Abstract 709: The fully human IGF-1 receptor antibody, CP-751,871, targets putative colon cancer stem cell populations

Abstract

Abstract The identification of cancer stem cells (CSCs) has the potential to provide answers to questions of tumor pathogenesis, metastasis, and therapeutic resistance. We have previously shown that insulin-like growth factor 1 (IGF-1) enriches putative colon CSC populations, an important finding with the potential to explain the association of colon cancer risk and chemoresistance with the levels of circulating IGF-1 and obesity. Here, we have employed three established methods (side population (SP) analysis, aldehyde dehydrogenase activity (ALDH+), and CD133 expression) to analyze a panel of 8 human colon cancer cell lines for putative cancer stem cell properties. We have found enrichment of SP and/or ALDH+ populations across the panel of 8 colon cancer cell lines, as well as many lines originating from other tissues. The enrichment of SP cells by IGF-1 is independent of altered ABC transporter activity as measured by mitoxantrone efflux. Enrichment of CSCs by IGF-1 does not appear to depend on the activity of MAP kinases (based on inhibition with PD098059 and U0126); therefore, we are currently exploring dependence on alternative IGF signaling pathways downstream of Akt, including NF-κB and mTOR. While we continue our efforts to unravel the mechanism by which IGF-1 enriches CSCs we are also interested in the more immediate clinical implications of our findings. CP-751,871 is a fully human antibody with specificity to the IGF-1 receptor and is currently being tested in clinical trials for a variety of solid malignancies. We have found that CP-751,871 reduces both SP and ALDH+ CSC populations in multiple colon cancer cell lines in vitro, and has promising activity against these populations in pilot experiments in vivo. We are currently repeating these studies to yield conclusions supported by statistics. Interestingly, CP-751,871 blocks IGF-1 enrichment of the side population in DLD1 cells, but not in SW480 cells suggesting a potential role of alternative receptors, such as the insulin receptor in some cell lines, a possibility we are currently analyzing. These studies have the potential to affect clinical oncology treatment strategies as the role of CSCs in tumor growth is delineated. Our results suggest that CP-751,871 has preferential activity against putative CSC populations, and therefore, may benefit current standard chemotherapeutic regimens that target cycling cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 709.