Abstract 6991: Targeting NONO as a therapeutic strategy for metastatic castration-resistant prostate cancer (CRPC)

Abstract Prostate cancer is among the most prevalent cancers among men, with approximately 300, 000 new cases diagnosed annually. While androgen deprivation therapy (ADT) is effective in controlling early-stage prostate cancer, treatment options are considerably limited once the disease advances to metastatic castration-resistant prostate cancer (CRPC). This progression underscores the critical need for innovative therapeutic strategies to address this difficult-to-treat stage. Resistance to ADT arises when androgen receptor (AR) signaling becomes active even in the absence of ligands. This resistance is often driven by mutations in the ligand-binding domain (LBD) of AR or the expression of alternative AR isoforms that lack the LBD, with ARv7 being the most prominent. ARv7, plays a crucial role in the progression and treatment resistance of advanced prostate cancer, and is a high priority target for drug development. A recent report identified an indirect mechanism for inhibiting the AR pathway through targeting NONO (non-POU domain-containing octamer-binding protein), an RNA binding protein which plays various roles in the nucleus, including transcriptional regulation and RNA splicing. Talus Bio has developed a groundbreaking technology, TF-Scan, the first cell-based global screening platform specifically designed to target transcription factors (TF). TF-Scan integrates functional proteomics, automated cell processing, and machine learning to evaluate a drug’s ability to modulate the activity of DNA-bound proteins in live human cells. Using our platform, we identified several compounds that bind NONO at the residue C145, stabilizing the protein on the RNA, and blocking splicing. Ongoing cross-functional studies aim to validate that NONO inhibition can effectively reduce AR and ARv7 splicing, suppress subsequent protein production, and disrupt the AR- and ARv7-dependent transcriptome. This disruption can potentially impede the growth and survival of prostate cancer cells that rely on these pathways. While these findings are promising, the application of NONO inhibition as a treatment for mCRPC is still under investigation. Further studies are necessary to confirm its efficacy and safety in clinical settings. Citation Format: Brian McEllin, Yang Gao, Bodhi Hueffmeier, Andrea Gutierrez, Julia Robbins, Lillian Tatka, Tonibelle Gatbonton-Schwager, Carolyn Allen, Erin Broderick, Daniele Canzani, William Fondrie, Gaelle Mercenne, Lindsay Pino, Alex Federation. Targeting NONO as a therapeutic strategy for metastatic castration-resistant prostate cancer (CRPC) [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 6991.