Abstract 4718: Evaluation of the potential use of glycosylation inhibitors for the treatment of chronic myeloid leukemia: A transformative approach to drug therapy
Authors: Norymar Ayala, Binyaz Ilavia, Zein Dib, Najlaa Alsini, Robert B. Campbell
Journal: Cancer Research (2025)

Abstract Background: Chronic Myeloid Leukemia (CML) is a clonal disorder of hematopoietic stem cells characterized by excessive production of neutrophils. The disease is driven by the Philadelphia chromosome (BCR-ABL1), caused by the translocation of chromosomes 9 (ABL - pro-oncogene) and 22 (BCR). The genetic alterations lead to heightened tyrosine kinase activity, thereby promoting the proliferation of myeloid cells and decreased levels of apoptosis. Leukemic cells have been shown to display aberrant glycosylation, particularly involving O-glycans, referred to as TACAs (Tumor Associated Carbohydrate Antigens). The relationship between glycosylation and drug effects has been shown for solid tumors, such as pancreatic cancer, but not yet for hematological malignant types, such as CML. For this reason, the following study investigated the influence of type O-glycosylation on drug uptake and activity against a model CML cell line (K-562-GFP) in vitro. Method: The CML cell line K-562-GFP was cultured in RPMI + 10% fetal bovine serum (FBS). To assess the cytotoxic effects, the glycosylation inhibitor (benzyl-α-GalNAc) was employed to establish the maximum non-toxic concentration. In general, the K-562-GFP cells were seeded in a 24-well plate and subsequently exposed to a non-toxic concentration of Benzyl-α-GalNAc for a required length of time. A fluorescently tagged anti-MUC1(SPM533) monoclonal antibody was initially employed to evaluate the glycosylation drug barrier effect and functional activity of imatinib in the presence and absence of the glycation mesh. Results: Preliminary studies demonstrated a significant increase in the uptake of Anti-MUC1 (SPM533) antibodies by K-562-GFP cells following exposure to the O-glycosylation inhibitor (P &amp;lt; 0.0001). Imatinib resulted in significantly higher cellular death for K-562-GFP cells pre-exposed to glycosylation inhibitor than in imatinib treatment alone (P &amp;lt; 0.0001). Early preliminary findings suggest that glycosylation may play an important role in regulating cytotoxic drug entry into target cells and in the subsequent functional activity in vitro. Additional studies involving other relevant drug agents are currently underway. Conclusion: Initial findings support the notion that targeting glycosylation could represent a promising therapeutic strategy, as O-glycosylation may serve as a barrier limiting drug effects in CML. Ongoing studies will evaluate the potential impact of glycosylation on FDA-approved agents used for the treatment of CML. Citation Format: Norymar Ayala, Binyaz Ilavia, Zein Dib, Najlaa Alsini, Robert B. Campbell. Evaluation of the potential use of glycosylation inhibitors for the treatment of chronic myeloid leukemia: A transformative approach to drug therapy [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 4718.