Targeting E-selectin to Tackle Cancer Using Uproleselan

Abstract

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties and therapy resistance. Therefore, being expressed in the tumor microenvironment, E-selectin can potentially be used to eradicate cancer. Uproleselan (also known as GMI-1271), a specific E-selectin antagonist, has been tested on leukemia, myeloma, pancreatic, colon and breast cancer cells, most of which involve the bone marrow as a primary or as a metastatic tumor site. This novel therapy disrupts the tumor microenvironment by affecting the two main steps of metastasis—extravasation and adhesion—thus blocking E-selectin reduces tumor dissemination. Additionally, uproleselan mobilized cancer cells from the protective vascular niche into the circulation, making them more susceptible to chemotherapy. Several preclinical and clinical studies summarized herein demonstrate that uproleselan has favorable safety and pharmacokinetics and is a tumor microenvironment-disrupting agent that improves the efficacy of chemotherapy, reduces side effects such as neutropenia, intestinal mucositis and infections, and extends overall survival. This review highlights the critical contribution of E-selectin and its specific antagonist, uproleselan, in the regulation of cancer growth, dissemination, and drug resistance in the context of the bone marrow microenvironment.

DMBA-Induced Kidney Dysfunction: Effects of Supplementary Dietary Vitamin K in Rats

“…Selectins (cluster of differentiation 62 or CD62) are a family of cell adhesion molecules (or CAMs), that played an important role in inflammation and progression of cancer. 39,40 Moreover, Yusuf et al 41 and Katz et al 42 have reported elevated concentrations of selectins, following DMBA administration. On the other hand, interleukin-2 (IL-2) is a cytokine signalling molecule, with pleiotropic effects on the immune system, helping the body fight off infections.…”

Glycan–Lectin Interactions in Cancer and Viral Infections and How to Disrupt Them

“…As selectins are physiologically important for the interactions involving leukocytes, platelets, or endothelial cells [ 109 ], it is not surprising that they play an essential role in tumor-promoting inflammation and cancer metastasis [ 131 ]. In particular, E-selectin was reportedly discovered to be upregulated during metastasis [ 132 ], representing an essential receptor in leukemia [ 133 ], and myeloma but also in solid tumors including pancreatic, prostate, colon, and breast carcinoma (reviewed in [ 134 ]). Moreover, there is strong evidence that the expression of sLe x and sLe a is also increased in many cancer types, for example, in gastrointestinal cancer, carcinoma or melanoma cells correlating with enhanced metastasis and poor prognosis [ 112 , 135 , 136 , 137 ].…”

“…The interaction between sLe x and E-selectin is well recognized to enhance the adhesion of cancer cells to the endothelium [ 138 ], one example being leukemic cells adhering to the bone marrow [ 139 , 140 ]. Additionally, E-selectin overexpression and the subsequent interaction with the tumor-microenvironment was shown to activate pro-survival and antiapoptotic signaling via the ERK/AKT, PI3K, NF-κB, or Wnt pathway (reviewed in [ 134 ]), which promoted tumor progression, chemoresistance [ 134 ], and also the maintenance of cancer cell stemness [ 141 ]. In particular, its role in acute myeloid leukemia (AML) is well researched.…”

“…By impeding the adhesion of cancer cells to bone marrow, Uproleselan mobilizes cancer cells to the blood circulation and thus sensitizes them for chemotherapy [ 133 , 139 ]. Moreover, Uproleselan has been suggested to also inhibit pro-survival signaling and cancer cell regeneration as well as to decrease therapeutic side effects due to specific targeting (reviewed in [ 134 ]). Currently, two phase III clinical trials are ongoing to evaluate the efficacy of Uproleselan in combination with different chemotherapeutic agents in newly diagnosed (NCT03701308) and relapsed/refractory (NCT03616470) adult AML patients [ 146 ].…”

“…Currently, two phase III clinical trials are ongoing to evaluate the efficacy of Uproleselan in combination with different chemotherapeutic agents in newly diagnosed (NCT03701308) and relapsed/refractory (NCT03616470) adult AML patients [ 146 ]. Furthermore, Uproleselan proved to be preclinically efficient in leukemia, myeloma, pancreatic, colon, as well as breast cancer cells [ 134 ], and is currently being tested in a phase II trial (NCT04682405) in multiple myeloma (MM) patients. Moreover, molecular biosimilars have already been developed targeting, for example, CXCR4 in addition to E-selectin (GMI-1359) [ 147 ].…”