Scientific Objective and Rationale: Gastric cancer is the fourth most common cancer and the second most deadly cancer worldwide. Due to few early warning signs and no established screening tests, the majority of patients present with incurable, late-stage disease. Therefore, there is an urgent need to identify novel biomarkers for gastric cancer, so that effective screening tests can be developed to detect the cancer before it spreads. Emerging evidence shows that cancer cells must adjust their metabolism to meet energy needs and sustain their frenzied growth. We therefore hypothesize that early gastric cancer exerts changes in plasma metabolites, thereby producing a metabolomic fingerprint that can be detected prior to diagnosis. The proposed research aims to identify these metabolite changes caused by early-stage gastric cancer, using blood drawn from patients before their diagnosis. In collaboration with the Broad Institute of MIT/Harvard, we will perform a comprehensive, untargeted analysis of thousands of measureable metabolites, including chemicals of unknown identify. This state-of-the-art, untargeted metabolomics platform vastly increases the potential to discover novel biomarkers that can be used to diagnose gastric cancer at an earlier stage when cure is still attainable.

Career Goals: My career goals are dedicated to a better understanding of the etiology of gastrointestinal (GI) cancer, and my primary research goal is to develop innovative preventive, diagnostic, and therapeutic strategies for understudied GI cancers. This Career Development Award is critical to the development of my career. The educational curriculum will allow me to gain essential skills in computational biology and bioinformatics necessary for the analysis of large-scale biological data. The research project will enable me to pursue a focused research program dedicated to gastric cancer, a critically understudied GI cancer, and thereby launch my own research program with the guidance from, yet independent of, my mentor. Thus, this award provides an excellent basis on which I can build a career as an independent, well-rounded GI cancer researcher.

Applicability of Research: The proposed research aims to elucidate the systemic metabolic changes caused by or associated with gastric cancer growth, and build the first-ever comprehensive roadmap of metabolic alterations in early-stage gastric cancer. This work is expected to fundamentally advance the field of gastric cancer biomarker discovery through the application of metabolomics, and the results are expected to have positive translational impact within a few years after the award. First, the identified novel circulating biomarkers can be leveraged to design screening tests for gastric cancer early detection. Second, because many of these metabolites and their associated pathways will likely be suited to direct interventions, with discovery of new biomarkers, the proposed research has great potential to aid in the development of new targets for preventive and therapeutic interventions that disrupt gastric tumor metabolism. Third, findings from this work can help identify high-risk population and formulate preventive recommendations based on an individual's circulating metabolite profile. This is particularly relevant in the context of highly prevalent obesity and metabolic disorders among nondiabetic U.S. adults in recent decades. Ultimately, the use of effective biomarkers in screening, risk stratification, and treatment strategies is crucial for reducing suffering and deaths from gastric cancer. Understanding the altered metabolism of early gastric cancer is a major contribution to the field and will yield many opportunities for future investigation.

Military Relevance: Gastric cancer is a Service-connected malignancy for Service members who experienced hazardous exposure to ionizing radiation. In addition, research has shown that U.S. Soldiers living under field conditions are at great risk of H. pylori infection, which is the main cause of gastric cancer. Furthermore, although the frequency of gastric cancer has declined in the general population, its incidence has risen significantly in individuals aged 25-39. This disturbing upward trend affects young adults including active duty Service members. The proposed research directly addresses the critical needs of Service members at elevated risk for gastric cancer and will have substantial impact on reducing suffering and mortality from gastric cancer among Service members and their families. As a result, this work is expected to expand the knowledge in gastric cancer research, patient care, and treatment options in the military health system.