Abstract 4278: HA-Irinotecan targeting of activated CD44 is an effective therapy for the eradication of colon cancer stem cells

Abstract

Abstract Introduction: Proprietary anticancer formulations based on the polysaccharide, hyaluronan (HA) are currently under development. The drugs utilize the unique physiochemical and biological properties of HA to entrain currently approved anticancer agent/s, where, after intravenous administration the HA moiety targets the drug complex to activated CD44 receptors which are over-expressed >95% of solid tumors. After extravasation into the tumor, the HA/drug complex forms a microembolism, increasing drug retention and tumor cell uptake, ultimately providing increased efficacy. The capacity to maintain tumor growth and resistance to therapy are associated with a small population of cells known as cancer stem cells (CSC). Current anticancer therapies focus on the eradication of proliferating cells, whereas CSCs have been demonstrated to be quiescent; often lacking hyperproliferation signals. CD44 is used as a reliable marker for colon cancer stem cells, therefore, through the high expression of this protein on both rapidly proliferating and CSCs there is strong rationale to use CD44 as a therapeutic target. In Phase ll clinical testing the anticancer drug, HA-Irinotecan has demonstrated superior efficacy in late-stage colon cancer patients but its effect on colon CSC is unknown. This study evaluated the efficacy of the CD44-targeted drug, HA-Irinotecan in the treatment of colon cancer CSC. Methodology: Two colon cancer cell lines were separated into CSC (CD44+CD133+ALDH+/−) and non-stem cell (CD44+CD133−ALDH+/−, CD44−CD133+ALDH+/−) sub-populations using FACS. Attachment and proliferation characteristics of the colon cancer sub-populations were established using real time electronic microsensory array assays. The activation status of CD44 was determined using a functional HA internalization assay. After confirming the CD44 activation status cell sub-populations were treated with HA-Irinotecan where efficacy was determined using clonogenic and microsensory array assays. Results: CD44s was the predominant CD44 isoform expressed on all CD44+ve colon cancer sub-populations where the CD44 was shown to be active via the active intenalisation and degradation of hyaluronan thereby providing rationale for CD44 as a therapeutic target. When CSC and non-CSC colon cancer sub-populations were treated the CD44-targeted drug, HA-Irinotecan, the EC50 was significantly reduced compared to drug alone. This increase in efficacy was negated when CD44−ve colon cancer sub-populations were treated with the CD44-targeted drug. Conclusions: This preliminary study has demonstrated that activated CD44 is a valuable therapeutic target in colon cancer. The treatment of human colon cancer with the CD44-targeted drug, HA-Irinotecan could provide a significant therapeutic advantage through eradication of all CD44+ve colon cancer populations including cancer stem 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 4278.