Prevention of hepatocellular carcinoma in vulnerable communities in Texas

描述（由申请方提供）：发生肝细胞癌（HCC）的风险，肝细胞癌是感染肝炎病毒（HV）的人类死亡的主要原因，通过饮食暴露于黄曲霉毒素（AF）显著增加。此外，AF的致癌性可以通过暴露于伏马菌素（FB）而“促进”，伏马菌素是AF的常见共污染物。重要的是，在贝克萨尔县的圣安东尼奥大都市区的多个地区，已记录了德克萨斯州HCC的显著增加。在一项初步研究中，我们已经表明，由于摄入受污染的食物，这一人群存在AF/FB暴露的风险。因此，预防HV/AF/FB诱导的HCC的创新策略是高度优先事项。我们开发了一种新的方法，使用蒙脱石粘土（NS），选择性地吸附胃肠道中的AF和FB。在德克萨斯州和加纳的临床试验中，我们证实了NS的安全性和有效性。在拟议的项目中，我们的目标是基于中心假设，即NS干预将减少贝克萨尔县研究参与者的AF/FB暴露。我们的目标集中于确认精制NS的分子机制，并研究其在啮齿动物模型中降低癌前肝病变发生率的能力。此外，在3个月的临床试验后，将在参与者的样本中测量毒素暴露的生物标志物。我们假设这种药物将减少AF/FB的主要暴露，从而降低德克萨斯州弱势社区HCC的发病率。2002年至2006年期间，贝克萨尔县人群中HCV感染和HCC的发病率明显高于德克萨斯州其他县。因此，在这些有HCC风险的人群中，需要减少AF/FB的饮食暴露。使用毒素肠吸附剂减轻AF/FB暴露（即，NS粘土）代表了一种创新、实用、可持续和环境友好的方法。此外，这种策略是“突破性的”，因为精制蒙脱石粘土可用于通过优先和紧密地从胃肠道隔离两种毒素来降低有效癌症引发剂（AF）以及有效癌症促进剂（FB）的生物利用度。治疗剂量的NS粘土的优选递送可最终通过将其包含在普通食物如花生酱、玉米粉、玉米饼或盐（如碘）中。 公共卫生相关性：这项研究的结果将与德克萨斯州服务不足的大都市，农村和边境社区直接相关，在这些社区，经常感染HV并暴露于饮食AF/FB的“穷人”的肝病发病率升高。长期目标是提供一种干预措施，通过减少AF和FB的暴露，改善“高危”人群的肝病管理。

DESCRIPTION (provided by applicant): The risk of developing hepatocellular carcinoma (HCC), a leading cause of death in humans infected with hepatitis virus (HV), is significantly enhanced by dietary exposure to aflatoxin (AF). Also, the carcinogenicity of AF can be "promoted" with exposure to fumonisin (FB), a common co-contaminant with AF. Importantly, a significant increase in HCC in Texas has been documented in multiple regions of the San Antonio metropolitan area of Bexar County. In a pilot study, we have shown this population is at risk for AF/FB exposure due to the intake of contaminated foods. Thus, innovative strategies for the prevention of HV/AF/FB-induced HCC are high priorities. We have developed a novel approach using a smectite clay (NS) that selectively sorbs AF and FB in the GI tract. In clinical trials in Texas and Ghana, we confirmed the safety and efficacy of NS. In the proposed project, our aims are based on the central hypothesis that intervention with NS will decrease AF/FB exposure in study participants in Bexar County. Our objectives focus on confirming the molecular mechanisms of refined NS and investigating its ability to diminish the incidence of preneoplastic hepatic lesions in a rodent model. Also, biomarkers of toxin exposure will be measured in samples from participants following a 3-month clinical trial. We postulate that this agent will reduce primary exposure to AF/FB and, in turn, reduce the incidence of HCC in vulnerable communities in Texas. Between 2002 and 2006, the incidence of HCV infection and HCC in populations in Bexar County was significantly higher compared to other counties in Texas. Therefore, in these populations at risk for HCC, it is desirable to decrease dietary exposure to AF/FB. Mitigating AF/FB exposure using a toxin enterosorbent (i.e., NS clay) represents an innovative, practical, sustainable and environmentally benign approach. Moreover, this strategy is "ground-breaking" in that a refined smectite clay can be used to decrease the bioavailability of a potent cancer initiator (AF) as well as a potent cancer promoter (FB) by preferentially and tightly sequestering both toxins from the GI tract. The preferred delivery of a therapeutic dose of NS clay may eventually be through its inclusion in common foods such as peanut butter, corn meal, tortillas, or salt (like iodine). PUBLIC HEALTH RELEVANCE: The findings from this research will be of direct relevance to underserved metropolitan, rural and border communities in Texas where the incidence of liver disease is elevated in the "poor" who are frequently infected with HV and exposed to dietary AF/FB. The long-term goal is to provide an intervention that will improve liver disease management in "high risk" populations by reducing exposure to AF and FB.