A mammalian, glutaminase-free asparaginase enhances venetoclax activity in preclinical AML models with chromosome 7 deletion.
[INTRODUCTION] Acute myeloid leukemia (AML) remains a malignancy with poor prognosis andfrequent resistance to standard therapies, underscoring the urgent need for novel treatmentstrategies.
APA
Majid D, Wang Z, et al. (2025). A mammalian, glutaminase-free asparaginase enhances venetoclax activity in preclinical AML models with chromosome 7 deletion.. Frontiers in oncology, 15, 1606239. https://doi.org/10.3389/fonc.2025.1606239
MLA
Majid D, et al.. "A mammalian, glutaminase-free asparaginase enhances venetoclax activity in preclinical AML models with chromosome 7 deletion.." Frontiers in oncology, vol. 15, 2025, pp. 1606239.
PMID
41743183
Abstract
[INTRODUCTION] Acute myeloid leukemia (AML) remains a malignancy with poor prognosis andfrequent resistance to standard therapies, underscoring the urgent need for novel treatmentstrategies. In this preclinical study, we evaluated the anti-leukemic efficacy of EBD-300, a novelmammalian-derived asparaginase lacking glutaminase activity, in combination with Venetoclax(VEN).
[RESULTS] EBD-300 monotherapy exhibited significant activity in AML cell lines harboringchromosome 7/7q deletions, which are likely dependent on extracellular asparagine due to thepresence of only a single copy of the asparagine synthetase (ASNS) gene - the enzymeresponsible for endogenous asparagine synthesis. The combination of EBD-300 with VENdecreased the IC50 values of some VEN-resistant AML cell lines and reduced the colony-formingcapacity of primary AML patient samples. In patient-derived xenograft (PDX) mouse models,EBD-300, alone or in combination with VEN, significantly reduced leukemic burden in theperipheral blood, bone marrow, and spleen, and improved overall survival in one model.
[DISCUSSION] Although survival benefits were observed in some, but not all, models, suggestingpotential model-specific effects, these findings collectively support a potential therapeutic roleEBD-300 in combination with VEN in AML. While weight loss was observed, EBD-300 mayrepresent a potentially safer alternative to conventional bacterial asparaginases by mitigatingthe adverse effects typically associated with the glutaminase coactivity of the bacterialasparaginases, an observation that requires further investigation.
[RESULTS] EBD-300 monotherapy exhibited significant activity in AML cell lines harboringchromosome 7/7q deletions, which are likely dependent on extracellular asparagine due to thepresence of only a single copy of the asparagine synthetase (ASNS) gene - the enzymeresponsible for endogenous asparagine synthesis. The combination of EBD-300 with VENdecreased the IC50 values of some VEN-resistant AML cell lines and reduced the colony-formingcapacity of primary AML patient samples. In patient-derived xenograft (PDX) mouse models,EBD-300, alone or in combination with VEN, significantly reduced leukemic burden in theperipheral blood, bone marrow, and spleen, and improved overall survival in one model.
[DISCUSSION] Although survival benefits were observed in some, but not all, models, suggestingpotential model-specific effects, these findings collectively support a potential therapeutic roleEBD-300 in combination with VEN in AML. While weight loss was observed, EBD-300 mayrepresent a potentially safer alternative to conventional bacterial asparaginases by mitigatingthe adverse effects typically associated with the glutaminase coactivity of the bacterialasparaginases, an observation that requires further investigation.