Abstract 4717: Glycosylation inhibition in multiple myeloma and its impact on treatment

Abstract Background: Multiple myeloma (MM) is a rare and incurable blood cancer that predominantly affects older adults. It is characterized by the uncontrolled proliferation of malignant plasma cells within the bone marrow, which often exhibit abnormal glycosylation patterns that may influence their interactions with chemotherapy. Notably, MUC1-C is aberrantly expressed in MM cells, playing a pivotal role in their growth and survival, making it a promising target for therapeutic intervention. Research has demonstrated that the inhibition of MUC1-C with benzyl-α-GalNAc enhanced the susceptibility of these cells to CTL-mediated immune responses and the effects of cytotoxic drugs. Modifying the glycosylation of MUC1-C has the potential to increase the susceptibility of MM cells to clinically relevant treatment approaches. Building on this, the current study investigated the use of glycosylation inhibitors as a strategy to improve drug efficacy in MM. We hypothesized that the glycosylation levels normally observed in MM cells functions as a cellular barrier to therapeutic agents. Method: The RPMI-8226 human plasmacytoma cell line (ATCC CCL-155) was cultured aseptically in RPMI-1640 growth medium supplemented with 10% fetal bovine serum (FBS). The cells were subsequently seeded into 24-well plates and pre-exposed to the glycosylation inhibitor, benzyl-α-GalNAc. Following a 48-hour incubation, the plates were next exposed to various agents for an additional 24-hr period. To assess the extent to which glycosylation influences drug uptake, one study involved the use of a fluorescently tagged anti-MUC1 antibody. To examine the influence of glycosylation on drug effects, the clinical agents imatinib and cyclophosphamide were also employed. Results: The pre-exposure of RPMI-8226 to glycosylation inhibitor cells resulted in greater uptake of the anti-MUC1 antibody compared to the untreated cells (P = 0.0008). Furthermore, the combination of glycosylation inhibitor and imatinib improved the drug effects when compared to imatinib alone (P = 0.0012). A similar observation was observed with cyclophosphamide (P = 0.0329). These findings emphasize the promising potential of combining therapeutic agents with glycosylation inhibitors to improve the effectiveness and precision of drug therapy. Conclusion: The application of a glycosylation inhibitor significantly enhanced drug uptake and subsequent drug effects. The promising findings suggest that the alteration of glycosylation patterns in MM may improve drug treatment efforts. Citation Format: Heni Patel, Sharnett Riley, Hiral Kapadia, Robert B. Campbell. Glycosylation inhibition in multiple myeloma and its impact on treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4717.