Abstract 2378: Developing new potent therapeutic strategies for neuroendocrine carcinomas

Abstract Neuroendocrine carcinomas, such as neuroendocrine prostate cancer (NEPC), small cell lung cancer (SCLC), and neuroblastoma, share common histological features, including expression of neuroendocrine markers, rapid relapse after treatment, and poor prognosis. Due to the poor clinical outcome of patients with neuroendocrine carcinomas, there is a critical need to identify new drivers, therapeutic targets, and effective therapeutic strategies for these malignancies. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a protease that has a dual function in regulating protein stability. We demonstrated that UCHL1 is significantly elevated in tissues from patients with NEPC, SCLC, and neuroblastoma. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 stabilizes POM121 to regulate POM121-associated nuclear transport of key transcriptional factors, E2F1 and c-MYC. Here, we developed novel and more potent UCHL1 small molecule inhibitors as a new therapeutic strategy to target neuroendocrine carcinomas. Our new compounds demonstrate high potency with safety profile in vivo for neuroendocrine carcinomas. Importantly, treatment with UCHL1 inhibitors significantly reduces tumor growth of neuroendocrine carcinomas in pre-clinical settings. Our study reveals new mechanisms of UCHL1 function in neuroendocrine carcinomas tumorigenesis, identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosis and monitoring treatment responses in neuroendocrine carcinomas and develops new inhibitors to target UCHL1. Citation Format: Tanya Ivanova Stoyanova. Developing new potent therapeutic strategies for neuroendocrine carcinomas [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 2378.