Novel Listeria Vectors Secreting Gut Flora-Altering Agents to Prevent Colon Cancer and Treat Colitis
Abstract
This proposal responds to the Peer Reviewed Medical Research Program focus on colorectal cancer and Listeria cancer vaccines, and also responds to the gaps and priority areas of cancer prevention. Scientific Objectives and Rationale: Pathologic alteration in gut microbes (dysbiosis) contributes to colitis and to increased risk from colorectal cancer. Mechanisms are obscure, but dysbiosis-driven alterations of metabolism, colon epithelial integrity, and immunity are likely. Mechanisms regulating dysbiosis are likewise obscure. B7-H1 is a molecule on the colon epithelial surface that regulates colon inflammation by regulating gut dysbiosis that increases colitis and colon cancer risk. We will use a well-validated mouse model of colitis and related colon cancer to test if manipulating colon epithelium B7-H1 expression using genetically engineered bacteria can mitigate gut dysbiosis that leads to age-related colitis and to related rising risk for colon cancer with age. We will use recombinant Listeria and E. coli bacteria that are known to be safe in humans and have been used in other clinical trials. Ultimate Applicability and Impact: Our studies will provide much detail on interactions between gut microbes, immunity, and inflammation, and cell signals that trigger inflammation and cancer. This information can be used to help understand age-related inflammation including colitis and its attendant risk for colorectal cancer, allowing development of additional and more effective cancer prevention strategies. If safe and easy-to-implement strategies to prevent gut dysbiosis are found, these could also be used to help prevent inflammatory bowel disease flares and related risks for colon cancer. Colon cancer is the top two or three cancer killer in the United States. Specific data on military populations are not well-established, but it is presumed that it is also a top killer of military, especially retirees, Veterans, and dependents. We are primarily looking at means to prevent colon inflammation (colitis) and related colon cancer. It is well established that disease prevention is a simpler and more cost-effective approach to health management than disease treatment. Types of Patients Helped and How: Colon cancer can significantly affect quality of life, productivity, and overall health. If colostomy is required, it is a life-altering experience. If colon cancer is late-stage, it usually shortens life span and reduces work productivity, in addition to economic, societal, personal, and military impact. Thus, many otherwise healthy, fit, productive, and active individuals could be helped greatly. Potential Clinical Applications, Benefits and Risks: The biggest impact could be in the prevention of colon cancer, but could also help reduce inflammatory bowel disease as it is also caused by abnormal bacteria in gut that cause excess inflammation. The bacteria we propose to use could be delivered for extended periods including many decades (in yogurt, for example), potentially with no significant adverse effects. Reductions in lost productivity, impact on society and the economy, and the cost-effectiveness are addressed above. Projected Time to Achieve a Clinically Relevant Outcome: As the Listeria we use for these studies is usable in human trials, we envision a clinical trial of candidate vectors to test safety and tolerability and test effects on colon microbes and inflammation within 3 years. Testing cancer prevention will ultimately take longer, but studies could begin within 3 years as well. We have extensive early phase clinical trials experience. Likely Contributions to Advancing Cancer Research and Patient Care: We propose a highly innovative and inexpensive approach to colon cancer prevention. Colon cancer is a top two or three cancer killer in the United States. Our approach should be safe and well-tolerated as the agents tested are generally regarded as safe and the delivery systems a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510155
Entities
People
- Tyler J Curiel
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio