Abstract 524: An integrative approach to unveiling biomarkers and therapeutic targets identifies novel treatment strategy for advanced prostate cancer

Abstract Advanced prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men in United states. Despite advances in treatment modalities, patients still develop resistance to treatment. Limited studies have focused on targeted therapeutic approach addressing the heterogeneity of the disease. However, a comprehensive multi-omics approach that integrates transcriptomic and proteomic profiles can discover pathways associated with the development of both primary and acquired resistance and remains a critical factor in identifying predictive markers of treatment efficacy to investigate new therapeutic options. In this study, we performed LC-MS/MS and downstream analysis in established patient derived xenograft (PDX) models of advanced castrated resistant PCa (CRPC) to detect protein abundance and enriched pathway. All terms and pathways with an FDR <0.05 after BH adjustment were used. To integrate and determine concordance, transcriptomic followed by enrichment pathway analysis was performed, revealing commonly enriched pathways at the proteomics and transcriptomics level. These data formed the bases for a biomarker-specified library of 100 FDA approved drugs for high throughput screening. Amongst all drugs tested, Trifluridine, previously FDA approved for viral eye infection and in combination with Tipiracil, approved for metastatic colorectal cancer, emerged as a promising candidate. Trifluridine in combination with enzalutamide, showed reduced cell proliferation in CRPC models. The potential of Trifluridine was further highlighted in CRPC cells exhibiting synergism when combined with PARP inhibitors. The synergistic impact of trifluridine alone or in combination will potentially enhance treatment efficacy in overcoming drug resistance by perhaps targeting the DNA repair mechanism. Therefore, our hypothesis is that repurposing Trifluridine alone or in combination with standard of care will be benefitable for treatment-resistant prostate cancers. Our current study has shown that changes in the proteomic landscape that are in concordance with changes at the transcriptomic level are associated with treatment resistance and can direct the best treatment option. This approach identified an FDA approved drug, trifluridine, that can be repurposed for treatment of CRPC, offering a promising treatment strategy for advanced disease. In summary, our studies highlight the unique benefits of using an integrative approach to unveil novel biomarkers and targets for enhanced therapeutic strategies for CRPC. Citation Format: Shreya Shyam Sundar, Ephraim J. Gardner, Surendra Gulla, Remi Adelaiye-Ogala. An integrative approach to unveiling biomarkers and therapeutic targets identifies novel treatment strategy for advanced prostate 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 524.