Abstract 4503: A small molecule glycomimetic antagonist of E-selectin (GMI-1271) prevents pancreatic tumor metastasis and offers a novel treatment for improved efficacy of chemotherapy

Abstract

Abstract The processes of intra- and extravasation of tumor cells into and out of the blood and lymphatic systems are crucial steps during metastasis to distant organ sites. These processes are tightly regulated by the initial binding of sialyl Lewis A and sialyl Lewis X (sialyl Le A/X) carbohydrate moeities found on tumor cells to the adhesion protein E-selectin expressed on the activated endothelium. GMI-1271 is a small molecule glycomimetic rationally designed based on the bioactive conformation of sialyl Lea/x and is a potent and specific antagonist of E-selectin. In vitro treatment of human lymphatic endothelial cells with GMI-1271 resulted in a decrease in the number of sialyl Lewis A-expressing pancreatic cancer cells (S2.013 and BxPC-3) binding to the endothelium in a dose-dependent manner. GMI-1271 treatment also inhibited the transendothelial migration of S2.013 and BxPC-3 cells through a lymphatic cell monolayer. We evaluated the in vivo efficacy of GMI-1271 following orthotopic implantation of pancreatic tumor cell line S2.013, which expresses high levels of sialyl Lewis A (CA19-9), into nude mice. Following 2 weeks of tumor growth, mice were treated by intraperitoneal injections for 4 weeks with either PBS once daily, once daily with 40mg/kg GMI-1271 (low dose), twice daily with 40mg/kg GMI-1271 (high dose), twice a week with 60mg/kg gemcitabine injections, combination low dose GMI-1271 and gemcitabine injections, or combination high dose GMI-1271 and gemcitabine injections. Co-treatment of either low or high dose GMI-1271 with gemcitabine resulted in a significant decrease in the number of metastasis to the lymph nodes (p=0.02 low dose; p=0.04 high dose). In addition, compared with gemcitabine alone, low dose GMI-1271 plus gemcitabine was found to be effective at reducing the number of metastatic lesions (per histological section) in the liver (p=0.001), lung (p=0.026) and diaphragm (p=0.01). Based on the significant effects of combination therapy on tumor metastasis, the small molecule glycomimetic antagonist to E-selectin, GMI-1271, offers great promise in preventing pancreatic tumor cell entry into the blood and lymphatic systems and offers a novel treatment for the improved efficacy of standard chemotherapy. Citation Format: Maria M. Steele, Prakash Radhakrishnan, John L. Magnani, Michael A. Hollingsworth. A small molecule glycomimetic antagonist of E-selectin (GMI-1271) prevents pancreatic tumor metastasis and offers a novel treatment for improved efficacy of chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4503. doi:10.1158/1538-7445.AM2014-4503