journal contribution
posted on 2023-03-31, 22:11 authored by 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. Trent, Lynn Hoang, Patrick Pirrotte, Yemin Wang, David G. Huntsman Mouse models of SCCOHT cell lines. A, Representative histology of kidney and liver from COV434-implanted mouse in the control group, and in the 30mg/kg ADI-PEG20 group which exhibited abnormal organs upon macroscopic examination at necropsy. B, BRG1 IHC for the masses above the heart found in 2 mice in the treatment groups. Top image: mass only (mouse DGH12-2-14); bottom image, mass adjacent to normal heart (mouse DGH12-2-15). C, tumor volume and weight of SCCOHT1 mouse model. Significance was calculated using ANOVA, followed by a post-hoc Tukey's test. Error bars represent standard error of mean. D, ASS1 re-expression in SCCOHT1 cells in both saline control group and 30mg/kg treated groups. E, Representative tunnel assay images from each treatment group indicating no significant increase in apoptosis in tumors from the ADI-PEG20 treated compared to saline-treated groups, and F, COV434 subcutaneous xenograft showing foci of ASS1 re-expression in treated groups. G, average mouse weight of each mouse model, and H, plots reflecting the tumour weight adjusted by mouse weight (tumour weight/mouse weight).
Funding
Canadian Cancer Society Research Institute
NCI
NIH
Terry Fox Research Institute
Canadian Institutes of Health Research
Polaris Pharmaceuticals
History
ARTICLE ABSTRACT
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.
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.
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.
Preclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT.
