Glutaminase Activity of <scp>L</scp>-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia

Chan, Wai Kin; Horvath, Thomas D.; Tan, Lin; Link, Todd; Harutyunyan, Karine G.; Pontikos, Michael A.; Anishkin, Andriy; Du, Di; Martin, Leona A.; Yin, Eric; Rempe, Susan; Sukharev, Sergei; Konopleva, Marina; Weinstein, John N.; Lorenzi, Philip L.

doi:10.1158/1535-7163.mct-18-1329

Cited by 55 publications

(67 citation statements)

References 16 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…l- asparaginases have variable amount of glutaminase activity as a secondary activity, and whether the glutaminase activity has any clinical relevance is debatable. 21 , 22 Recent studies by Parmentier et al 23 and Chan et al 24 have shown that glutaminase activity is required along with L-asparaginase activity for the effective management of ALL. Many of the toxic adverse effects of l- asparaginase therapy previously were attributed to the l- glutaminase activity.…”

Section: Discussionmentioning

confidence: 99%

Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia

Krishnamurthy

Narula

Gandhi

et al. 2020

JCO Global Oncology

View full text Add to dashboard Cite

PURPOSE Pegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and nonavailability in low- and middle-income countries limits its use. In 2014, the first generic of pegaspargase (Hamsyl) was approved in India for use as a second-line treatment option for ALL. The aim of this study was to assess whether the generic pegaspargase (the test product) was bioequivalent with the reference product (Oncaspar). PATIENTS AND METHODS This study was an open-label, parallel-group, comparative pharmacokinetic study in pediatric patients with relapsed ALL receiving their first dose (1,000 IU/m2) of pegaspargase administered intramuscularly. Patients were randomly assigned 1-to-1 to either the test or the reference product. The 2 formulations were considered equivalent if the 90% CIs for area under the plasma asparaginase activity–time curve (AUC0-t) geometric mean test-to-reference ratio was within 75% to 133%. RESULTS Twenty-nine patients (6-18 years of age) were enrolled in this study, of whom 24 completed the study criteria and were considered for safety analysis (5 patients were ineligible for the assessment). Three patients were excluded from analysis, because of presence of anti-asparaginase antibodies, leaving 21 patients who were considered for bioequivalence pharmacokinetics data. The point estimate of AUC0-t for the test-to-reference ratio was 95.05 (90% CI, 75.07% to 120.33%). Maximum plasma concentration, trough concentrations (day 14), half-life, volume of distribution, drug clearance, and changes in the asparagine and glutamine levels were not significantly different between products. Adverse events were comparable in both groups. CONCLUSION Generic and reference pegaspargase had equivalent pharmacokinetics with comparable safety. This could be a safe and cost-effective alternative for patients with ALL, especially in low- and middle-income countries.

show abstract

Section: Discussionmentioning

confidence: 99%

Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia

Krishnamurthy

Narula

Gandhi

et al. 2020

JCO Global Oncology

View full text Add to dashboard Cite

show abstract

“…Unfortunately, no attempt was made to correlate ASNS protein expression to enzymatic activity. However, more recent results from the same group, obtained with a murine leukemia model of ASNS-null ALL, indicate that, actually, glutaminase activity was needed for a durable suppression of the tumor (32). Further investigation is needed to fully understand the role of cellular Gln levels on ASNase sensitivity and glutaminase action in ALL progression.…”

Section: Low Asns Expression In Acute Lymphoblastic Leukemia: Old Obsmentioning

confidence: 99%

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

et al. 2020

View full text Add to dashboard Cite

Asparagine Synthetase (ASNS) catalyzes the synthesis of the non-essential amino acid asparagine (Asn) from aspartate (Asp) and glutamine (Gln). ASNS expression is highly regulated at the transcriptional level, being induced by both the Amino Acid Response (AAR) and the Unfolded Protein Response (UPR) pathways. Lack of ASNS protein expression is a hallmark of Acute Lymphoblastic Leukemia (ALL) blasts, which, therefore, are auxotrophic for Asn. This peculiarity is the rationale for the use of bacterial L-Asparaginase (ASNase) for ALL therapy, the first example of anti-cancer treatment targeting a tumor-specific metabolic feature. Other hematological and solid cancers express low levels of ASNS and, therefore, should also be Asn auxotrophs and ASNase sensitive. Conversely, in the last few years, several reports indicate that in some cancer types ASNS is overexpressed, promoting cell proliferation, chemoresistance, and a metastatic behavior. However, enhanced ASNS activity may constitute a metabolic vulnerability in selected cancer models, suggesting a variable and tumor-specific role of the enzyme in cancer. Recent evidence indicates that, beyond its canonical role in protein synthesis, Asn may have additional regulatory functions. These observations prompt a re-appreciation of ASNS activity in the biology of normal and cancer tissues, with particular attention to the fueling of Asn exchange between cancer cells and the tumor microenvironment.

show abstract

“…Nevertheless, despite all advances and a high rate of therapeutic success in ALL, several deficiencies of asparaginase therapy have been reported. A still debated question is whether substrate specificity, particularly the l -glutaminase activity, is required for clinical efficiency 10 , or it is mainly a contributor to side effects 11 – 13 .…”

Section: Introductionmentioning

confidence: 99%

Generalized enzymatic mechanism of catalysis by tetrameric l-asparaginases from mesophilic bacteria

Strzelczyk

Zhang

Dyba

et al. 2020

Sci Rep

View full text Add to dashboard Cite

The mechanism of catalysis by the l-glutaminase-asparaginase from Pseudomonas 7A (PGA) was investigated using structural, mass spectrometry, and kinetic data. We had previously proposed mechanism of hydrolysis of l-Asn by the type II l-asparaginase from E. coli (EcAII), but that work was limited to just one enzyme. Based on results presented in this report, we postulate that all homotetrameric l-asparaginases from mesophilic bacteria utilize a common ping-pong mechanism of catalysis consisting of two subsequent nucleophilic substitutions. Several new structures of non-covalent complexes of PGA with different substrates, as well as structures of covalent acyl-enzyme intermediates of PGA with canonical substrates (l-Asp and l-Glu) and an opportunistic ligand, a citrate anion, were determined. The results of kinetic experiments monitored by high-resolution LC/MS, when combined with new structural data, clearly show that the reaction catalyzed by l-glutaminase-asparaginases proceeds through formation of a covalent intermediate, as observed previously for EcAII. Additionally, by showing that the same mechanism applies to l-Asn and l-Gln, we postulate that it is common for all these structurally related enzymes.

show abstract

Glutaminase Activity of L-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia

Cited by 55 publications

References 16 publications

Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia

Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

Generalized enzymatic mechanism of catalysis by tetrameric l-asparaginases from mesophilic bacteria

Contact Info

Product

Resources

About