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Key Points: Knockdown of the sialyl-transferase, ST3GAL6, in MM inhibits in vivo homing and prolongs survival in xenograft mice. In MM patients, high expression of ST3GAL6 is associated with inferior overall survival.

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 have 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. Humans differentially express twenty different sialyltransferases in a tissue-specific manner, each of which catalyze the attachment of sialic acids via different glycosidic linkages (2-3; 2-6 or 2-8) to the underlying glycan chain. One important mechanism whereby overexpression of sialyltransferases 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 1-3-fucosyltransferases, 2-3-sialyltransferases, 1-4-galactosyltranferases, and N-acetyl--glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these sialyltransferases 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 sialyltransferases, could be beneficial to many cancer patients. Potential strategies include sialyltransferase 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 sialyltransferase 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.

Abnormal glycosylation is a hallmark of cancer, and the hypersialylated tumor cell surface facilitates abnormal cell trafficking and drug resistance in several malignancies, including multiple myeloma (MM). Furthermore, hypersialylation has also been implicated in facilitating evasion of natural killer (NK) cell–mediated immunosurveillance but not in MM to date. In this study, we explore the role of hypersialylation in promoting escape from NK cells. We document strong expression of sialic acid-derived ligands for Siglec-7 (Siglec-7L) on primary MM cells and MM cell lines, highlighting the possibility of Siglec-7/Siglec-7L interactions in the tumor microenvironment. Interactomics experiments in MM cell lysates revealed PSGL-1 as the predominant Siglec-7L in MM. We show that desialylation, using both a sialidase and sialyltransferase inhibitor (SIA), strongly enhances NK cell–mediated cytotoxicity against MM cells. Furthermore, MM cell desialylation results in increased detection of CD38, a well-validated target in MM. Desialylation enhanced NK cell cytotoxicity against CD38+ MM cells after treatment with the anti-CD38 monoclonal antibody daratumumab. Additionally, we show that MM cells with low CD38 expression can be treated with all trans-retinoic acid (ATRA), SIA and daratumumab to elicit a potent NK cell cytotoxic response. Finally, we demonstrate that Siglec-7KO potentiates NK cell cytotoxicity against Siglec-7L+ MM cells. Taken together, our work shows that desialylation of MM cells is a promising novel approach to enhance NK cell efficacy against MM, which can be combined with frontline therapies to elicit a potent anti-MM response.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

The tumour necrosis factor family member TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of cancer cells through the activation of death receptors 4 (DR4) and 5 (DR5) and is considered a promising anticancer therapeutic agent. As apoptosis seems to occur primarily via only one of the two death receptors in many cancer cells, the introduction of DR selectivity is thought to create more potent TRAIL agonists with superior therapeutic properties. By use of a computer-aided structure-based design followed by rational combination of mutations, we obtained variants that signal exclusively via DR4. Besides an enhanced selectivity, these TRAIL-DR4 agonists show superior affinity to DR4, and a high apoptosis-inducing activity against several TRAIL-sensitive and -resistant cancer cell lines in vitro. Intriguingly, combined treatment of the DR4-selective variant and a DR5-selective TRAIL variant in cancer cell lines signalling by both death receptors leads to a significant increase in activity when compared with wild-type rhTRAIL or each single rhTRAIL variant. Our results suggest that TRAIL induced apoptosis via high-affinity and rapid-selective homotrimerization of each DR represent an important step towards an efficient cancer treatment.