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Arginine depletion through ADI-PEG20 to treat argininosuccinate synthase deficient ovarian cancer, including small cell carcinoma of the ovary, hypercalcemic type

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

Posted 17 Nov 2019
bioRxiv DOI: 10.1101/845586

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. Immunohistochemistry of tissue microarrays were used as validation of 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 to HGSC. Low ASS1 levels were validated through IHC in a large patient cohort. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 2/15 cases, and expressed in less than 5% of the tumor cells in 8/15 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 of ADI-PEG20 (30mg/kg and 15mg/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.

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