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Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges
Open accessAbstract
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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“and therapies that deplete exogenous arginine (Table 1) may be effective in treating malignancies where FH is lost (Phillips et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Phillips et al., 2013
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Metadata
- 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.
- 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
- 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
- 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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