Abstract 1771: Ecubectedin's role in targeting transcriptional regulators in neuroendocrine prostate cancer
Authors: Laura Almalé, Maria José Guillen, Paula Diaz, Ismael Fernández-Miranda, Paula Iglesias, Marcelo Lima Ribeiro, Maria Ovejero-Sánchez, Elena Castro, Pedro P. López-Casas, Carmen Cuevas, Pablo Avilés, David Olmos
Journal: Cancer Research (2025)

Abstract Introduction: Neuroendocrine prostate cancer (NEPC) is a highly aggressive variant of prostate cancer with poor clinical outcomes and limited treatment options, highlighting the urgent need for therapies targeting its unique molecular profile of ecubectedin, a novel inhibitor of transcription from the ecteinascidin’s family, in both in vitro and in vivo models of NEPC. Methodology: Human NEPC cells, NCI-H660, along with eight NE-SCLC cell lines (as the well-known NE model) were treated with ecubectedin for 72 hours. Cell viability was assessed using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) short-term assay. Treatment-induced changes in gene expression profiles were analyzed by bulk RNA sequencing. In vivo antitumoral activity of ecubectedin was evaluated in in two human-derived NEPC models: H660 (cell-derived xenograft or CDX) and CP-IBI-034 (a transformed NEPC patient-derived xenograft or PDX obtained from a liver metastasis, confirmed histologically). Both H660 and CPI-IBI-034 were implanted subcutaneously (s.c.) in athymic nu/nu mice. Ecubectedin/placebo was intravenously (i.v.) administered (at 0.75 mg/kg) on days 0, 7 and 14 in n=6-8 mice per arm and model. Results: Ecubectedin markedly reduced NCI-H660 cell viability in similar proportions to NE-SCLC, with an average IC50 of 2.3 nM. At a transcriptional level, ecubectedin induced significant downregulation of key NE regulators, including ASCL1, NEUROD1, POU3F2, MYCN, EZH2 and SOX2, in both NEPC and NE-SCLC. In CP-IBI-034 tumor bearing mice, ecubectedin significantly reduced (vs placebo) the tumor volume during the experimental phase (up to Day 35) with a 22% of ecubectedin-treated mice resulting in complete tumor remissions. In H660 xenografts, a significantly antitumor activity (vs placebo) was also observed with complete tumor remissions in 100% of mice that lasted until the end of the experiment (Day 91). Conclusions: Ecubectedin may impact transcriptional networks driving the cell plasticity and NE transformation in NEPC tumors. More importantly, a significant in vitro and in vivo antitumor activity of ecubectedin was observed in NEPC models, suggesting a significant potential as a promising novel therapeutic for this indication associated to very poor outcomes. Citation Format: Laura Almalé, Maria José Guillen, Paula Diaz, Ismael Fernández-Miranda, Paula Iglesias, Marcelo Lima Ribeiro, Maria Ovejero-Sánchez, Elena Castro, Pedro P. López-Casas, Carmen Cuevas, Pablo Avilés, David Olmos. Ecubectedin's role in targeting transcriptional regulators in neuroendocrine 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 1771.