# Repurposing Glucosylceramide Synthase to Promote Mitochondrial Lethality and Potentiate an Anti-Tumor Immune Response in Triple-Negative Breast Cancer

> **NIH NIH R37** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $453,927

## Abstract

Project Summary
 Current approaches to treating triple-negative breast cancer (TNBC) remain unsatisfactory. 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 that may render additional opportunity
for combination with emerging immunotherapy. We have uncovered a novel onco-metabolic feature in TNBC
wherein cancer cells exploit a sphingomyelin lipid scavenging phenotype that is targetable through repurposing
of the selective glucosylceramide synthase inhibitor eliglustat, an FDA approved drug for treatment of Gaucher
Disease. Our preliminary studies demonstrate that eliglustat promotes accumulation of mitotoxic ceramides with
resultant shift from survival mitophagy to lethal mitophagy and subsequent cancer cell death. Moreover, we show
that eliglustat suppresses tumor growth at clinically achievable doses in TNBC tumor-bearing mice and that the
anti-cancer effects of eliglustat are associated with pronounced increases in tumor infiltrating CD4+ and CD8+
T-cells, suggesting an additional role of eliglustat in potentiating an anti-tumor immune response. The primary
objectives of this proposal are to establish novel utility for eliglustat as an ‘immunometabolic adjuvant’ for the
treatment of TNBC and to also define the mechanism(s) by which eliglustat potentiates an anti-cancer immune
response. To test this, we will assess the anti-cancer efficacy of eliglustat in patient-derived xenograft (PDX)
models generated from patients with primary treatment-naïve TNBC that did or did not go on to respond to
chemotherapy (Specific Aim 1a). To test whether the combination of eliglustat plus anti-PD-L1 yields improved
anti-cancer effects compared to either treatment alone, we will use the BRCA1co/co; MMTV-Cre; p53+/- and
4T1 orthotopic syngeneic mouse models of TNBC (Specific Aim 1b). Primary endpoints of interest for in vivo
studies will be overall survival and tumor growth; effects on the tumor immunophenotype following intervention
will be assess using multiplex immunofluorescence panels and single cell transcriptomics for single cell-level
expression profiling of tissues. We also aim to define the mechanisms by which eliglustat induces an anti-cancer
immune response. First, we will evaluate the effect of eliglustat on cGAS-STING signaling proteins and
downstream pathway activities in TNBC cells (Specific Aim 2a). Next, we will use advanced mass spectrometry
technologies coupled with novel isolation methods for extracellular vesicles (EVs) to define the MHC-I bound
peptidome on surfaces of TNBC cells and TNBC-derived circulating and intra-tumor EVs following eliglustat
treatment. ELIspot and Cytotoxic T Cell-based tumor killing live-cell assays will be used to test the functionality
of EVs on activating T-cells ex vivo (Specific Aim 2b). If successful, our potential findings will provide key pre-
clinical evidence for the use of eliglusta...

## Key facts

- **NIH application ID:** 10852003
- **Project number:** 5R37CA269611-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Johannes F Fahrmann
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,927
- **Award type:** 5
- **Project period:** 2023-05-31 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852003

## Citation

> US National Institutes of Health, RePORTER application 10852003, Repurposing Glucosylceramide Synthase to Promote Mitochondrial Lethality and Potentiate an Anti-Tumor Immune Response in Triple-Negative Breast Cancer (5R37CA269611-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10852003. Licensed CC0.

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