Targeting Selectins and Their Ligands in Cancer

Abstract

Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

Exploration of the Sialic Acid World

“…1110 The involvement of selectins in cancer metastasis has drawn many researchers to this field. 1118 In 1989, the lymph node homing receptor, as well as E-and P-selectins, were cloned. 1119 This protein family was then named "selectins," belonging to the "C-type" lectins.…”

Advances in targeted therapy for acute myeloid leukaemia

“…GMI‐1271 is a novel antagonist of E‐selectin that inhibits the interaction between E‐selectin (an adhesion molecule on cells in the bone marrow) and E‐selectin ligands and thereby down‐regulates cell survival pathways and enhances chemotherapy response (Winkler et al , ; Natoni et al , ). Very recently, GMI‐1271 (GlycoMimetics Inc.) was granted breakthrough therapy designation by the FDA and orphan drug designation by the European Commission for the treatment of patients with relapsed/refractory AML.…”

Multivalent Sialosides: A Tool to Explore the Role of Sialic Acids in Biological Processes

“…Interestingly, tumor cells also express the SL x residue, which binds to selectins. Such selectins have a role in tumor‐cell migration and metastasis . Finally, the discovery that β‐amyloid binds to Sia has had a significant impact on the field of Alzheimer′s disease targeting …”

“…Such selectins have ar olei nt umor-cell migration and metastasis. [20] Finally,t he discovery that b-amyloid binds to Sia has had as ignificant impact on thef ield of Alzheimer'sd isease targeting. [21] All of these aforementioned biological eventsa nd many more demonstrate the importanceo fs ialoglycans in biological processes and highlight the potential of these molecules.…”