Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia

Khokhlatchev, Andrei; Sharma, Aruna; Deering, Tye; Shaw, Jeremy J.P.; Costa-Pinheiro, Pedro; Golla, Upendarrao; Annageldiyev, Charyguly; Cabot, Myles C.; Conaway, Mark R.; Tan, Su‐Fern; Ung, Johnson; Feith, David J.; Claxton, David F.; Fox, Todd E.; Kester, Mark

doi:10.1096/fj.202200765r

Cited by 10 publications

(13 citation statements)

References 45 publications

(84 reference statements)

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“…Long-chain ceramides, such as C16-ceramide, may be more cytotoxic than very long-chain ceramides, such as C24:1-ceramide [29]. We previously demonstrated that elevated C16/C24:1 ceramide ratios are associated with increased cell death [11]. LCL-805 increased both C16- and C24:1-ceramides ( Figure 2E, F ) and C16/C24:1 ceramide ratios ( Figure 2G, H ).…”

Section: Resultsmentioning

confidence: 90%

“…The development of ceramide-generating therapeutics is an enticing antineoplastic strategy as ceramides are important mediators of cell death and cancer cells modulate ceramide catabolism to maintain survival. Elevating intracellular ceramides through exogenous supplementation [10, 11] or metabolic blockade [12, 13] are actively being explored as anticancer therapies.…”

Section: Introductionmentioning

confidence: 99%

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Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Ung,

Tan,

Fox

et al. 2023

Preprint

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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

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Section: Resultsmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Ung,

Tan,

Fox

et al. 2023

Preprint

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“…Future studies should confirm these findings and investigate the pharmacologic vulnerabilities of the two sphingolipid subtypes. Given the promise of targeting sphingolipid metabolism in AML 7,23,24 , we envision that sphingolipidomic subtyping could contribute to tailored treatment selections for AML patients that otherwise lack targetable alternatives.…”

Section: Resultsmentioning

confidence: 99%

Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes

Paudel

Tan

Fox

et al. 2023

Preprint

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Acute myeloid leukemia (AML) is an aggressive disease with complex and heterogeneous biology. Although several genomic classifications have been proposed, there is a growing interest in going beyond genomics to stratify AML. In this study, we profile the sphingolipid family of bioactive molecules in 213 primary AML samples and 30 common human AML cell lines. Using an integrative approach, we identify two distinct sphingolipid subtypes in AML characterized by a reciprocal abundance of hexosylceramide (Hex) and sphingomyelin (SM) species. The two Hex-SM clusters organize diverse samples more robustly than known AML driver mutations and are coupled to latent transcriptional states. Using transcriptomic data, we develop a machine-learning classifier to infer the Hex-SM status of AML cases in TCGA and BeatAML clinical repositories. The analyses show that the sphingolipid subtype with deficient Hex and abundant SM is enriched for leukemic stemness transcriptional programs and comprises an unappreciated high-risk subgroup with poor clinical outcomes. Our sphingolipid-focused examination of AML identifies patients least likely to benefit from standard of care and raises the possibility that sphingolipidomic interventions could switch the subtype of AML patients who otherwise lack targetable alternatives.

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“…Finally, several studies have tried to better understand the role of OXPHOS [ 110 ], mitochondrial respiration [ 111 ], amino acids [ 112 ], and lipids such as fatty acids [ 113 , 114 , 115 , 116 ], nicotinamide [ 117 ], and ceramide [ 118 , 119 ], in VEN response. It is likely that a better understanding of the integrated stress response (ISR) mediated by the ATF4 transcription factor will help to fill the gap between cell death, metabolism, and VEN resistance [ 46 , 91 , 106 , 120 ].…”

Section: Non-genetic Factors Driving Venetoclax Efficacymentioning

confidence: 99%

Venetoclax Resistance in Acute Myeloid Leukemia

Garciaz,

Hospital,

Collette

et al. 2024

Cancers

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Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need. Clinical and preclinical studies have been conducted to identify factors driving resistance. Among them, the most documented are molecular alterations including IDH, FLT3, TP53, and the newly described BAX mutations. Several non-genetic factors are also described such as metabolic plasticity, changes in anti-apoptotic protein expression, and dependencies, as well as monocytic differentiation status. Strategies to overcome venetoclax resistance are being developed in clinical trials, including triplet therapies with targeted agents targeting IDH, FLT3, as well as the recently developed menin inhibitors or immunotherapies such as antibody–drug conjugated or monoclonal antibodies. A better understanding of the molecular factors driving venetoclax resistance by single-cell analyses will help the discovery of new therapeutic strategies in the future.

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Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia

Cited by 10 publications

References 45 publications

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes

Venetoclax Resistance in Acute Myeloid Leukemia

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