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Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

SIMPLE SUMMARY: L-asparaginase (L-ASNase) therapy is key for achieving the very high cure rate of pediatric acute lymphoblastic leukemia (ALL), yet its use is mostly confined to this indication. One main reason preventing the expansion of today’s FDA-approved L-ASNases to solid cancers is their high...

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Autores principales: Van Trimpont, Maaike, Peeters, Evelien, De Visser, Yanti, Schalk, Amanda M., Mondelaers, Veerle, De Moerloose, Barbara, Lavie, Arnon, Lammens, Tim, Goossens, Steven, Van Vlierberghe, Pieter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870365/
https://www.ncbi.nlm.nih.gov/pubmed/35205650
http://dx.doi.org/10.3390/cancers14040902
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author Van Trimpont, Maaike
Peeters, Evelien
De Visser, Yanti
Schalk, Amanda M.
Mondelaers, Veerle
De Moerloose, Barbara
Lavie, Arnon
Lammens, Tim
Goossens, Steven
Van Vlierberghe, Pieter
author_facet Van Trimpont, Maaike
Peeters, Evelien
De Visser, Yanti
Schalk, Amanda M.
Mondelaers, Veerle
De Moerloose, Barbara
Lavie, Arnon
Lammens, Tim
Goossens, Steven
Van Vlierberghe, Pieter
author_sort Van Trimpont, Maaike
collection PubMed
description SIMPLE SUMMARY: L-asparaginase (L-ASNase) therapy is key for achieving the very high cure rate of pediatric acute lymphoblastic leukemia (ALL), yet its use is mostly confined to this indication. One main reason preventing the expansion of today’s FDA-approved L-ASNases to solid cancers is their high toxicity and side effects, which become especially challenging in adult patients. The design of optimized L-ASNase molecules provides opportunities to overcome these unwanted toxicities. An additional challenge to broader application of L-ASNases is how cells can counter the pharmacological effect of this drug and the identification of L-ASNases resistance mechanisms. In this review, we discuss recent insights into L-ASNase adverse effects, resistance mechanisms, and how novel L-ASNase variants and drug combinations can expand its clinical applicability, with a focus on both hematological and solid tumors. ABSTRACT: L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.
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spelling pubmed-88703652022-02-25 Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy Van Trimpont, Maaike Peeters, Evelien De Visser, Yanti Schalk, Amanda M. Mondelaers, Veerle De Moerloose, Barbara Lavie, Arnon Lammens, Tim Goossens, Steven Van Vlierberghe, Pieter Cancers (Basel) Review SIMPLE SUMMARY: L-asparaginase (L-ASNase) therapy is key for achieving the very high cure rate of pediatric acute lymphoblastic leukemia (ALL), yet its use is mostly confined to this indication. One main reason preventing the expansion of today’s FDA-approved L-ASNases to solid cancers is their high toxicity and side effects, which become especially challenging in adult patients. The design of optimized L-ASNase molecules provides opportunities to overcome these unwanted toxicities. An additional challenge to broader application of L-ASNases is how cells can counter the pharmacological effect of this drug and the identification of L-ASNases resistance mechanisms. In this review, we discuss recent insights into L-ASNase adverse effects, resistance mechanisms, and how novel L-ASNase variants and drug combinations can expand its clinical applicability, with a focus on both hematological and solid tumors. ABSTRACT: L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability. MDPI 2022-02-11 /pmc/articles/PMC8870365/ /pubmed/35205650 http://dx.doi.org/10.3390/cancers14040902 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Van Trimpont, Maaike
Peeters, Evelien
De Visser, Yanti
Schalk, Amanda M.
Mondelaers, Veerle
De Moerloose, Barbara
Lavie, Arnon
Lammens, Tim
Goossens, Steven
Van Vlierberghe, Pieter
Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy
title Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy
title_full Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy
title_fullStr Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy
title_full_unstemmed Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy
title_short Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy
title_sort novel insights on the use of l-asparaginase as an efficient and safe anti-cancer therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870365/
https://www.ncbi.nlm.nih.gov/pubmed/35205650
http://dx.doi.org/10.3390/cancers14040902
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