Abstract C119: E7130’s tumor microenvironment ameliorating activity enhances treatment efficacy in urothelial carcinoma

Abstract Background: E7130 is a novel anticancer agent created during a study of the total synthesis of natural product norhalichondrin B. Previous preclinical studies have shown that E7130 had both antiproliferative activity against cancer cells as well as tumor microenvironment (TME) ameliorating activities featuring vascular remodeling effect and anti-CAF (cancer-associated fibroblasts) effect. These TME ameliorating activities of E7130 contributed to its significant combination efficacy with fulvestrant in ER+ breast cancer models, cetuximab in head and neck squamous cell carcinoma models, enzalutamide in castration-resistant prostate cancer models. TME alterations, including CAF activation and intratumoral hypoxia, are known to drive tumor malignancy and lead to therapy resistance in urothelial carcinoma as well. In this study, we examined the TME ameliorating activities-dependent antitumor activity of E7130 in urothelial cancer (UC) models. Methods: Several human UC cell lines were subcutaneously implanted to establish αSMA-positive-CAF-rich and αSMA-positive-CAF-poor UC xenograft models. Histological changes following E7130 treatment were assessed via immunohistochemical staining for αSMA ,CD31 and CA9. The antitumor efficacy of E7130 monotherapy and combination therapy with gemcitabine or erdafitinib was evaluated in UC xenograft models. The correlation between UC patient survival time and CAF-related gene expression was investigated using the TCGA database. Summary: E7130 demonstrated significantly stronger antitumor activity than gemcitabine and paclitaxel in UC xenograft models. Combination therapy of E7130 with gemcitabine significantly inhibited tumor growth compared with monotherapies alone in αSMA-positive-CAF-rich models, but not in αSMA-positive-CAF-poor model. Histological analyses revealed that E7130 treatment reduced αSMA-positive-CAF, and decreased intratumoral hypoxic regions in αSMA-positive-CAF-rich models. In sequential combination therapy, pretreatment of E7130 followed by erdafitinib showed superior antitumor activity to posttreatment of E7130 following erdafitinib, suggesting that TME ameliorating activity of E7130 contributes to enhanced combination therapy efficacy. Database analysis revealed a clear correlation between UC patient survival time and CAF-related genes downregulated by E7130 treatment. Conclusions: E7130 demonstrated potent antitumor activity as monotherapy and in combination with gemcitabine and erdafitinib in UC xenograft models. Mechanistic analyses indicated that TME ameliorating effects of E7130 enhanced combination therapy efficacy by reducing αSMA-positive CAF and decreasing intratumoral hypoxic regions. These findings suggest that E7130 may be a promising antitumor agent and warrants further investigation. Citation Format: Takanori Abe, Shogo Yamaguchi, Ken Ito, Hiroki Jozawa, Ryoga Ishida, Osamu Asano. E7130’s tumor microenvironment ameliorating activity enhances treatment efficacy in urothelial carcinoma [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 C119.