論文 - 詳細
| RRC ID | 59791 |
|---|---|
| 著者 | Ji JX, Cochrane DR, Tessier-Cloutier B, Chen SY, Ho G, Pathak KV, Alcazar IN, Farnell D, Leung S, Cheng A, Chow C, Colborne S, Negri GL, Kommoss F, Karnezis A, Morin GB, McAlpine JN, Gilks CB, Weissman BE, Trent JM, Hoang L, Pirrotte P, Wang Y, Huntsman DG. |
| タイトル | Arginine Depletion Therapy with ADI-PEG20 Limits Tumor Growth in Argininosuccinate Synthase-Deficient Ovarian Cancer, Including Small-Cell Carcinoma of the Ovary, Hypercalcemic Type. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Many 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 DESIGN:We 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. RESULTS:Global 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. CONCLUSIONS:Preclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT. |
| 巻・号 | 26(16) |
| ページ | 4402-4413 |
| 公開日 | 2020-8-15 |
| DOI | 10.1158/1078-0432.CCR-19-1905 |
| PII | 1078-0432.CCR-19-1905 |
| PMID | 32409304 |
| PMC | PMC7442649 |
| MeSH | Animals Arginine / antagonists & inhibitors Arginine / genetics Argininosuccinate Synthase / deficiency Argininosuccinate Synthase / genetics* Carcinoma, Small Cell / drug therapy* Carcinoma, Small Cell / genetics Carcinoma, Small Cell / pathology Cell Line, Tumor Cell Proliferation / drug effects Female Humans Hydrolases / pharmacology* Mice Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / genetics Ovarian Neoplasms / pathology Ovary / metabolism Ovary / pathology Parathyroid Hormone-Related Protein / genetics Parathyroid Hormone-Related Protein / immunology Polyethylene Glycols / pharmacology* Proteomics Xenograft Model Antitumor Assays |
| IF | 10.107 |
| リソース情報 | |
| ヒト・動物細胞 | JHOC-5(RCB1520) JHOC-7(RCB1688) JHOC-9(RCB2226) |