Abstract A077: Determining how early ovarian tumors mitigate the immunostimulatory effects of transcribed repetitive elements

Abstract Ovarian high grade serous carcinoma (HGSC) accounts for ∼80% of all ovarian cancer deaths with a devastating 5-year survival of <40%. Frequent relapses following initial response to first-line chemotherapy underscores the urgent clinical need to increase therapeutic options against HGSC. Identifying new therapeutic strategies requires: i) improved understanding of mechanisms underlying HGSC tumorigenesis and ii) exploitation of dependencies established by these mechanisms. Towards this goal, we recently reported a previously unknown mechanism by which early HGSCs evade the immune system. Briefly, premalignant lesions that develop into HGSCs exhibit dysregulated transcription of repetitive elements. A subset of these transcribed repetitive elements form double stranded RNAs (dsRNAs) that induce an antiviral response described as ‘viral mimicry’. Chronic viral mimicry induction diminishes secretion of proinflammatory cytokines that are required to promote adaptive immune responses against premalignant cells. We call this phenomenon ‘viral mimicry evasion’ (Ishak, Marhon et al., Cancer Discovery , 2025). This study explores mechanisms underlying viral mimicry evasion to identify therapeutic vulnerabilities that can be exploited against early HGSCs. Specifically, we explore the hypothesis that viral mimicry evasion establishes dependencies that can be exploited as therapeutic vulnerabilities against HGSC. Using CRISPR screens in cell culture models of early HGSC, our team indeed identifies mechanistic dependencies required by cells to evade lethal viral mimicry. Excitingly, pharmacological inhibition of key mediators of this dependency attenuates tumor growth in preclinical models of HGSC. Altogether, this study improves our understanding of etiology underlying how early HGSCs evade viral mimicry and reveals opportunities to translate identified dependencies into new therapeutic opportunities against HGSC. Citation Format: Charles A. Ishak, Kevin Wanniarachchi, Junwoo Lee. Determining how early ovarian tumors mitigate the immunostimulatory effects of transcribed repetitive elements [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 A077.