Abstract CN13-05: A novel approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis
Authors: Huang Shaoyi , Zhang Ling , Ren Xianoyang , Alt Eckhard , Bai Xiaowen , Xu Zhengming , Lynch Patrick M. , Moyer Mary P. , Wen Xian-Feng , Wu Xiangwei 
Published: January 2011

Current approaches for colorectal cancer (CRC) chemoprevention, including the use of NSAID, have tended predominantly toward modulating tumorigenic pathways rather than eliminating large number of premalignant or subclinical malignant cells. This tendency reflects the effort to keep toxicity to a minimum. The effectiveness of such modulative agents, however, is generally low to moderate, and long-term treatment is often required to produce any significant preventive benefit. In turn, long-term therapy frequently produces unanticipated adverse effects even with agents generally thought to have low toxicity.

To overcome the challenges in current chemoprevention, we propose to perform chemoprevention in a therapy-like fashion, i.e., through short-term and intermittent treatments. The concept underlying this approach is based on elimination of large number of premalignant cells (to a greater degree than sought generally in chemoprevention) via short-tem treatments by specifically targeting genetic or epigenetic changes in premalignant cells. Periodically reducing or eliminating the number of premalignant cells through a series of noncontinuous/intermittent short-term therapies potentially will significantly reduce the chance of accumulation multiple mutations in same cells, which is required to generate malignant clones. This will delay or even completely prevent cancer in long-term. In this way, the potential side effects and costs often associated with long-term treatment could be minimized and controlled. In a recent paper (Nature. 2010 Apr 15; 464(7291): 1058-61. Epub 2010 Mar 28), we reported the development of a novel therapy-like chemoprevention procedure for CRC. This procedure is based on our finding that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of β-catenin lead to the repression of cellular caspase-8 inhibitor cFLIP expression through activation of c-Myc, and that all-transretinyl acetate (RAc) independently upregulates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and represses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we demonstrate that short-term and noncontinuous TRAIL and RAc treatment induces apoptosis specifically in intestinal polyps, strongly inhibits tumor growth, and promotes survival in ApcMin mice. We further show that TRAIL and RAc induce significant cell death in human colon polyps in organ culture in vitro, providing a potentially selective therapeutic approach for CRC chemoprevention by targeting APC-deficient cells for apoptosis. This study demonstrated the feasibility, efficacy, and potential tolerability of therapy-like chemoprevention in an in vivo preclinical setting. Progress toward a clinical trial will be discussed.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN13-05.