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Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase
Open accessAbstract
BACKGROUND: Arginine-depleting therapy with pegylated arginine deiminase (ADI-PEG20) was reported to have activity in advanced melanoma in early phase I-II trial, and clinical trials are currently underway in other cancers. However, the optimal patient population who benefit from this treatment is unknown. METHODS: Advanced melanoma patients with accessible tumours had biopsy performed before the start of treatment with ADI-PEG20 and at the time of progression or relapse when amenable to determine whether argininosuccinate synthetase (ASS) expression in tumour was predictive of response to ADI-PEG20. RESULTS: Twenty-seven of thirty-eight patients treated had melanoma tumours assessable for ASS staining before treatment. Clinical benefit rate (CBR) and longer time to progression were associated with negative expression of tumour ASS. Only 1 of 10 patients with ASS-positive tumours (ASS+) had stable disease, whereas 4 of 17 (24%) had partial response and 5 had stable disease, when ASS expression was negative (ASS-), giving CBR rates of 52.9 vs 10%, P=0.041. Two responding patients with negative ASS expression before therapy had rebiopsy after tumour progression and the ASS expression became positive. The survival of ASS- patients receiving at least four doses at 320 IU m(-2) was significantly better than the ASS+ group at 26.5 vs 8.5 months, P=0.024. CONCLUSION: ADI-PEG20 is safe and the drug is only efficacious in melanoma patients whose tumour has negative ASS expression. Argininosuccinate synthetase tumour positivity is associated with drug resistance and tumour progression.
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“However, the use of arginine-catabolizing enzymes may not be an effective therapeutic strategy for all ASS1-deficient cancers, as some ADI-treated tumors have been found to re-express ASS1 (Feun et al., 2012; Long et al., 2013; Shen et al., 2003).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Feun et al., 2012
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Metadata
- Authors
- Feun, L. G., Marini, A., Walker, G., Elgart, G., Moffat, F., Rodgers, S. E., Wu, C. J., You, M., Wangpaichitr, M., Kuo, M. T., Sisson, W., Jungbluth, A. A., Bomalaski, J., & Savaraj, N.
- Affiliations
- University of Miami (US)
- The University of Texas MD Anderson Cancer Center (US)
- Polaris Group (United States) (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Feun, L G
- Venue
- British Journal of Cancer
- Published
- 2012-04
- Volume
- 106
- Issue
- 9
- Pages
- 1481-1485
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC3341859
- OpenAlex
- W2033556277
- Cited by
- 113
- References
- 33
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 12 · 2022: 6 · 2021: 15 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 10 · 2016: 9 · 2015: 9 · 2014: 13 · 2013: 7 · 2012: 2
- FWCI
- 8.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA109578, R01CA152197)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- argininosuccinate synthetase, melanoma, pegylated arginine deiminase, predictive biomarkers, clinical benefit rate, time to progression, drug resistance, survival
- MeSH terms
- Adult, Aged, Aged, 80 and over, Arginine, Argininosuccinate Synthase, Female, Humans, Hydrolases, Liver Neoplasms, Lung Neoplasms, Male, Melanoma, Middle Aged, Polyethylene Glycols, Skin Neoplasms, Survival Rate, Treatment Outcome
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