Abstract C135: CBL0137 as a promising therapeutic strategy for anaplastic, treatment-emergent neuroendocrine prostate cancer

Abstract Treatment-emergent neuroendocrine prostate cancer (tNEPC) is a highly aggressive, anaplastic form of prostate cancer with no effective curative treatments. Accordingly, there is an urgent clinical need to find novel therapeutic targets and/or strategies to improve the survival outcomes of men harbouring tNEPC. Recent studies have identified overexpression of the facilitates chromatin transcription (FACT) complex in anaplastic tumours, and in particular those possessing a neuroendocrine phenotype. Recently, a curaxin-based molecule, CBL0137, has been shown to be an effective targeted-agent for inhibiting FACT function. Therefore, this study aims to assess the effect of CBL0137 as a novel targeted treatment for tNEPC, both as a monotherapy and as a co-therapy alongside the standard platinum-based chemotherapy, cisplatin and characterise the molecular consequences of CBL0137 by multi-omic profiling. By taking advantage of several clinically relevant ex-vivo patient-derived xenograft organoid (PDXO) models, anti-tumour activity of CBL0137 was evaluated and has further probed its therapeutic potential as a companion therapy with cisplatin. This project also conducts a comprehensive multi-omic investigation into the molecular mechanisms enacted by CBL0137. CBL0137 exhibits potent inhibitory effects across all the PDXO models tested, with calculated IC50 values in low micromolar ranges confirming its strong anti-tumour activity against tNEPC. Western blot analysis revealed a marked reduction in tumour proliferation and enhanced apoptotic mechanisms following CBL0137 treatment. Notably, combination treatment with cisplatin and CBL0137 resulted in improved therapeutic efficacy compared to either drug alone, indicating a potential beneficial effect that enhances overall treatment response. Mechanistically, CBL0137 upregulated p53-mediated tumour suppression, and induced cell cycle arrest via p21 in NEPC models. In conclusion, our findings confirmed that CBL0137 demonstrates robust anti-tumour activity across diverse NEPC PDXO models, significantly suppressing tumour proliferation and enhancing therapeutic efficacy when combined with cisplatin. The co-treatment consistently outperformed either drug alone, highlighting its potential as a more effective strategy for aggressive NEPC. Ongoing multi-omic profiling will further unravel the molecular consequences of CBL0137 treatment and support the development of improved therapeutic approaches for patients with anaplastic and treatment-resistant prostate cancer phenotypes. Citation Format: Sayuri Herath, Charles Bidgood, Momin Rahman, Thomas Tang, Nataly Stylianou, Melanie Lehman, Anja Rockstroh, Himisha Beltran, Arun Azad, Katerina Gurova, Yuzhuo Wang, Martin Gleave, Eva Corey, Jennifer Gunter, Colleen Nelson, Brett Hollier. CBL0137 as a promising therapeutic strategy for anaplastic, treatment-emergent neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C135.