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（由申请人提供）：世界上一半的人口感染幽门螺杆菌，它会导致慢性胃炎和胃腺癌。需要基于高风险变量的干预措施。抗生素并不能完全消除感染，并且对于减少癌前病变患者的胃癌发病率的益处尚未确定。我们的研究直接表明源自限速酶鸟氨酸脱羧酶 (ODC) 的多胺与胃炎症和癌发生有关。我们已经报道，小鼠幽门螺杆菌胃炎中的多胺增加，并且用 α-二氟甲基鸟氨酸 (DFMO) 抑制 ODC 可减少胃多胺，并降低幽门螺杆菌定植和胃炎的严重程度。在胃癌沙鼠模型中，多胺水平与胃炎、DNA 损伤和进展为不典型增生/癌的水平相关，而 DFMO 可以抑制多胺和 DNA 损伤，并将不典型增生/癌的发生率降低 50% 以上。我们已经证明，幽门螺杆菌引起的 DNA 损伤的机制是诱导精胺氧化酶 (SMO)，该酶位于 ODC 下游，通过精胺代谢产生 H2O2。在北美受试者以及哥伦比亚和洪都拉斯的病例中，SMO 表达随着从胃炎到癌前肠化生的组织学级联而增加，这些国家的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，但重点关注 ODC 作为化学预防的目标，使用 DFMO，因为它在人体研究中的使用已有二十多年的经验，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风险和对 DFMO 的反应，并且我们表明胃癌与 ODC+316 SNP 的 GG 等位基因相关；因此，我们将检查 ODC SNP 状态与 DFMO 响应的关联。我们还发现 DFMO 可以减少促炎巨噬细胞和 T 细胞反应，并且可以在体外和体内对幽门螺杆菌毒力产生影响。我们假设患有癌前胃病变的高危受试者将受益于 DFMO 治疗。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 名高风险患者的临床试验中的效果 洪都拉斯和哥伦比亚患有癌前病变的受试者随机接受安慰剂或 DFMO 治疗 18 个月，并评估 DNA 损伤、胃多胺和组织病理学评分。 2) 与 DFMO 反应相关的宿主因素，包括 ODC SNP 状态、SMO 和其他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.) 幽门螺杆菌细菌因素，包括菌株基因型和输出菌株的功能状态。我们预计我们的研究结果将为未来胃癌化学预防的长期研究奠定基础。