Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Department of Molecular Oncology, BC Cancer Agency, Vancouver, Canada.
Clin Cancer Res. 2020 Aug 15;26(16):4402-4413. doi: 10.1158/1078-0432.CCR-19-1905. Epub 2020 May 14.
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 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 . 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 .
Preclinical and studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT.
由于其侵袭性和对标准铂类和紫杉烷类化疗的耐药性，许多罕见的卵巢癌亚型，如小细胞卵巢癌、高钙血症型（SCCOHT），预后较差。由于这些肿瘤的罕见性，有效的治疗方法的发展受到了阻碍。我们试图确定罕见卵巢癌亚型中的可靶向弱点。
我们比较了 6 例子宫内膜样卵巢癌（ENOC）、透明细胞卵巢癌（CCOC）和 SCCOHT 以及最常见的高级别浆液性卵巢癌（HGSC）的全球蛋白质组景观，以确定潜在的治疗靶点。使用组织微阵列的 IHC 作为精氨琥珀酸合酶（ASS1）缺陷的验证。使用代表 SCCOHT 的细胞系和患者来源的异种移植小鼠模型评估精氨酸剥夺治疗 ADI-PEG20 的疗效。
与 HGSC 相比，全球蛋白质组分析发现 ENOC、CCOC 和 SCCOHT 中的 ASS1 表达较低。通过大的患者队列中的 IHC 验证了低 ASS1 水平。在 31 例 SCCOHT 中，ASS1 缺失的比例为 12/31，在 31 例中，ASS1 的表达少于肿瘤细胞的 5%。ASS1 缺陷的卵巢癌细胞对 ADI-PEG20 治疗敏感，与亚型无关。此外，在两种细胞系小鼠异种移植模型和一种 SCCOHT 患者来源的小鼠异种移植模型中，每周一次用 ADI-PEG20（30mg/kg 和 15mg/kg）治疗抑制肿瘤生长。
临床前和临床研究表明，ADI-PEG20 可能是包括 SCCOHT 在内的罕见卵巢癌患者的潜在治疗方法。
