Translational Impact of Electrophile Adducts in Colorectal Cancer
Abstract
Our project is related to the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area: colorectal cancer, and to the Military Health Focus Areas: (1) Environmental/exposure risk factors associated with cancer; and (2) Mission Readiness, specifically, Gaps in cancer prevention and early detection; and Gaps in quality of life and survivorship. Colorectal cancer (CRC) is a very serious and common disease. According to the International Agency for Research on Cancer of the World Health Organization “Globocan 2018” statistics, there were 1,849,518 new cases of cancer of the colon and rectum in 2018, 10.2% of all new cancer cases. CRC accounted for 880,792 documented deaths in 2018, which was 9.8% of all cancer deaths, and is the second leading cause of cancer death after only lung cancer. The world incidence rate of 19.7/100,000 is even higher in North America, with 26.2/100,000, and 8.4 deaths/100,000. The number of cases is expected to nearly double by 2040. The Principal Investigator is a gastrointestinal physician (gastroenterologist) practicing at the Veterans Affairs Tennessee Valley Healthcare System, Nashville Campus with his academic appointment at the adjacent Vanderbilt University Medical Center (VUMC); both of these positions will facilitate the execution of this project. In our field of gastroenterology, a major focus of our work is CRC. We perform a high percentage of our colonoscopy procedures for prevention or early detection of CRC. However, beyond standard clinical guidelines, we lack personalized approaches that are sufficiently patient-specific, because we do not have enough scientific clues about how to apply our research to exact strategies to help determine who may get CRC and how we can intervene to prevent it. We do know that there is one type of CRC that can result from the chronic damage to the colon caused by inflammatory bowel disease (IBD), which has two forms, ulcerative colitis (UC) and Crohn’s disease (CD). We also know that military deployment can increase risk for getting IBD, due to many potential factors, including acquired infections, changes to the normal microbes colonizing the gut, and post-traumatic stress; this results in high frequency of IBD in Veterans. Other than frequent colonoscopy, we have no other strategies in the military or in Veterans to assess for changes of early cancer. Our goal is to develop a new, more rational strategy. Our work has shown that, during the process of inflammation, there can be damage to the DNA of cells. DNA is the genetic code that is the building block of life. When there are abnormalities in the DNA (mutations), this can lead to cancer. This project brings a new perspective in which we will study a specific form of injurious agents, called electrophiles, which we have now shown for the first time, to be produced in the colon as a result of inflammation and oxidative stress. These electrophiles can react with important molecules, such as DNA, as well as proteins, and therefore transform normal cells into cancerous cells. We have found in mice that a drug that helps to remove the electrophiles greatly reduces the development of tumors in a model of colitis-associated CRC. Our objective now is to establish the role of the electrophiles in human colon and rectum tissues from IBD patients, and cells that we will grow from these patient tissues, called organoids, so that we will be able to better predict CRC risk and establish a way to monitor who should be treated with drugs, called scavengers, that eliminate the electrophiles. These studies will seek to relate the generation of the dangerous binding of electrophiles to DNA and protein with other markers of cancerous behavior in cells, and to assess if we can prevent such negative events. The only risk of the study is that of the colonoscopy and obtaining biopsies; however, we will only be taking additional biopsies from patients already undergoing clinically needed procedures at th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110617
Entities
People
- Keith T. Wilson
Organizations
- United States Army
- Vanderbilt University