Novel High-Fidelity Screening of Environmental Chemicals and Carcinogens and Mechanisms in Colorectal Cancer
Abstract
Environmental chemicals (ECs) including chemical warfare agents and carcinogens confer potential cancer risks to military personnel and their families during service. The relative contribution of EC exposure and genetic susceptibility in the etiology of cancer is poorly understood, making the translation of existing data into meaningful prevention and/or therapeutic strategies for military personnel difficult. Such exposure to ECs during deployment and other operations is unavoidable. Although cancers arise due to multiple etiologies, environmental contributions are a critical component. Unlike many other cancers, the molecular characteristics of most colorectal cancers (CRC) are quite well understood in terms of their initiation, progression, and even prevention. Although CRC is an important cause of morbidity and death in the military community, it is not known how ECs contribute to CRC-causing pathways. Therefore, there is an urgent need to study the potential risks and mechanisms whereby such chemicals cause cancer. While this project addresses one focus topic described in the Peer Reviewed Cancer Research Program call for proposals, the approach can be applied to any disease process relevant to the military. Exposure to ECs could interfere with many cellular targets via many possible mechanisms. These mechanisms include direct interaction with human cells, indirectly affecting UV light-mediated suppression of cell functions, and via their intrinsic chemical nature, which affect normal functions of the cells and contribute to the development of cancer. In this proposal, using our novel model and methods (Chemo-Phenotypic based Toxicity Measurement - CPTM), we will identify toxicity end points of each environmental chemicals and which part of the cell pathways (each cell is connected by many protein pathways and collectively engage in specific function) are affected upon exposure to these chemicals. As a case study, we seek to determine the interaction of ECs with the Vitamin D Receptor (VDR) and Wnt/beta-catenin pathways so important in the development of CRC. Our proposed novel screening methods will identify mechanisms with unprecedented accuracy which ECs have the potential to influence the development of cancer, specifically CRC. The project outcome will provide insights into mechanisms of CRC initiation and fill gaps in the treatment and prevention paradigm for active duty Service members, their families, and other military beneficiaries. There are thousands of ECs with the potential to cause cancer but for which toxicity mechanisms are either limited or nonexistent. This is key to moving beyond high-dose animal toxicity tests to estimate human risk at realistic exposure levels. Our proposed screening using "CPTM" can reveal this information in significantly less time and at lower costs without compromising prediction accuracy. The CPTM is a quantitative method that determines target signatures of ECs to provide the framework to predict cancer toxicity risks of ECs, and may ultimately serve as a tool to predict chemical design guidelines before they are released in the environment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510423
Entities
People
- Sivanesan Dakshanamurthy
Organizations
- Georgetown University
- United States Army