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

摘要： 许多癌症都被认为是由炎症引起的。胃癌，第三大致癌原因 全球范围内的死亡，是原型-它是由感染幽门螺杆菌引起的 90%的病例。对于结直肠癌(CRC)，癌症死亡的第二大原因是炎症性肠病 疾病(IBD)是常见的前驱病变。这项STTR第一阶段提案是威尔逊夫妇 范德比尔特大学医学中心(VUMC)的实验室，专注于胃肠道炎症- 和MTI生物技术公司(MTI Biotech，Inc.)共同开发一种新的治疗策略 来预防癌症。在慢性粘膜炎症的情况下，酶活性增加会导致 二羰基亲电体的形成，这是包括异丁香素(Isuglandins)在内的脂质过氧化产物， 丙二醛、4-氧代-壬烯醛和丙烯醛，所有这些都能与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的异常和肿瘤转化的风险。这个 化合物2-羟基苯甲胺(2-HOBA)可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的 在啮齿动物和最近的人类I期临床试验中，生物利用度为零，没有毒性。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，isoLG 幽门螺杆菌感染患者和小鼠的胃组织中的加合物增加；ii)人的结肠中 炎症性肠病引起的慢性结肠炎和结肠炎相关癌症(CAC)，以及接受 偶氮甲烷-葡聚糖硫酸钠(AOM-DSS)，CAC模型。实验室发现一种2-Hoba类似物， 在两种模型中，也清除亲电体的EtHOBA显著减少了胃不典型增生和肿瘤 幽门螺杆菌诱发的胃癌、转基因FVB/N胰岛素-胃泌素(INS-GAS)小鼠和蒙古沙土鼠， 并在AOM-DSS CAC模型中减少结肠肿瘤的发生。然而，与2-Hoba不同，EtHOBA没有 达到了供人类使用的开发。我们假设亲电体在炎症驱动中起着关键作用。 通过与大分子形成加合物而致癌，是治疗胃肠道肿瘤的新分子靶点 2-HOBA预防癌症。我们将确定2-HOBA对幽门螺杆菌诱导的胃的保护作用 INS-GAS小鼠和沙土鼠的致癌作用(目标1)和AOM-DSS的结肠炎相关致癌作用 小鼠模型(目的2)。主要终点是异型增生、癌症和肿瘤形成的减少，以及 次要终点将对DNA损伤和等LG加合物产生影响。一项成功的STTRI期成果 将是2-HOBA对胃癌和结肠癌发生的保护作用，并将是主要的GO/NO GO 第二阶段STTR项目的终点。我们设想未来的研究将在动物身上测试2-HOBA， 已经完全确定；进一步评估潜在的保护作用的分子机制，包括 在人类器官中；以及在胃癌和结肠癌前病变患者中进行的人类临床试验。

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.