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: 9321431
• 负责人: Douglas Morgan
• 金额: $ 71.16万
• 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/9321431
• 关键词: Alleles; American; Antibiotics; Atrophic; Atrophic Gastritis; Attenuated; Biological Markers; Cancer Etiology; Carcinoma; Chemoprevention; Chronic; Chronic Gastritis; Clinical Trials; Colombia; Colonic Adenoma; DL-alpha-Difluoromethylornithine; DNA Damage; Data; Development; Disease; Dysplasia; Effectiveness; Eflornithine; Enzyme Induction; Enzymes; Flow Cytometry; Future; Gastric Adenocarcinoma; Gastric Tissue; Gastritis; Genes; Genotype; Gerbils; Helicobacter Infections; Helicobacter pylori; Histologic; Histopathology; Honduras; Human; Hydrogen Peroxide; IL8 gene; Immune response; In Situ; In Vitro; Infection; Inflammation; Injury; Integration Host Factors; Intervention; Intestinal Metaplasia; Latin America; Lesion; Malignant Neoplasms; Metabolic; Metabolism; Modeling; Mus; Neoplasms; Oral; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Output; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Placebos; Polyamines; Population; Premalignant; Prevalence; Prevention; Prevention strategy; Purines; Putrescine; Randomized; Reporting; Risk; Risk Factors; Risk Marker; Safety; Severities; Single Nucleotide Polymorphism; Spermidine; Spermine; Staining method; Stains; Stomach; System; T cell response; Virulence; base; burden of illness; cancer biomarkers; cancer chemoprevention; cancer risk; carcinogenesis; cohort; enzyme pathway; experience; functional status; high risk; high risk population; human subject; human tissue; in vivo; inhibitor/antagonist; macrophage; malignant stomach neoplasm; mortality; pathogen; polyamine oxidase; pre-clinical; predicting response; prevent; prospective; public health relevance; response; treatment effect

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。抗生素不能均匀地根除感染，并且在癌前病变患者中减少胃癌的益处尚未确定。我们的研究直接表明，从限速酶鸟氨酸脱羧酶（ODC）中提取的多胺与胃炎症和癌变有关。我们报道了幽门螺杆菌胃炎小鼠中多胺增加，α -二氟甲基鸟氨酸（DFMO）抑制ODC可减少胃中多胺，降低幽门螺杆菌定植和胃炎的严重程度。在沙鼠胃癌模型中，多胺水平与胃炎水平、DNA损伤和发展为非典型增生/癌相关，而DFMO抑制多胺和DNA损伤，并将非典型增生/癌的发生率降低50%以上。我们已经证明，导致幽门螺杆菌诱导DNA损伤的机制是精子胺氧化酶（SMO）的诱导，该酶位于ODC的下游，通过精子胺的代谢产生H2O2。SMO的表达随着从胃炎到癌前肠化生的组织学级联而增加，在北美受试者和哥伦比亚和洪都拉斯的病例中，幽门螺杆菌患病率和胃癌发病率是世界上最高的。虽然抑制SMO也可以减少沙鼠的癌症，但目前还没有适合人类使用的药物。因此，我们将使用SMO作为风险标记，但将重点放在ODC作为化学预防的目标，使用DFMO，因为它在人体研究中有20多年的使用经验，包括安全性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，我们将研究ODC SNP状态与DFMO反应的关系。我们还发现DFMO降低了促炎巨噬细胞和T细胞的反应，并且可以在体外和体内对幽门螺杆菌的毒力产生影响。我们假设胃癌前病变的高风险受试者将受益于DFMO治疗。这将包括减少氧化应激相关的DNA损伤、炎症和细菌毒力，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效果