-HOBA在动物中的疾病是 已经完全确立;进一步评估保护作用的分子机制，包括 在人类类器官中;以及在胃癌和结肠癌前病变患者中的人类临床试验。