Relevance to Fiscal Year 2015 Prostate Cancer Research Program Congressionally Directed Topic Areas: Stomach Cancer

One goal of this proposal is to gain insights into the mechanism(s) whereby bacteria known as Helicobacter pylori causes stomach or gastric cancer, which is the second deadliest cancer worldwide killing about 700,000 people per year. H. pylori infect more than half of the world's population and generally become established as a chronic infection. Most infected individuals either lack symptoms or have gastritis, but in some the infection can lead to serious diseases of the stomach, which include peptic (gastric or duodenal) ulcer disease and gastric cancer. Stomach cancer is a deadly disease because it is usually diagnosed late since there are no early symptoms and 80% of cases are associated with H. pylori infection. Unfortunately, we do not have sufficient understanding of how H. pylori promotes stomach cancer to be able to effectively prevent it. Because stomach cancer is caused by an infectious agent, a vaccine may be an effective way to prevent this deadly disease. We propose to use novel technology known as next-generation sequencing to examine in detail the genomes of a collection of H. pylori strains from stomach cancer cases and compare them to the genomes of H. pylori strains isolated from peptic ulcer disease and gastritis cases to identify genetic characteristics that are unique to strains from stomach cancer cases. Those genetic features may represent genes encoding virulence factors associated with disease promotion. This information may in turn open doors to novel strategies to prevent and/or treat stomach cancer.

Another goal of these studies is to use a powerful novel approach that allows the modeling of human gastric disease using primary cultures of human stomach that recapitulate the stomach architecture in order to investigate the presence of candidate biomarkers of disease in infected cultures. Advantages of these cultures is that they reproduce the complexity of the different epithelial cell types found in the region of the stomach infected by H. pylori, they are not cancer cells but grow indefinitely, and they are polarized as the epithelium in the stomach. Those cultures are known as gastric organoids and can be infected with H. pylori strains from stomach cancer cases and with strains from other gastric diseases to determine if there are differences in the induction of proteins that are found in cancers and are also induced by H. pylori. Those proteins are known to have negative immunoregulatory properties that prevent the immune system from attacking tumors. We expect to observe that strains from stomach cancer cases will differ from other strains in the induction of these proteins. Furthermore, since recent studies have found that these proteins can be secreted, we will investigate whether they are found in soluble form in H. pylori-infected human organoids as these may represent candidate biomarkers of disease. Such biomarkers could have significant clinical impact because they may allow early detection of stomach cancer development, which would allow for early intervention in patients with early stages of stomach cancer and this may allow us to save many lives. Since Service members have been reported to have a 25% rate of seropositivity for H. pylori, are frequently deployed to regions where H. pylori is prevalent, and stomach cancer is one of the top cancers treated in the Veterans Affairs (VA) system, the findings from these studies are expected to benefit members of the US military and their families, since intrafamilial infection occurs. Upon successful completion of these Idea Award studies, the next phase will include studies to assess the presence of the identified biomarkers in serum of patients with stomach cancer compared to patients with peptic ulcer disease, gastritis, and healthy individuals to determine whether they may be potential biomarkers. Also, future studies will seek to target the H. pylori genes identified or their products in the development of strategies to prevent stomach cancer. Clinical translation of the findings is a major objective and the timeframe for their implementation will depend on the necessary clinical trials.