Stabilization of MDA-7/IL-24 for colon cancer therapy

Colon cancer is one of the most commonly diagnosed cancers in the United States. Recombinant MDA-7/IL-24 has showed its selective cytotoxicity against cancer cells, and Ad-mda7 (INGN-241) is currentlyunder clinical investigation for solid tumors. Here, we investigated the expression of MDA-7/IL-24 incolorectal cancer (CRC) tissues from 202 patients. Compared with the adjacent mucosa, CRC tissues displayedsignificantly lower MDA-7/IL-24 levels. The MDA-7/IL-24 levels in CRC were significantly associatedwith patients’ survival rate in a 6-year period. These results indicate MDA-7/IL-24 level is both adiagnostic and prognostic biomarker for CRC, and support the role of MDA-7/IL-24 in the treatment ofCRC. To elevate MDA-7/IL-24 level for colon cancer treatment, we successfully developed asmall-molecule compound SC144 with the ability to up-regulate MDA-7/IL-24 expression via direct bindingand stabilizing MDA-7/IL-24 in human colon cancer cells. Among the analogs tested, SC144 exhibitedthe highest cytotoxicity in a panel of colon cancer cell lines in a p53-independent manner, accompaniedby cell cycle arrest in G0/G1 with downregulation of Cyclin D1 levels, and apoptosis induction with upregulationof cell surface-bound Fas/CD95. These results combined with our previous studies support theanticancer role of MDA-7/IL-24 as well as the clinical development of SC144 for colon cancer treatment.