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. 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.
Translational relevance Many rare ovarian cancers lack effective management strategies and are resistant to the standard platinum- and taxane-based chemotherapy. Thus, for a rare ovarian cancer subtype like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) - an aggressive malignancy affecting young women in their twenties, effective targeted therapeutics are urgently needed. We used global proteomics to identify a deficiency in arginosuccinate synthase (ASS1) as a common feature among some rare ovarian cancer subtypes. Using in-vitro and in-vivo models, we demonstrated that the arginine-depriving investigational agent ADI-PEG20 effectively inhibited cell growth in ASS1 deficient ovarian cancers including SCCOHT, establishing it as a potential therapeutic agent for rare ovarian cancer subtypes deficient in ASS1. Further clinical investigation is warranted.
Footnotes
Financial support: This research is supported by funds from the Canadian Cancer Society Research Institute (Impact grant #705647 and Innovation grant #703458), the National Cancer Institute of NIH (United States; 1R01CA195670-01), the Terry Fox Research Institute Initiative New Frontiers Program in Cancer (TFF1021), the Canadian Institute of Health Research Foundation Grant (#154290) and the Janet D. Cottrelle Foundation through the BC Cancer Foundation. The VGH & UBC Hospital Foundation and the BC Cancer Foundation provided funding to OVCARE: BC’s Ovarian Cancer Research Team. J.X.Ji is supported by a Vanier Canada graduate scholarship and UBC-BCCA MD/PhD studentship. D.G. Huntsman is supported by the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology and the Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology).
A conflict of interest disclosure statement: The authors do not have any conflict of interest.