Abstract CN15-03: Targeting APC-deficient cells for apoptosis: a therapeutic approach for colorectal cancer prevention

CN15-03

Cancer prevention is generally perceived as long-term process and inevitably associated with adverse effects. Here we report the development of a procedure that specifically targets premalignant tumor cells for apoptosis, potentially making cancer prevention work like therapy. This procedure is based on our finding that deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of β-catenin leads to repression of cFLIP expression through activation of c-Myc. Independently, retinoid (RA) upregulates tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Combination of TRAIL and RA results in specific killing of APC-deficient cells without harming normal cells. We further show that co-treatment with TRAIL and RA in APC⁺/Min mice induces apoptosis specifically in intestinal polyps and strongly inhibits tumor growth. Since mutations in the APC tumor suppressor gene are frequently associated with early stages of colorectal cancer (CRC), these results provide a therapeutic approach for chemoprevention of CRC by targeting APC-deficient cells for apoptosis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN15-03.