Abstract 5439: Sphingolipid modulating compounds BXQ-350 and desipramine display synergy in reducing viability across multiple cancer cell types in vitro

Abstract Background: A cancer cell’s ability to dictate sphingolipid metabolism is necessary for its survival. Two sphingolipids play a key role in cancer cell survival: Ceramide and Sphingosine-1-Phosphate (S1P), and the relationship between these two is known as the Ceramide-S1P rheostat. High levels of S1P, which favors cancer cell survival, proliferation, chemotherapeutic resistance and immune suppression, have been associated with poorer clinical outcomes; while higher levels of Ceramide, which is associated with cell death signaling and immune activation, lead to more favorable outcomes. Pushing this ratio in favor of Ceramide can weaken cancer cells making them more susceptible to a variety of therapeutic treatments. BXQ-350 is a novel anti-cancer and anti-neuropathy drug consisting of the lysosomal activator protein Saposin C (SapC) and the anionic phospholipid Dioleoyl Phosphatidylserine (DOPS). Together they are an allosteric activator of glucocerebrosidase (GCase) which is responsible for converting glucosylceramides into Ceramide (and glucose). Desipramine is a tricyclic antidepressant that blocks the reuptake of norepinephrine and serotonin. It binds to the inner leaflet of the lysosomal membrane changing the polarity and preventing certain enzymatic activities. Of note, it prevents acid-Ceramidase (ACMase) from converting Ceramide into Sphingosine, the precursor to S1P. Method: Cells were treated, in vitro, with BXQ-350 and Desipramine for 72hrs. Viability was measuring using the MTT kit from Roche (#11465007001). Synergy was calculated utilizing the online website Synergy Finder (https://synergyfinder.fimm.fi/synergy/synfin_docs/). The aim of synergy calculations is to quantitate the change between an assumed no interaction reference model and the observed response when drugs are used in combination. The Zero Interaction Potency (ZIP) model (Yadav, et al., 2015) assumes the single drugs have no effect on the other’s potency curve. Results: Although BXQ-350 and Desipramine concentrations varied between specific cell lines, synergy was observed in colorectal, glioblastoma multiforme and pancreatic cancer cell lines. Conclusion: Disrupting a cancer cell’s sphingolipid metabolism, specifically the Ceramide-S1P rheostat, is a viable strategy for clinical therapeutics. The synergy BXQ-350 and Desipramine combinations show across cancer cell types, with varying oncogenic profiles, suggests that targeting sphingolipid metabolism is an agnostic approach to treating cancer, not related to any specific mutation or cell type. The possibility exists for sphingolipid modulating drugs to be combined with specific chemotherapeutics to increase their efficacy. Citation Format: Tariq Arshad, Tim Stephens, Nikhil Wilkins, Robin Furnish, Mike Gazda. Sphingolipid modulating compounds BXQ-350 and desipramine display synergy in reducing viability across multiple cancer cell types in vitro [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 5439.