Targeted chemoprevention of gastric carcinogenesis in high risk populations

高危人群胃癌的靶向化学预防

• 批准号: 9248746
• 负责人: Douglas Morgan
• 金额: $ 52.85万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248746
• 关键词: Targeted; chemoprevention; gastric; carcinogenesis; risk

DESCRIPTION (provided by applicant): Half of the world's population is infected with Helicobacter pylori, which causes chronic gastritis and gastric adenocarcinoma. Interventions based on high risk variables are needed. Antibiotics do not uniformly eradicate the infection, and benefits in reduction of gastric cancer in patients with precancerous lesions are not established. Our studies have directly implicated polyamines, derived from the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric inflammation and carcinogenesis. We have reported that polyamines are increased in H. pylori gastritis in mice, and inhibition of ODC with alpha-difluoromethylornithine (DFMO) reduces gastric polyamines, and severity of H. pylori colonization and gastritis. In the gerbil model of gastric cancer, polyamine levels correlate with levels of gastritis, DNA damage, and progression to dysplasia/carcinoma, and DFMO suppresses polyamines and DNA damage, and reduces rates of dysplasia/carcinoma by more than 50%. We have demonstrated that the mechanism leading to H. pylori-induced DNA damage is induction of the enzyme spermine oxidase (SMO), which is downstream of ODC and generates H2O2 via metabolism of spermine. SMO expression increases along the histologic cascade from gastritis to precancerous intestinal metaplasia in North American subjects and in cases from Colombia and Honduras where H. pylori prevalence and gastric cancer rates are amongst the highest in the world. While inhibition of SMO also reduces cancer in gerbils, there are no suitable agents available for human use. Thus we will use SMO as a marker of risk, but focus on ODC as the target for chemoprevention, using DFMO, since there is more than two decades of experience in its use in human studies, including safety data and effectiveness in suppression of polyamine levels. ODC single nucleotide polymorphism (SNP) studies have predicted colon adenoma risk and response to DFMO, and we show that gastric cancer is associated with the GG allele of the ODC+316 SNP; thus we will examine the association of ODC SNP status with DFMO response. We have also found that DFMO reduces proinflammatory macrophage and T cell responses, and can have effects on H. pylori virulence both in vitro and in vivo. We hypothesize that high risk subjects with precancerous gastric lesions will benefit from DFMO treatment. This will include reduced oxidative stress associated DNA damage, inflammation, and bacterial virulence, leading to attenuated histopathology and cancer risk. Our Aims are to determine: 1.) The effect of DFMO in a clinical trial of 300 high risk subjects with precancerous lesions in Honduras and Colombia randomized to placebo or DFMO for 18 months, with assessment of DNA damage, gastric polyamines, and histopathology score. 2) Host factors associated with response to DFMO, including ODC SNP status, expression of SMO and other polyamine pathway and metabolic enzymes, and shift to immunotolerant immune responses. 3.) H. pylori bacterial factors, including strain genotypes and functional status of output strains. We expect our findings will set the stage for future longer-term studies of gastric cancer chemoprevention.

描述(申请人提供)：世界上一半的人口感染幽门螺杆菌，导致慢性胃炎和胃腺癌。需要基于高风险变量的干预措施。抗生素并不能完全根除感染，对减少癌前病变患者的胃癌也没有确定的益处。我们的研究直接表明，来源于限速酶鸟氨酸脱羧酶(ODC)的多胺与胃炎症和癌症的发生有关。我们已报道幽门螺杆菌在小鼠胃炎中多胺增加，用α-二氟甲基鸟氨酸(DFMO)抑制ODC可减少胃多胺，减少幽门螺杆菌定植和胃炎的严重程度。在沙土鼠胃癌模型中，多胺水平与胃炎、DNA损伤和异型增生/癌的进展相关，DFMO抑制多胺和DNA损伤，并将异型增生/癌的发生率降低50%以上。我们已经证明，导致幽门螺杆菌DNA损伤的机制是诱导位于ODC下游的精胺氧化酶(SMO)，该酶通过精胺的代谢产生过氧化氢。在北美受试者和来自哥伦比亚和洪都拉斯的病例中，SMO的表达沿着从胃炎到癌前肠化生的组织级联增加，这些病例的幽门螺杆菌感染率和胃癌发病率是世界上最高的之一。虽然抑制SMO也可以减少沙土鼠的癌症，但目前还没有合适的药物可供人类使用。因此，我们将使用SMO作为风险标记，但重点关注ODC作为使用DFMO进行化学预防的目标，因为在人体研究中使用SMO已有20多年的经验，包括安全数据和抑制多胺水平的有效性。ODC单核苷酸多态性(SNP)研究预测了结肠腺瘤的风险和对DFMO的反应，我们发现胃癌与ODC+316 SNP的GG等位基因相关；因此，我们将检查ODC SNP状态与DFMO反应的相关性。我们还发现，DFMO减少了促炎巨噬细胞和T细胞的反应，并在体外和体内都能对幽门螺杆菌的毒力产生影响。我们假设，患有癌前病变的高危受试者将从DFMO治疗中受益。这将包括减少与DNA损伤、炎症和细菌毒力相关的氧化应激，从而降低组织病理学和癌症风险。我们的目标是确定：1)DFMO在300例高危人群临床试验中的作用 洪都拉斯和哥伦比亚有癌前病变的受试者随机服用安慰剂或DFMO 18个月，评估DNA损伤、胃多胺和组织病理学评分。2)与DFMO应答相关的宿主因素，包括ODC SNP状态、SMO等多胺途径和代谢酶的表达，以及向免疫耐受免疫反应的转变。3.)幽门螺杆菌的细菌因子，包括菌株的基因型别和输出菌株的功能状态。我们希望我们的发现将为未来胃癌化学预防的长期研究奠定基础。