Prevention of hepatocellular carcinoma in vulnerable communities in Texas

描述（由申请人提供）：发生肝细胞癌（HCC）的风险，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）显着增加。此外，房颤的致癌性可以通过暴露于伏马菌素（FB）而“促进”，伏马菌素是房颤的一种常见共污染物。重要的是，在德克萨斯州，Bexar县圣安东尼奥大都市区的多个地区都有记录显示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，这一人群有暴露于AF/FB的风险。因此，预防HV/AF/ fb诱导的HCC的创新策略是当务之急。我们开发了一种新的方法，使用蒙脱石粘土（NS）选择性吸收胃肠道中的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干预将减少贝尔县研究参与者的AF/FB暴露。我们的目标集中在确认精制NS的分子机制，并研究其在啮齿动物模型中减少肿瘤前肝脏病变发生率的能力。此外，在为期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。我们假设该制剂将减少AF/FB的初次暴露，进而减少德克萨斯州易感社区HCC的发生率。2002年至2006年间，贝尔县人群中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HCC风险人群中，减少饮食中AF/FB的暴露是可取的。使用毒素肠吸收剂（即NS粘土）减轻AF/FB暴露是一种创新、实用、可持续和环保的方法。此外，这一策略是“突破性的”，因为精炼的蒙脱石粘土可以通过优先和紧密地隔离胃肠道中的毒素来降低强效癌症引发剂（AF）和强效癌症促进剂（FB）的生物利用度。治疗剂量的NS粘土的首选递送可能最终通过将其包含在常见食品中，如花生酱、玉米粉、玉米饼或盐（如碘）中。

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.