1. Arginine Depletion Therapy with ADI-PEG20 Limits Tumor Growth in Argininosuccinate Synthase–Deficient Ovarian Cancer, Including Small-Cell Carcinoma of the Ovary, Hypercalcemic Type
- Author
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Ji, Jennifer X, Cochrane, Dawn R, Tessier-Cloutier, Basile, Chen, Shary Yutin, Ho, Germain, Pathak, Khyatiben V, Alcazar, Isabel N, Farnell, David, Leung, Samuel, Cheng, Angela, Chow, Christine, Colborne, Shane, Negri, Gian Luca, Kommoss, Friedrich, Karnezis, Anthony, Morin, Gregg B, McAlpine, Jessica N, Gilks, C Blake, Weissman, Bernard E, Trent, Jeffrey M, Hoang, Lynn, Pirrotte, Patrick, Wang, Yemin, and Huntsman, David G
- Subjects
Biotechnology ,Ovarian Cancer ,Cancer ,Rare Diseases ,Orphan Drug ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Arginine ,Argininosuccinate Synthase ,Carcinoma ,Small Cell ,Cell Line ,Tumor ,Cell Proliferation ,Female ,Humans ,Hydrolases ,Mice ,Ovarian Neoplasms ,Ovary ,Parathyroid Hormone-Related Protein ,Polyethylene Glycols ,Proteomics ,Xenograft Model Antitumor Assays ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeMany rare ovarian cancer subtypes, such as small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), have poor prognosis due to their aggressive nature and resistance to standard platinum- and taxane-based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes.Experimental designWe compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype, high-grade serous ovarian cancer (HGSC), to identify potential therapeutic targets. IHC of tissue microarrays was used as validation of arginosuccinate synthase (ASS1) deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient-derived xenograft mouse models representing SCCOHT.ResultsGlobal proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared with HGSC. Low ASS1 levels were validated through IHC in large patient cohorts. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 12 of 31 cases, and expressed in less than 5% of the tumor cells in 9 of 31 cases. ASS1-deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient-derived mouse xenograft model of SCCOHT, once-a-week treatment with ADI-PEG20 (30 mg/kg and 15 mg/kg) inhibited tumor growth in vivo.ConclusionsPreclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT.
- Published
- 2020