bims-aspsyn Biomed News
on Asparagine synthetetase
Issue of 2025–08–17
six papers selected by
Victor Tatarskiy, Institute of Gene Biology Russian Academy of Science
  1. Resilience and vulnerabilities of tumor cells under purine shortage stress.
  2. Arginine depletion potentiates standard-of-care chemo-immunotherapy in preclinical models of high-risk neuroblastoma.
  3. Asparaginase Enhances CAR-T Cell Antitumor Immunity by Asparagine Metabolic Reprogramming and Induction of Central Memory Phenotype in ALL.
  4. Repurposing Asparaginase Therapy to Target Cisplatin-Resistant Cancer Cells.
  5. Targeting Arginine Metabolism in Immune Cells for the Treatment of Pulmonary Inflammatory Diseases.
  6. Evaluating Asparaginase Toxicity in Hispanic Patients With Acute Lymphoblastic Leukemia in a Large Safety-Net Hospital.
  1. Clin Cancer Res. 2025 Aug 11.
    Resilience and vulnerabilities of tumor cells under purine shortage stress.
    Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang.
       PURPOSE: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.
    EXPERIMENTAL DESIGN: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.
    RESULTS: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity.
    CONCLUSIONS: Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-1667
  2. J Exp Clin Cancer Res. 2025 Aug 14. 44(1): 239
    Arginine depletion potentiates standard-of-care chemo-immunotherapy in preclinical models of high-risk neuroblastoma.
    Kimberley M Hanssen, Jayne Murray, Ruby Pandher, Stephanie Alfred, Laura D Gamble, Jennifer Brand, Erin Mosmann, Frances K Kusuma, Crystal Mak, Adam Kearns, Alvin Kamili, Caroline Atkinson, Alexis Z Minchaca, Jean Bertoldo, David S Ziegler, Francis Mussai, Paul N M Cheng, Murray D Norris, Jamie I Fletcher, Michelle Haber.
       BACKGROUND: Dysregulated amino acid metabolism creates cancer-specific vulnerabilities. Neuroblastoma tumors have dysregulated arginine metabolism that renders them sensitive to systemic arginine deprivation. Arginase therapy has been proposed as a therapeutic approach for neuroblastoma treatment and has a favorable safety profile in pediatric cancer patients, however optimal therapeutic combinations remain unexplored.
    METHODS: The anti-tumor effects of BCT-100, a pegylated human arginase, were studied in neuroblastoma cell models by metabolite profiling, proteomics, and viability, clonogenicity, and protein translation assays. BCT-100 efficacy was assessed in the Th-MYCN transgenic neuroblastoma mouse model and in neuroblastoma cell line and patient-derived xenograft models.
    RESULTS: In vitro, depletion of arginine by BCT-100 arrested protein translation and cellular proliferation, with effects on clonogenicity enhanced in combination with standard-of-care chemotherapeutics SN-38/temozolomide and mafosfamide/topotecan. In vivo, BCT-100 treatment spared liver arginine while significantly depleting plasma and tumor arginine in Th-MYCN mice, and extended tumor latency (> 100 vs. 45.5 days) in mice pre-emptively treated at weaning. In mice with established tumors, BCT-100 prolonged tumor progression delay when combined with standard-of-care chemo- (> 90 vs. 25 days) or chemo-immuno-therapy (49.5 vs. 35.5 days). Tumor progression delay was also observed in cell line and patient-derived xenografts with BCT-100 treatment, including relapsed/refractory disease models. No increased toxicity was observed with the addition of BCT-100 to established therapies.
    CONCLUSIONS: The arginase BCT-100 profoundly disrupts neuroblastoma growth in vitro and in vivo, an effect enhanced in combination with standard-of-care chemo-immuno-therapy. Our data supports further assessment of arginine-depleting combination therapies as a new treatment strategy for neuroblastoma.
    Keywords:  Arginase; Arginine; Metabolism; Neuroblastoma; Patient-derived xenografts; Preclinical testing
    DOI:  https://doi.org/10.1186/s13046-025-03502-8
  3. Mol Ther. 2025 Aug 12. pii: S1525-0016(25)00650-1. [Epub ahead of print]
    Asparaginase Enhances CAR-T Cell Antitumor Immunity by Asparagine Metabolic Reprogramming and Induction of Central Memory Phenotype in ALL.
    Xinting Zhu, Leng Han, Dingyuan Bai, Lei Yi, Yonghong Zhao, Shuaibing Liu, Run Gan, Bo Xin, Yixing Tu, Jianping Zhang, Yonglong Han, Juan Hao, Zixue Xuan, Cheng Guo, Quanjun Yang.
      High levels of asparagine synthetase (ASNS) in acute lymphoblastic leukemia (ALL) lead to immunotherapy resistance. Our study showed ASNS overexpression (OE) in NALM6-GL cancer cells attenuated CAR-T cells mediated cancer cell lysis. Asparaginase (ASPG) is an approved drug that breaks down circulating asparagine in leukemia cells, thereby depriving cancer cells of asparagine and inhibiting cancer growth. We proposed a hypothesis that ASPG engineered CAR-T cells undergo phenotype switching to overcome immunotherapy resistance in ALL. Coculture killing assay showed ASPG-OE CAR-T cells exhibited increased killing efficacy against ASNS - OE cancer cells by enhancing expression of granzyme B, IFN-γ, and TNF-α, whereas ASPG-KO CAR-T cells showed decreased cancer cells lysis efficiency. Phenotypic analysis revealed that ASPG-OE CAR-T cells exhibited distinct phenotypes, including increasing central memory T cells percentage, while decreasing effector memory T cells and effector memory cells that re-expressed CD45RA cells proportions. This distinct phenotype switch of ASPG - OE CAR-T cells toward central memory T cells exerted the increased killing efficacy against NALM6-GL cells even without ASNS-OE. The in vivo xenograft mouse model confirmed that ASPG-OE CAR-T cells exhibited superior anticancer activity against NALM6-GL cancer cells, while ASPG-KO CAR-T cells exhibited inferior anticancer activity. Taken together, ASPG orchestrates CAR-T cell distinct phenotype toward central memory T cells and reprogramming of asparagine metabolism for the enhancing antitumor immunity.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.08.019
  4. Fundam Clin Pharmacol. 2025 Oct;39(5): e70044
    Repurposing Asparaginase Therapy to Target Cisplatin-Resistant Cancer Cells.
    Jiantao Wang, Nasim Pouryaghoub, Robert Strauss, Jiri Bartek, Si Min Zhang, Sean G Rudd.
       BACKGROUND: Cisplatin and its derivatives remain a cornerstone in the treatment of solid malignancies. Resistance is a major factor limiting their clinical utility.
    OBJECTIVES: In the present study, we set out to interrogate therapeutic approaches to target cisplatin-resistant cancer cells. We focused on therapies exploiting metabolic pathways that are altered in drug-resistant cells. We sought to find an existing therapy that has monotherapy efficacy against cisplatin-resistant cancer cells that can also re-sensitize to cisplatin.
    METHODS: We used lung and ovarian cancer cell lines with acquired resistance to cisplatin together with drug sensitivity assays, conducted both with monotherapies and cisplatin combinations.
    RESULTS: We show that cancer cell lines with acquired resistance to cisplatin have altered levels of enzymes involved in glutamine metabolism, which can result in differential sensitivity to targeted agents. We show that expression of one of these enzymes-the glutamate-cystine antiporter SLC7A11, up-regulated 6-fold in a cisplatin-resistant lung cancer cell line-has potential prognostic significance in lung cancer but not ovarian cancer. After identifying a common dependency of cisplatin-resistant cancer cells upon extracellular glutamine, we then evaluate the utility of the long-standing anti-leukemic therapy asparaginase (ASNase)-which possesses both asparaginase and glutaminase activity-as a potential approach. We show ASNase preferentially inhibits the proliferation of cisplatin-resistant cancer cells and can potentially re-sensitize these cells to cisplatin.
    CONCLUSIONS: Our results underpin the prevalence of altered metabolism in cisplatin-resistant cells and highlight the potential utility of re-purposing ASNase to target these cells, warranting further investigation.
    Keywords:  SLC7A11; asparaginase (ASNase); chemoresistance; cisplatin; glutamine; metabolic rewiring
    DOI:  https://doi.org/10.1111/fcp.70044
  5. Curr Allergy Asthma Rep. 2025 Aug 11. 25(1): 35
    Targeting Arginine Metabolism in Immune Cells for the Treatment of Pulmonary Inflammatory Diseases.
    Hangyu Li, Yuemei Liang, Jingyi Deng, Yisen Cheng, Su Chen, Xinlong Lian, Suidong Ouyang.
       PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of the role of arginine and its metabolic pathways in regulating immune cell function, with a particular focus on their involvement in pulmonary inflammatory diseases. Additionally, it highlights recent advances in therapeutic strategies that target arginine metabolism as a potential therapeutic approach for the treatment of these conditions.
    RECENT FINDINGS: Arginine is a conditionally essential amino acid that plays a pivotal role in numerous physiological processes, including immune regulation, tissue repair, airway tone modulation, and vasodilation. We found emerging evidence underscores that arginine metabolism is tightly controlled by various regulatory mechanisms, with two key enzymes-nitric oxide synthase (NOS) and arginase (ARG)-occupying central roles. These enzymes exert opposing yet coordinated effects within immune cells, contributing to the delicate balance between immune activation and resolution. Dysregulation of arginine metabolism has been implicated in the pathogenesis of several pulmonary inflammatory diseases, including respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. Aberrant arginine metabolic activity in immune cells promotes either excessive inflammation or impaired immune defense, depending on the context. Understanding the immunometabolic functions of arginine offers valuable insights into the mechanisms underlying pulmonary inflammatory diseases. Therapeutic modulation of the arginine metabolic pathway represents a promising strategy for controlling disease progression and improving clinical outcomes, paving the way for the development of novel targeted treatments.
    Keywords:  Arginine metabolism. immune cells. pulmonary inflammatory diseases. therapeutic targets
    DOI:  https://doi.org/10.1007/s11882-025-01216-7
  6. World J Oncol. 2025 Aug;16(4): 342-346
    Evaluating Asparaginase Toxicity in Hispanic Patients With Acute Lymphoblastic Leukemia in a Large Safety-Net Hospital.
    Dominick Zheng, Marcin Dragan, Jeffrey Jang, Sarah Tomassetti.
       Background: Acute lymphoblastic leukemia (ALL) is relatively rare in adults with poor rates of long-term remission. Chemotherapy protocols for adults have been adapted from pediatric protocols, including asparaginase. While asparaginase has shown significant efficacy in pediatric patients, its use in adults is limited due to hepatotoxicity, pancreatitis, and thrombosis. This study seeks to review the toxicity profile in Hispanic adults at a large safety-net hospital.
    Methods: We performed a chart review of patients over the age of 18 with ALL treated with asparaginase. Data were collected between the years of 2015 and 2021 and included demographics, laboratory parameters on diagnosis, treatment details, and information on complications related to treatment.
    Results: A total of 14 Hispanic patients diagnosed with ALL and treated with asparaginase from January 2016 to November 2021 were included in this study. Our patient population had an average body mass index (BMI) of 34 (standard deviation (SD) 8.7), with the majority (64%) classified as obese (BMI ≥ 30). Twelve patients (86%) were Philadelphia chromosome negative. The incidence of grade 3 to 4 hyperbilirubinemia (> 3 times the upper limit of normal (ULN) for serum bilirubin) was six out of 14 patients (43%). The incidence of grade 3 to 4 transaminitis (> 5 times the ULN for alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels) was 13 out of 14 patients (93%). Thrombosis occurred in six out of 14 patients (43%), with one patient experiencing disseminated intravascular coagulation (DIC).
    Conclusions: Our cohort of Hispanic adults experienced transaminitis and hyperbilirubinemia at a high rate (93%). The higher incidence noted in our patients with class III obesity is in line with recent expert recommendations for dose reduction of asparaginase in patients with severe obesity. Our study suggests that our Hispanic population is at higher risk for developing hepatotoxicity after asparaginase use, though this could also be related to the high prevalence of obesity in our population. This is important for future care in selecting candidates for asparaginase therapy including those who may be at higher risk for adverse events.
    Keywords:  Acute lymphoblastic leukemia; Asparaginase; Hispanic; Safety-net; Toxicity
    DOI:  https://doi.org/10.14740/wjon2553
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