Cited by 229Bacterial Cancer TherapyAmino Acid Enzymes and MetabolismCancer, Hypoxia, and Metabolism

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Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges

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Phillips, Melissa M., Sheaff, Michael T., Szlosarek, Peter W.·2013·Cancer Research and Treatment

DOI 10.4143/crt.2013.45.4.251PMC PMC3893322

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Abstract

Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.

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Fig. 1 Heterogeneity of argininosuccinate synthetase 1 (ASS1) expression in lung adenocarcinoma. Immunohistochemical staining (BD ASS1 antibody 1:500, BioGenex Super Sensitive Detection System) of a non-small cell lung cancer composed of a mixed population of ASS1 positive and negative tumor cells (×400).CC BY-NC · PubMed Central

Fig. 2 Multiagent chemotherapy for arginine auxotrophic cancers. Applying the analogy of ten-pin bowling, a 'strike' is rarely seen in cancer therapy whereas a 'half-strike' is more likely with multiagent drug regimens; various drug combination studies are underway including the example shown here of the triplet, ADI-PEG20, cisplatin and pemetrexed. ASS1, argininosuccinate synthetase 1.CC BY-NC · PubMed Central

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Authors: Phillips, M. M., Sheaff, M. T., & Szlosarek, P. W.
Affiliations: St Bartholomew's Hospital (GB)
Queen Mary University of London (GB)
Corresponding author: Szlosarek, Peter W.
ORCID: Sheaff, Michael T.
Szlosarek, Peter W.
Venue: Cancer Research and Treatment
Publisher: Korean Cancer Association
Published: 2013-12-31
Volume: 45
Issue: 4
Pages: 251-262
ISSN: 1598-2998 (ISSN-L)
2005-9256
DOI: 10.4143/crt.2013.45.4.251
PMC: PMC3893322
OpenAlex: W2106712645
Cited by: 229
References: 105
Citations by year: 2026: 6 · 2025: 19 · 2024: 6 · 2023: 16 · 2022: 43 · 2021: 26 · 2020: 14 · 2019: 11 · 2018: 17 · 2017: 23 · 2016: 18 · 2015: 20 · 2014: 10
FWCI: 2.39
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/3.0/ (tdm)
Locations: Cancer Research and Treatment (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: arginine deprivation, argininosuccinate synthetase 1, argininosuccinate lyase, fumarate hydratase, arginine deiminase, ADI-PEG20, arginase, urea cycle enzymes, epigenetic silencing, melanoma, hepatocellular carcinoma, glioblastoma, renal cell carcinoma, treatment response biomarkers, drug resistance, multimodal therapy

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Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges

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