Abstract PS4-03-15: Repurposing eliglustat as an anti-cancer agent for triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by high pathological grade, strong invasiveness, local recurrence, high metastasis rate, and poor prognosis. Chemotherapy and in some cases, immunotherapy, remain the main choice of systemic treatment. However, response is variable, lacks durability, and acquired resistance to chemotherapy is a frequent manifestation. There remains an unmet need to establish novel alternative therapies that can both exert targeted effects on cancer cells as well as stimulate an anti-cancer immune response. We have uncovered an onco-metabolic biochemical feature in TNBC wherein cancer cells increase chemical conversion of sphingomyelin to ceramide with subsequent glycation to glycosphingolipid derivatives. Our mechanistic studies have established that this biochemical program is essential for survival mitophagy. The activation state of this program in cancer cells opens a metabolic vulnerability that is targetable through biochemical inhibition of glucosylceramide synthase (UGCG), a rate-initiating enzyme that mediates glycation of ceramides to glycosphingolipid derivatives. Our preclinical studies using orthotopic syngeneic mouse models of Brca-deficient TNBC as well as human cell line and patient-derived xenograft models of TNBC have demonstrated that targeting of cancer cell UGCG via repurposing eliglustat, an FDA-approved selective UGCC inhibitor for long-term use in patients with Gaucher’s disease, at clinically achievable doses elicits potent anti-cancer effects by targeting cancer cell mitochondria, resulting in accumulation of mitotoxic ceramides, induction of compensatory mitophagy, and induction of cyclic GMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway activities to promote an anti-cancer immune response. Importantly, assessment of eliglustat-associated toxicity revealed that extended-use of eliglustat was safe and tolerable in treated mice with histopathological examination of kidney and liver from treated mice revealing no remarkable differences compared to saline control. Clinical chemistry tests following eliglustat treatment indicated dose-dependent elevations in blood ALT and AST levels, consistent with clinical studies. Our study highlights utility of eliglustat as a potential anti-cancer agent for the treatment of TNBC. Citation Format: J. Vykoukal, Y. Chen, M. Zuo, R. Ballaro, M. Hong, H. Krishna, D. Rodriquez-Perera, H. Katayama, E. Irajizad, R. Wu, R. León-Letelier, J. Dennison, A. Gutierrez, A. Paulucci-Holthauzen, Y. Cai, F. Hsiao, S. Park, B. Arun, S. Hanash, J. F. Fahrmann. Repurposing eliglustat as an anti-cancer agent for triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-03-15.