Abstract 7239: Investigating the role of topoisomerase IIB in the regulation of antigen presentation pathway in high-grade serous ovarian cancer

Abstract Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy and accounts for 90% of ovarian tumors. High grade serous ovarian cancer (HGSOC), an aggressive subtype of EOC, develops rapidly and is correlated with poor prognosis. Importantly, HGSOC accounts for 70-80% of deaths related to ovarian cancer. Immunotherapies that have revolutionized the field of cancer therapy demonstrate limited therapeutic efficacy in HGSOC. HGSOC tumors are characterized by low immune cell infiltration and reduced anti-tumor immune response. Hence, it is crucial to develop new therapeutic strategies that improve anti-tumor immune response in HGSOC. Epigenetic suppression of antigen processing and presentation pathway (APP) is one of the major mechanisms adopted by cancer cells to escape T-cell cytotoxicity. APP entails binding of the cytotoxic CD8+ T cells to neoantigen presented by Major Histocompatibility Complex Class I (MHC class I) on the membrane of cancer cells. Neoantigen recognition by CD8+ T cells lead to activation of CD8+T cells and subsequent killing of the antigen-presenting cells (APC). Previous studies have demonstrated that defects in the expressions and functions of APP components correlate with reduced T-cell infiltration, metastasis, and poor overall survival. Our bioinformatics analysis of publicly available ovarian cancer patient dataset from The Cancer Genome Atlas (TCGA) and ovarian cancer cell line database (Depmap) revealed DNA topoisomerase 2-beta (TOP2B) as a potential negative regulator of APP. TOP2B is a topoisomerase that regulates the transcription of its target genes by altering the topological state of DNA. Recently, a small molecule inhibitor, CX-5461, was discovered to specifically target TOP2B. It has also completed Phase I clinical trials for solid tumor and hematological malignancies demonstrating its safety and efficacy in human patients. Understanding the role of TOP2B in cancer progression may lead to the development of a novel therapeutic strategy to improve overall survival of HGSOC patients. Citation Format: Shraddha G. Gupta, Sangeeta Kumari, Adam Karami, Aisha Jamil, Sergey Karakashev. Investigating the role of topoisomerase IIB in the regulation of antigen presentation pathway in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7239.