{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:47:31Z","timestamp":1785818851800,"version":"3.56.0"},"reference-count":44,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pigment Cell Melanoma Res"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Uveal melanoma is a hard\u2010to\u2010treat arginine\u2010dependent cancer secondary to argininosuccinate synthetase 1 (ASS1) loss with half of patients succumbing to liver\u2010dominant metastases. Arginine deprivation with pegargiminase is a novel antimetabolite strategy for patients with uveal melanoma. We investigated the preclinical rationale for combining pegargiminase with melphalan, an alkylating agent approved recently for the treatment of hepatic\u2010centric disease. Drug sensitivity of ASS1\u2010deficient uveal melanoma cell lines was performed in 2D culture using proliferation and cytotoxicity assays, with analysis of cell death, cell cycle, DNA double\u2010strand breaks, and interrogation of the molecular mechanism of action by RNA\u2010seq. ADI\u2010PEG20 and melphalan suppressed uveal melanoma cell line proliferation and triggered cytotoxicity, effects which were enhanced with the drug combination. ADI\u2010PEG20 downregulated multiple genes of the Fanconi anemia pathway and synergized with melphalan to increase DNA double\u2010strand breaks. Melphalan and pegargiminase is a rational new drug combination that warrants clinical testing in uveal melanoma.<\/jats:p>","DOI":"10.1111\/pcmr.70104","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T04:22:03Z","timestamp":1781929323000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pegargiminase Suppresses the Fanconi Anemia Pathway and Promotes Melphalan\u2010Induced\n                    <scp>DNA<\/scp>\n                    Double\u2010Strand Breaks in Uveal Melanoma"],"prefix":"10.1111","volume":"39","author":[{"given":"Iuliia","family":"Pavlyk","sequence":"first","affiliation":[{"name":"Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)\u2014A Cancer Research UK Center of Excellence, John Vane Science Center Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Field","sequence":"additional","affiliation":[{"name":"Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)\u2014A Cancer Research UK Center of Excellence, John Vane Science Center Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9775-1956","authenticated-orcid":false,"given":"Matthew","family":"Young","sequence":"additional","affiliation":[{"name":"Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)\u2014A Cancer Research UK Center of Excellence, John Vane Science Center Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Carpentier","sequence":"additional","affiliation":[{"name":"Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)\u2014A Cancer Research UK Center of Excellence, John Vane Science Center Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia A.","family":"Szlosarek","sequence":"additional","affiliation":[{"name":"Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)\u2014A Cancer Research UK Center of Excellence, John Vane Science Center Queen Mary University of London  London UK"},{"name":"University of East Anglia  Norwich UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela R.","family":"O'Keeffe\u2010Brown","sequence":"additional","affiliation":[{"name":"Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute (BCI)\u2014A Cancer Research UK Center of Excellence, John Vane Science Center Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Crook","sequence":"additional","affiliation":[{"name":"The London Clinic  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelofer","family":"Syed","sequence":"additional","affiliation":[{"name":"Department of Brain Sciences, Hammersmith Hospital Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Bomalaski","sequence":"additional","affiliation":[{"name":"Polaris Pharmaceuticals Inc.  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