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.

概括： 许多癌症被认为具有炎症病因，胃癌是癌症的第三大原因。 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% 的病例为结直肠癌 (CRC)，炎症性肠病是癌症死亡的第二大原因。 疾病 (IBD) 是一种常见的前兆病变。 STTR I 期提案是 Wilson 之间的合作伙伴关系。 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，以及 MTI BioTech, Inc. (MTI)，他们正在共同开发一种新的治疗策略 在慢性粘膜炎症的情况下，酶活性增加会导致癌症。 二羰基亲电子试剂的形成，脂质过氧化产物，包括异黄酮素 (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。 化合物 2-羟基苄胺 (2-HOBA) 可以作为所有亲电子试剂的清除剂，从而防止 2-HOBA 是一种源自荞麦种子的天然产物，已被证明具有很高的加合物形成能力。 在啮齿动物和最近的人体 I 期临床试验中，2-HOBA 具有生物利用度，无毒性，可保护小鼠免受感染。 威尔逊实验室发现 isoLG 可以抑制高血压和阿尔茨海默病模型中的氧化损伤。 i) 在感染幽门螺杆菌的患者和小鼠的胃组织中 ii) 在人类的结肠中； 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，以及接受过 氧化偶氮甲烷-葡聚糖硫酸钠 (AOM-DSS)，CAC 的一个模型，实验室发现了 2-HOBA 类似物， EtHOBA 还能清除亲电子试剂，在两种模型中显着减少胃发育不良和癌症 幽门螺杆菌诱导的胃癌、转基因 FVB/N 胰岛素胃泌素 (INS-GAS) 小鼠和蒙古沙鼠， 在 AOM-DSS CAC 模型中，EtHOBA 可以减少结肠肿瘤发生，但与 2-HOBA 不同，EtHOBA 却不会。 我们勇敢地相信亲电子试剂在炎症驱动中发挥着关键作用。 通过与大分子形成加合物而发生胃肠道癌变，并且是新的分子靶标 通过2-HOBA预防癌症我们将确定2-HOBA对幽门螺杆菌引起的胃的保护作用。 INS-GAS 小鼠和沙鼠的致癌作用（目标 1）以及 AOM-DSS 中结肠炎相关的致癌作用 小鼠模型（目标 2）是减少发育异常、癌症和肿瘤形成。 次要终点将是对 DNA 损伤和 isoLG 加合物的影响 STTR 第一阶段的成功结果。 将是 2-HOBA 对胃癌和结肠癌发生的保护作用，并将是主要的通过/不通过 我们设想未来的研究将在患有疾病的动物身上测试 2-HOBA。 已经完全建立；进一步评估潜在保护作用的分子机制，包括 人类类器官；以及胃癌前期和结肠病变患者的人体临床试验。