Abstract 3496: Self-renewal as a therapeutic target in human colorectal cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (C-ICs) in tumors that survive therapy. Together with recent reports showing that C-IC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key stemness property unique to C-ICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation, and more specifically human colorectal C-IC function are dependent on the canonical self-renewal regulator BMI-1. Down-regulation of BMI-1 inhibits the ability of colorectal C-ICs to self-renew resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with small molecule BMI-1 inhibitors resulted in colorectal C-IC loss with long-term and irreversible impairment of tumor growth. Targeting the Bmi-1 related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3496. doi:1538-7445.AM2012-3496