Posted July 12, 2016
Seulki Lee, Ph.D., Johns Hopkins University
RESEARCH TOPIC: Colorectal Cancer
AWARD MECHANISM: Career Development Award - with Nested Postdoctoral Fellow
Members of the tumor necrosis factor (TNF) family of cytokines are proteins that activate cellular receptors to initiate a type of cell death pathway termed apoptosis. These molecules are promising antitumor therapeutics due to their unique ability to induce apoptosis in cancer cells. However, their utility in the clinic has been disappointing due to the rapid metabolism of TNF within the body as well as cancer’s ability to circumvent apoptosis.
Dr. Seulki Lee, together with his postdoctoral fellow Dr. Yumin Oh, at Johns Hopkins University, developed a new drug delivery platform with the potential to avoid both of these clinical setbacks. Drs. Lee and Oh focused on maximizing the in vivo antitumor activity of a single member of the TNF super family, tumor necrosis factor-related apoptosis inducing ligand (TRAIL). By adding a long polymer chain to shield the TRAIL protein (TRAILPEG) from its degradation pathway, the researchers can extend the half-life of the drug.
With a fiscal year 2013 Career Development Award, the team mapped the signaling molecules involved in TRAIL-induced apoptosis specifically within colitis-associated cancer (CAC) cells. Utilizing a mouse model of CAC, they have determined that the transition from ulcerative colitis, or inflammatory bowel disease (IBD), to colon cancer is marked with distinctive changes in the amounts of TRAIL signaling elements and markers of inflammation within affected tissue. These changes are unique to the location along the length of the colon and characterize different stages of the disease progression. These same constituents of TRAIL signaling, when measured in cell lines or CAC patient tissues, showed similar changes in gene expression. Most striking are the increased levels of TRAIL-specific receptors that are initiating factors of the TRAIL-induced apoptosis cascade. The researchers plan to further investigate these molecular signatures of CAC progression for their potential utility as clinical biomarkers of CAC susceptibility.
The utility of TRAILPEG as a therapeutic in combination with a sensitizing agent was also investigated within the first year of this award. Preliminary experiments in cell lines resistant to TRAIL-induced apoptosis were used to detect molecules that would confer TRIAL sensitivity. IL-1β, a mediator of inflammatory response, was identified as a promising sensitizing molecule. Pre-application of this protein resulted in increased TRAILPEG apoptosis due to a higher amount of TRAIL-specific receptors within treated cells. Further research within the final year of the grant will focus on validating this new targeted therapy and sensitization strategy on the CAC mouse model as well as tissue derived from IBD and CAC patients.
Dr. Lee’s contribution to the field of targeted medicine reinvigorates the potential for TRAIL-based therapy by overcoming two major hurdles. The development of a long-acting TRAIL variant used in combination with a sensitizing agent is a game-changing step for chemotherapy research and its highly translational nature builds a solid foundation for progression towards clinical application.
Last updated Wednesday, July 13, 2016