DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Role of TRAIL Signaling through the Development of Carcinogen-Induced Colorectal Cancer

Principal Investigator: LEE, SEULKI
Institution Receiving Award: JOHNS HOPKINS UNIVERSITY
Program: PRCRP
Proposal Number: CA130460
Award Number: W81XWH-14-1-0239
Funding Mechanism: Career Development Award - Optional Nested Postdoctoral Fellow Traineeship
Partnering Awards:
Award Amount: $388,800.00


PUBLIC ABSTRACT

Colorectal cancer (CRC) is widely considered to be an environmental disease. Continuous exposure to varying amounts of chemical carcinogens contributes significantly to the development of CRC. Identification of prognostic and predictive biomarkers of CRC due to exposure to environmental or chemical carcinogens plays a critical role to improve treatment and identify new therapeutic targets. While we are developing a novel anticancer protein drug targeting CRC, bioengineered TRAIL, we serendipitously realized that TRAIL-associated signaling molecules, biomolecules involved in the TRAIL-induced tumor cell killing mechanism, vary across different stages of cancer. This finding led us to propose the high-risk study that seeks to identify TRAIL signaling molecules as potent prognostic and/or predictive markers for CRC. Although TRAIL protein has been intensively studied as an anticancer agent for the last decade, its role as a biomarker in developing CRC induced by continuous exposure to environmental or chemical carcinogens has not been reported. In this project, we intend to discover the unexplored role of TRAIL signaling molecules as predictive and/or prognostic biomarkers in human sporadic colon cancer particularly in carcinogen-induced colitis-associated colon cancer (CAC) models.

The Principal Investigator (PI) has a unique research background as he was the leader of the Theranostic Nanomedicine Section, the only section at National Institutes of Health dedicated to both nanomedicine and diagnosis, since its development before he joined Johns Hopkins University (JHU). During that time, his research was focused on developing targeted cancer therapy and early cancer diagnosis. This award will advance the PI's career as an interdisciplinary colorectal cancer researcher. The PI's current position at JHU is providing invaluable opportunities to collaborate and lead a team in a translational research environment. With the new opportunities from this Career Development Award, the PI and the PI's group can focus on fundamental research in CRC while aiming for a clinical output, thus allowing fundamental yet translational CRC research. This experience will smoothly combine with the PI's established platform in cancer nanomedicine and imaging and will greatly benefit his research career as a whole. In addition, mentoring from his designated mentor, a nationally renowned oncologist, will help widen the PI's vision and knowledge beyond the bench and to the bedside. This award will play a central role in the PI's transition as an independent translational cancer researcher at the forefront of CRC.

With the support of this award, the discovery proposed here may arise new avenues for CRC therapy including: (1) identifying novel predictive and prognostics biomarkers across additional CRC types, (2) confronting the large heterogeneity in histological analysis of CRC, and (3) developing personalized and advanced therapeutic options for CRC patients. Since our proof-of-concept study will be explored initially using cancer animal models (Year 1) and validated in colonic tissues from CAC patients (Year 2), we can achieve a clinically relevant outcome. Our positive outcomes can be immediately applied to the clinic followed by further validation steps with additional clinical samples. In addition, by combining our ongoing research related to developing TRAIL-based, CRC targeted anticancer agents, we will propose a therapeutic strategy to prevent and/or cure CRC patients.

CRC is one of the most common forms of cancer among active duty military personnel, thus thousands of warfighters are at risk for slowly developing this environmental disease. It should be noted that CRC is highly curable when diagnosed early during screening. Thus, identifying novel biomarkers that can stage the status of CRC and/or monitor symptoms will significantly contribute to increased success rates of preventative screening and help service members, their families, and the American public.

This proposed research primarily addresses "identification of predictive and prognostic biomarkers of developing cancers due to exposure to militarily relevant environmental or chemical carcinogens." Overall, this project aims to provide a complete package that offers prevention, detection, diagnosis, and treatment of CRC utilizing TRAIL-associated molecules as biomarkers and TRAIL itself as a therapeutic agent.