The cellular and molecular composition of the pancreatic tumor microenvironment includes a complex matrix that encases tumor cells and presents a conundrum in respect to therapy. The dense desmoplasia that accompanies tumor growth reduces blood flow to tumors and creates an environment that compromises delivery of therapeutics. As well, elimination of certain stromal elements enhances the aggressiveness and metastatic potential of pancreatic cancer cells. Recent studies attempt to target stroma in an effort to enhance delivery and efficacy of therapeutic agents and to block metastasis. In this context we have investigated the activity of GMI-1359, a potent dual antagonist that targets both E-selectin and CXCR4. Adhesion protein E-selectin is crucial for regulating vascular and lymphatic endothelial cell (EC) interactions with tumor cells during transmigration. The CXCL12-CXCR4 chemokine axis contributes to the formation of the tumor microenvironment including fibroblast and immune cell recruitment, lymph- and angiogenesis, tumor cell proliferation/survival, and tumor stem cell mobilization. Our in vitro results demonstrate that pancreatic fibroblasts secrete significant amounts of CXCL12 which promotes tumor cell and lymphatic and vascular EC directional migration; this migration toward CXCL12-secreting fibroblasts was completely blocked by GMI-1359. Additionally, CXCL12-stimulated ECs facilitated increased transendothelial migration (TEM) by pancreatic tumor cells. Dual antagonist GMI-1359 inhibited this CXCL12-dependent increase in pancreatic tumor cell TEM and was more effective than an independent small molecule E-selectin only inhibitor. Using an in vivo orthotopic model of pancreatic cancer in athymic mice, we evaluated the ability of GMI-1359 (with and without co-administration Gemcitabine (Gem)) to suppress tumor progression, modulate tumor microenvironment composition, and prolong survival. Our work demonstrated GMI-1359 slightly inhibited tumor growth when used alone or in combination with Gem but did not prolong survival in this immune compromised model. However, GMI-1359 inhibited tumor metastasis to the spleen, liver, and lungs. Interestingly, GMI-1359 significantly modulated the cellular composition of the tumor microenvironment. Immunohistochemical analysis revealed mice treated with GMI-1359 (with or without Gem administration) had drastically reduced desmoplasia and reduced lymphatic and blood vessel densities compared to mice treated with vehicle control or Gem alone. The E-selectin only inhibitor had no effect on tumor microenvironment composition. Further studies of GMI-1359, particularly in immune competent models, are warranted to understand its potential for disrupting the pancreatic tumor microenvironment, inhibiting dissemination, and enhancing anti-tumor immune responses.
Citation Format: Maria M. Steele, William E. Fogler, John L. Magnani, Michael A. Hollingsworth. A small molecule glycomimetic antagonist of E-selectin and CXCR4 (GMI-1359) delays pancreatic tumor metastasis and significantly alters the pancreatic tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 902.