Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

Abstract

Ovarian clear cell carcinoma (OCCC) is one of the major types of ovarian cancer and is of higher relative prevalence in Asians. It also shows higher possibility of resistance to cisplatin-based chemotherapy leading to poor prognosis. This may be attributed to the relative lack of mutations and aberrations in homologous recombination-associated genes, which are crucial in DNA damage response (DDR), such as BRCA1, BRCA2, p53, RAD51, and genes in the Fanconi anemia pathway. On the other hand, OCCC is characterized by a number of genetic defects rendering it vulnerable to DDR-targeting therapy, which is emerging as a potent treatment strategy for various cancer types. Mutations of ARID1A, PIK3CA, PTEN, and catenin beta 1 (CTNNB1), as well as overexpression of transcription factor hepatocyte nuclear factor-1β (HNF-1β), and microsatellite instability are common in OCCC. Of particular note is the loss-of-function mutations in ARID1A, which is found in approximately 50% of OCCC. ARID1A is crucial for processing of DNA double-strand break (DSB) and for sustaining DNA damage signaling, rendering ARID1A-deficient cells prone to impaired DNA damage checkpoint regulation and hence sensitive to poly ADP ribose polymerase (PARP) inhibitors. However, while preclinical studies have demonstrated the possibility to exploit DDR deficiency in OCCC for therapeutic purpose, progress in clinical application is lagging. In this review, we will recapitulate the preclinical studies supporting the potential of DDR targeting in OCCC treatment, with emphasis on the role of ARID1A in DDR. Companion diagnostic tests (CDx) for predicting susceptibility to PARP inhibitors are rapidly being developed for solid tumors including ovarian cancers and may readily be applicable on OCCC. The potential of various available DDR-targeting drugs for treating OCCC by drawing analogies with other solid tumors sharing similar genetic characteristics with OCCC will also be discussed.

Correlation between clinicopathological factors and clinical outcomes of recurrent epithelial ovarian cancer at a tertiary hospital in Surabaya, Indonesia

“…6 Clear cell carcinoma has many genetic mutations in the AT-rich interaction domain 1a (ARID1A) gene, phosphatidylinositol-4,5-biphosphate 3-kinase catalytic alpha subunit, phosphatase and tensin homolog, and microsatellite instability. 23 The CA-125 level can reflect the patient's tumor burden and an elevated level indicates disease progression. 24 The results of this study confirm with a study in 303 patients which showed CA-125 was significantly associated with recurrence and affects DFS and OS.…”

Advanced ovarian clear cell carcinoma with RAD50 mutation treated by PARP inhibitor pamiparib combined with anti-angiogenesis therapy: a case report

“…About 10% of ovarian cancer patients were found to be associated with genetic risk and the first known susceptibility genes are BRCA1 and BRCA2 [ 6 , 7 ]. Other HRR pathway-related genes (ATM, ATR, CDK12, FANCA, FANCD2 and RAD50) were also found to play an essential role in ovarian cancer pathogenesis [ 8 , 9 ]. Due to the limited knowledge about the molecular etiology of ovarian cancer, if only the BRCA1/2 gene is tested, more than 5% of patients with deleterious variants in other known risk genes will be missed [ 10 , 11 ].…”

Towards Personalized Management of Ovarian Cancer

“…Ovarian clear cell carcinoma (OCCC) is rare, with higher prevalence in Asian populations, and characterized by chemoresistance and poor prognosis. 85 However, pre-clinical evidence suggests PARPi may act as potent chemosensitizers in OCCC 86 and is reviewed in more detail in. 85 Due to its low prevalence, it is challenging to extrapolate data from the small numbers of OCCC patients included in clinical trials of antiangiogenic and immunotherapy agents, although the current evidence is reviewed by Ogasawara et al 87 The same issue plagues the mucinous subtype, with a paucity of cases present in large clinical trials limiting the reliability of conclusions from subtype-specific analysis.…”

“… 85 However, pre-clinical evidence suggests PARPi may act as potent chemosensitizers in OCCC 86 and is reviewed in more detail in. 85 Due to its low prevalence, it is challenging to extrapolate data from the small numbers of OCCC patients included in clinical trials of antiangiogenic and immunotherapy agents, although the current evidence is reviewed by Ogasawara et al 87 The same issue plagues the mucinous subtype, with a paucity of cases present in large clinical trials limiting the reliability of conclusions from subtype-specific analysis. Despite not reaching statistical significance; however, evidence from GOG-0241 and ICON-6 suggest potentially beneficial effects of bevacizumab and cediranib respectively and is reviewed in more detail in.…”