Introduction: Ovarian clear cell carcinoma (OCCC) accounts for 5-11% of ovarian cancers in North America with a higher frequency reported in East Asia cohorts. OCCC is inherently resistant to standard chemotherapies, and the outcomes for advanced stage OCCC have not changed in several decades. Therefore, there is an urgent need for new treatment options for OCCC.
OCCC possess a distinct genetic profile; >50% harbour ARID1A mutations typically resulting in loss of protein function and often with co-occurrence of PIK3CA mutation or gene amplification leading to PI3K/AKT pathway hyper-activation. ARID1A mutations leads to accumulation of ROS, decrease in GSH due to downregulation of SLC7A11 and related reduction in the GSH precursor cystine thereby rendering cancer cells highly dependent on OXPHOS.
EO3001 is a small-molecule drug candidate with selective activity against ARID1A-deficient cell lines in vitro. It has been shown that EO3001 directly binds and inhibits FDX-1 function to block iron-sulfur cluster formation in complex I, a critical component of the mitochondrial electron transport chain. Iron–sulfur clusters play a critical role in the oxidation-reduction reactions of electron transport in mitochondria relied on by cancer cells that have made an adaptive shift from glycolysis to OXPHOS. It is suggested that these complex I-dependent events contribute to tumor formation, resistance to cell death, and metastasis of cancer cells, in part by causing an increase in ROS levels.
Methods: We generated isogenic ovarian cancer cell lines (RMG-1 and OVCA438, -/+ ARID1A loss) using CRISPR/Cas9. We will assess effects of EO3001 on cells’ tumorigenic potential in vitro -under ambient and stress conditions, notably endometriotic cyst content which derives malignant transformation, and in vivo on cell viability, cell proliferation, ROS levels, migration, invasion, and metastasis. We will use the organoids modeling system -using primary endometrial cells harboring ARID1A mutations- to assess the impact of EO3001 on organoid growth and response to stress conditions and evaluate the effect of EO3001 on cancer metastases by the ex vivo pulmonary metastasis assay (PuMA).
Conclusions: Exploiting the vulnerability in reliance on OXPHOS in ARID1A-deficient OCCC using EO3001 may represent a promising strategy for the treatment of cancers harboring ARID1A-deficient malignancies.