Abstract 4292: Targeting YB-1 as a treatment strategy for high-grade serous ovarian carcinoma

Background: High-grade serous ovarian carcinoma (HGSC) is an aggressive type of ovarian cancer, accounting for 75% of ovarian epithelial cancers. It is often diagnosed at advanced stages and frequently develops treatment resistance, resulting in poor survival rates. A key protein associated with this resistance is Y-box binding protein 1 (YB-1), which binds to both RNA and DNA. We hypothesize that pharmacological inhibition of YB-1 may enhance HGSC treatment effectiveness and reduce the development of treatment resistance. Method: We collected tumor tissue and adjacent normal tissue samples from HGSC patients whose disease relapsed after receiving four to six different therapies. These tissues were used for proteomics, multiplex immunohistochemistry (mIHC), and to create patient-derived xenograft (PDX) models. In mice, the PDX tumors were subjected to treatment with a combination therapy of YB-1 inhibition and chemotherapy agents. Additional proteome analysis was conducted on mouse HGSC cells. Results: Proteome profiling of patient HGSC samples revealed that malignant tissues significantly overexpress YB-1 and related mRNA processing pathways in comparison to adjacent normal tissues. mIHC analysis of patient HGSC tissue indicated high YB-1 expression correlated with low infiltration of CD45-positive immune cells. In vivo mouse studies using the PDX models derived from HGSC samples indicated that treatment with a YB-1 inhibitor (monotherapy with SU056) slowed tumor progression and enhanced sensitivity to cisplatin and paclitaxel. Consistent with the analysis of patient tissues and PDX models, both in vitro and in vivo studies of mouse cell lines indicated that treatment with SU056 hindered tumor growth and the development of treatment resistance. Furthermore, proteome profiling of mouse HGSC cells treated with SU056 corroborated the patient tissue observations, demonstrating that YB-1 inhibition resulted in the downregulation of mRNA processing-associated pathways. Conclusions: Combination therapy using a YB-1 inhibitor with chemotherapy enhances chemotherapeutic responses in HGSC PDX models. Citation Format: Dhanir Tailor, Fernando Jose Garcia-Marques, Abel Bermudez, Wenqi Li, Arpit Dheeraj, Annah Rolig, Chia-Feng Tsai, Tao Liu, Tanja Pejovic, Sharon J. Pitteri, Sanjay V. Malhotra. Targeting YB-1 as a treatment strategy for high-grade serous ovarian carcinoma [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 4292.