Abstract IA018: Advancing precision therapy through molecular profiling and targeting DNA replication vulnerabilities in ovarian cancer

Abstract Ovarian cancer remains the most lethal gynecologic malignancy, with five-year survival rates below 50% largely due to late-stage diagnosis and the development of drug resistance. The advent of precision medicine offers new opportunities to improve patient outcomes. To date, molecular profiling has identified key therapeutic targets in ovarian cancer, including homologous recombination deficiency (HRD), BRCA mutations, and mismatch repair defects. PARP inhibitors have demonstrated significant clinical benefit in patients with HRD-positive tumors. Also, folate receptor alpha (FRa) targeting antibody drug conjugate, mirvetuximab soravtansine has demonstrated improved overall survival in platinum resistant ovarian cancer expressing high levels of FRa. To exploit DNA replication vulnerabilities in ovarian cancer cells, inhibitors of cell cycle regulators ATR and CHK1, have been studied in ovarian cancer preclinical and clinical settings. DHX9 helicase inhibition represents another novel approach, targeting RNA/DNA helicase activity critical for transcriptional regulation and DNA repair processes in cancer cells. Additional emerging targets include KIF18A that regulates mitotic progression and microtubule dynamics, which have demonstrated selective activity in chromosomally instable high-grade serous ovarian cancer cells. Novel therapeutic targets such as DHX9 helicase and KIF18A, offer new opportunities for patients with limited treatment options. Future directions include expanding biomarker testing, developing combination therapeutic strategies that exploit multiple vulnerabilities simultaneously, and addressing resistance mechanisms. Citation Format: Jung-Min Lee. Advancing precision therapy through molecular profiling and targeting DNA replication vulnerabilities in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr IA018.