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: 9126254
• 负责人: Douglas Morgan
• 金额: $ 57.45万
• 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/9126254
• 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; Health; 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; Longitudinal Studies; Malignant Neoplasms; Metabolic; Metabolic Pathway; 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; Staging; Staining method; Stains; Stomach; System; T cell response; Virulence; base; burden of illness; cancer chemoprevention; cancer risk; carcinogenesis; cohort; enzyme pathway; experience; functional status; high risk; human subject; human tissue; in vivo; inhibitor/antagonist; macrophage; malignant stomach neoplasm; mortality; pathogen; polyamine oxidase; pre-clinical; predicting response; prevent; prospective; 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）：全球一半的人口感染了幽门螺杆菌，该幽门螺杆菌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。抗生素不会统一地消除感染，并且尚未确定癌性病变患者的胃癌的益处。我们的研究直接牵涉到源自限制酶鸟氨酸脱羧酶（ODC）的多胺，这是胃炎和致癌作用。我们已经报道说，小鼠幽门螺杆菌胃炎中的多胺增加，并用α-二氟甲基氨基氨酸（DFMO）抑制ODC可降低胃多胺，以及幽门螺杆菌结肠和胃炎的严重程度。在胃癌的沙鼠模型中，多胺水平与胃炎，DNA损伤和发展不良/癌的进展相关，而DFMO抑制了多胺和DNA损害，并降低了发育不良/癌瘤的速率。我们已经证明，导致幽门螺杆菌诱导的DNA损伤的机制是诱导精子氧化酶（SMO）的诱导，该酶是ODC的下游，并通过精子的代谢产生H2O2。 SMO表达沿着北美受试者的组织学级联反应从胃炎到癌前肠上皮的组织学级联反应增加，在哥伦比亚和洪都拉斯的情况下，幽门螺杆菌患病率和胃癌的发生率是世界上最高的。虽然对SMO的抑制也可以减少沙鼠的癌症，但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，但要专注于ODC作为化学预防的目标，使用DFMO，因为在人类研究中使用了超过二十年的经验，包括安全数据和在抑制多胺水平方面的有效性。 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，我们表明胃癌与ODC+316 SNP的GG等位基因有关。因此，我们将研究ODC SNP状态与DFMO响应的关联。我们还发现，DFMO降低了促炎性巨噬细胞和T细胞反应，并且可以对幽门螺杆菌在体外和体内产生影响。我们假设患有癌前胃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，从而导致组织病理学和癌症风险减弱。我们的目的是确定：1​​。）DFMO在300高风险的临床试验中的影响 洪都拉斯和哥伦比亚随机癌性病变的受试者随机分配到安慰剂或DFMO 18个月，评估DNA损伤，胃聚胺和组织病理学评分。 2）与DFMO反应相关的宿主因子，包括ODC SNP状态，SMO和其他多胺途径和代谢酶的表达，以及转向免疫耐受的免疫反应。 3.）幽门螺杆菌细菌因子，包括菌株基因型和输出菌株的功能状态。我们预计我们的发现将为胃癌化学预防的未来长期研究奠定基础。