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

Award Number: R37CA269611
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/31/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Repurposing Glucosylceramide Synthase to Promote Mitochondrial Lethality and Potentiate an Anti-Tumor Immune Response in Triple-Negative Breast Cancer - 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 eliglustat and justification for moving eliglustat into early phase clinical trials. Given that eliglustat is already FDA-approved for another indication, it has high potential to be readily translated into clinical use, and potentially providing a new paradigm for cancer immunotherapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $480,171 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	4/9/2025	NON-COMPETING CONTINUATION	$432,155
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$48,016
														Subtotal = $480,171

Issue Date FY: 2024 ( Subtotal = $453,927 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	4/8/2024	NON-COMPETING CONTINUATION	$453,927
														Subtotal = $453,927

Issue Date FY: 2023 ( Subtotal = $477,817 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	5/31/2023	NEW	$477,817
														Subtotal = $477,817

Grand Total All Awards = $1,411,915

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

Award Number: R37CA269611

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/31/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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