Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the USA. A growing body of evidence indicates that CRC tumors contain a small population of stem/progenitor cells (colorectal cancer stem cells, CRCSCs) capable of self-renewal that contribute to tumor maintenance, resistance to therapy and metastasis. Selective therapeutic targeting of CRCSCs in combination with approved therapies could improve treatment response and prolong patient survival. The endogenous protein TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) selectively induces cell death in cancer cells while sparing normal cells. This approach is particularly attractive for targeting CRCSCs potentially avoiding toxic effects in normal stem/progenitor cells in the colonic crypt. TIC10 is a first-in-class anti-tumor agent that transcriptionally induces TRAIL via the transcription factor Foxo3a, independent of tumor suppressor p53 status. We previously demonstrated that TIC10 activates Foxo3a by dual inhibition of the upstream regulators Akt and ERK. TIC10 induces TRAIL-mediated cell death in cancer cells in vitro and in vivo. TIC10 improves the half-life, tissue distribution, route of administration and spectrum of activity of TRAIL. These attributes overcome therapeutic limitations of recombinant TRAIL and TRAIL-agonist antibodies that have been or are in clinical trials to combat human cancer. TIC10 exhibits potent anti-tumor efficacy in a wide range of preclinical mouse models of cancer including subcutaneous and orthotopic colon cancer without observed toxicity. We hypothesize that the potent anti-tumor effect of TIC10 in colon cancer involves targeting of the CRCSC population. In this study we evaluated the effects of TIC10 on the CRCSC population in three human colon cancer cell lines. Flow cytometric analysis revealed that TIC10 significantly depleted CD133-, CD44- and Aldefluor-positive CRCSCs in HCT116 and SW480 cells. TIC10 significantly induced surface TRAIL expression in CD133- and CD44-positive CRCSCs. TIC10 also significantly inhibited colonosphere formation in DLD1 and SW480 cells. A targeted network analysis of gene expression profiles of HCT116 p53-null human colon cancer cells treated with TIC10 revealed that several stem cell-related pathways and proteins are affected by TIC10 and are likely involved in the anti-CRCSC effects of TIC10. In particular, mRNA transcript levels of Id2 (3.2 fold) and Wnt16 (13.5 fold) were significantly downregulated. Ongoing studies will validate these potential anti-CRCSC molecular targets of TIC10 and determine their contribution to the overall anti-CRCSC effect, evaluate the anti-CRCSC efficacy of TIC10 in vivo and examine combinatorial anti-CRCSC effects of TIC10 with chemotherapies used to treat CRC. In conclusion, TIC10 targets bulk tumor cells as well as CRCSCs, making this molecule a promising novel agent for the treatment of CRC.
Citation Format: Varun Vijay Prabhu, Joshua E. Allen, David T. Dicker, Yifu Ding, Wafik S. El-Deiry. Therapeutic targeting of colorectal cancer stem cells by TRAIL-inducing small molecule TIC10. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3732. doi:10.1158/1538-7445.AM2013-3732
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