Abstract 4501: Temporal Validation of Novel Therapeutic Targets in Non-Hodgkin Lymphoma

Abstract In 2024, we reported the development of knowledge graph machine learning (KGML) models focused on 41 blood cancers (1), using several public resources. Our disclosure identified 19 drug targets that are likely to be druggable and fall into the "Tchem" category—that is, targets perturbed by small molecules (2). These 19 genes had limited or no known blood cancer associations, when evaluated via the DISEASES platform (3). Upon re-evaluation a year later, five genes (BLK, FCER2, FRK, CAMK2D, and EPHB1) were no longer investigated due to a growing body of literature. Of the remaining 14 genes (see Table 1), only two (IRAK3 and ITPKB) have marginally relevant associations with lymphoma, leukemia, or myeloma, according to the DISEASES platform (3). Table 1 summarizes cytotoxicity assays for the 14 targets, using compounds specific for each target. Non-Hodgkin lymphoma cell lines were: Toledo (CL1), SU-DHL-6 (CL2), TMD8 (CL3), and JeKo-1 (CL4). CC50 (50% cytotoxic concentration) values, measured in micromolar concentrations, were collected at 3 (_3d) and 7 days (_7d), respectively; "nd" - not determined; "gt" - greater than value. Except for GRM8, all targets exhibited at least one micromolar CC50 value. Five kinases (IRAK3, ITPKB, PRKCE, ACVR2B, and PIM1), one enzyme (ADCY1), and one ion channel (TRPV4) have at least one sub-micromolar CC50 value (25 values total). Some targets (e.g., GPR18, a G-protein coupled receptor; and ITPKB, a kinase) show low micromolar CC50s at 7 days, with gt 20 CC50 after 3 days, suggesting target engagement. Confirmatory target engagement experiments are in progress. Although preliminary, these data validate our KGML approach (1), as they implicate at least seven targets in non-Hodgkin lymphoma disease biology, with potentially novel therapeutic applications. References 1. Quazi M, et al. Cancer Res (2024) 84 (6_Supplement): 3535. 2. Oprea TI, et al. Nat Rev Drug Discov. (2018) 17:317-32. 3. Grissa D, et al. Database (2022) baac019. Citation Format: Tudor I. Oprea, Mohammed Quazi, Suman Sirimulla, Cristian G. Bologa, Ruben Karapetian, Alexey Pushechnikov, Bill Farley, Nikolay Savchuk. Temporal Validation of Novel Therapeutic Targets in Non-Hodgkin Lymphoma [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 4501.