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Introduction Clear cell ovarian cancer (CCC) accounts for 5-11% of ovarian cancers in North America with a higher frequency reported in cohorts from Japan. CCC usually arises directly from endometriosis, which is associated with oxidative stress. The latter plays a critical role in the pathogenesis of both endometriosis and CCC. CCC is inherently resistant to standard chemotherapies, and the outcomes for patients with advanced stage CCC have not changed in several decades. Therefore, there is an urgent need for new treatment options for advanced CCC. CCC 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 oxidative phosphorylation. 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 high mitochondrial dependence. Complex I plays a role in redox control and the biosynthesis of macromolecules and nucleic acids necessary for cell proliferation. 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 therapeutic 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 metastesis by the ex vivo pulmonary metastasis assay (PuMA). Conclusions Exploiting the vulnerability in reliance on OXPHOS in ARID1A-deficient CCC using EO3001 might represent a promising strategy for the treatment of these patients as well as patients harboring other ARID1A-deficient malignancies. Citation Format: Amal M. EL-Naggar, Yuchen Ding, Lucy Li, Forouh Kalantari, Jeffrey Bacha, Dennis Brown, David Huntsman. Investigating the therapeutic efficacy of EO3001 in clear cell carcinoma of the ovary. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4967.