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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Therapies that deplete exogenous arginine may be effective in treating malignancies where FH is lost.
“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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- [73]Phillips M Szlosarek PW Arginine metabolism and tumour-associated macrophages Lawrence T Hagemann T Tumour-associated macrophages New York Springer 2012 77 90
- [80]Deorukhkar A Diep N Chatterjee D Diagardjane P Bomalaski J Krishnan S Arginine deiminase: a novel radiosensitizer in pancreatic cancer in vitro and in vivo 2014 ASCO Gastrointestinal Cancers Symposium 2014 Jan 16-18 San Francisco, CA Abstr no. 221
- [103]Szlosarek PW Steele JP Sheaff MT Avril NE Szyszko T Ellis S A randomised phase II trial of pegylated arginine deiminase (ADI-PEG20) in patients with malignant pleural mesothelioma (MPM) 2013 World Conference on Lung Cancer 2013 Oct 27-30 Sydney Abstr no. MO09.02
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Self-citationIdentification of metabolites in plasma for predicting survival in glioblastoma
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Arginine Metabolism in Cancer Biology and Immunotherapy
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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.
- 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 › Cancer Research and Treatments
- 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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