Arginine Depletion Therapy with ADI-PEG20 Limits Tumor Growth in Argininosuccinate Synthase-Deficient Ovarian Cancer, Including Small-Cell Carcinoma of the Ovary, Hypercalcemic Type

Jennifer X. Ji, Dawn R. Cochrane, Basile Tessier-Cloutier, Shary Yutin Chen, Germain Ho, Khyatiben V. Pathak, Isabel N. Alcazar, David Farnell, Samuel Leung, Angela Cheng, Christine Chow, Shane Colborne, Gian Luca Negri, Friedrich Kommoss, Anthony Karnezis, Gregg B. Morin, Jessica N. McAlpine, C. Blake Gilks, Bernard E. Weissman, Jeffrey M. TrentLynn Hoang, Patrick Pirrotte, Yemin Wang, David G. Huntsman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4402-4413
Number of pages12
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume26
Issue number16
DOIs
StatePublished - Aug 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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