Esophageal adenocarcinoma (EAC) is one of the fastest growing cancers, for which no effective therapy exists. EAC develops from a precursor intestinal-like metaplasia in the distal esophagus, a condition known as Barrett's esophagus (BE). BE affects more than 3 million people in the United States and is a consequence of reflux of gastric and /or duodenal content into esophagus, i.e. gastroesophageal reflux disorder (GERD). Patients with GERD are chronically exposed to a combination of stomach acid and duodenal juice, as well as to variable concentrations of bile secreted by the liver. Multiple studies in human patients and experimental animal models demonstrated the carcinogenic effect of bile exposure on esophageal epithelium. This has been attributed to deoxycholic acid, which constitutes one of the major bile components. Currently, there is no effective strategies capable of preventing malignant esophageal transformation in patients with GERD and BE. This highlights an urgent need for development of novel approaches to EAC chemoprevention. Here, I plan to investigate the anti-carcinogenic effect of bioactive compounds derived from the plant Cannabis sativa in experimental models of EAC. The bioactive compounds from the plant Cannabis sativa, acting through cannabinoid receptors, can attenuate oxidative stress in multiple degenerative diseases such as diabetes mellitus, cardiomyopathy, and liver fibrosis. Moreover, cannabinoids and terpenes also exhibit a potent anti- inflammatory response in the setting of auto-immunity. In the preliminary data presented in this proposal, I determined that a specific cannabinoid/terpene admixture could counteract the DNA-damaging effect of deoxycholic acid on human primary esophageal epithelial cells. I plan to further examine the in vivo potential of this therapeutic approach for prevention of bile acid-induced carcinogenesis in the setting of GERD utilizing a preclinical rat model of EAS development. I will investigate cellular mechanisms by which these bioactive compounds can reverse bile-acid-induced DNA damage by examining the deoxycholic acid- mediated mitochondrial membrane disruption, reactive oxygen species production, and endoplasmic reticulum calcium release in primary human esophageal epithelial cells. Additionally, I will also study the long-term DNA- stabilizing effect of a cannabinoid/terpene admixture by evaluating the evolution of genomic instability in the setting of prolonged deoxycholic acid exposure. These studies will identify the relationship of bile acids to esophageal carcinogenesis and have outstanding potential to lead to novel cancer prevention strategies to overcome significant rise in esophageal cancer, a disease for which no effective treatment exists.
In the US, esophageal adenocarcinoma has the fastest growing incidence of all other cancers, in part due to lack of effective preventive measures. Esophageal adenocarcinoma arises as a consequence of repeated exposure to acid and bile reflux. The goal of this proposal is to determine if bioactive compounds from the plant Cannabis sativa are able to counteract the carcinogenic effect of bile and thus would have therapeutic potential for esophageal cancer chemoprevention.
