Abstract B081: Targeting Tryptophan Hydroxylase 1 in Neuroendocrine Prostate Cancer

Abstract Background: Advanced prostate cancer has increasingly evolved into a lethal neuroendocrine form, small cell/neuroendocrine prostate cancer (NEPC), as a consequence of the widespread use of highly potent androgen receptor signaling inhibitors in castration-resistant disease, for which the molecular mechanisms remain unclear and no effective therapies currently exist. This study investigates the role, mechanism, and therapeutic targeting potential of TPH1 tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme responsible for peripheral serotonin biosynthesis in NEPC. Methods: TPH1 expression and its association with NEPC were examined in tissue samples using immunohistochemistry and analyzed across multiple publicly available patient datasets. Human prostate cancer (PC) adenocarcinoma and NEPC cells were manipulated for stable overexpression or knockdown of TPH1, respectively, and then analyzed using a range of functional and molecular biology assays both in vitro and in vivo. Results: TPH1 is upregulated in multiple NEPC patient cohorts and in both de novo and therapy-induced NEPC cell models. Wild-type TPH1, but not an enzymatically inactive mutant, promotes neuroendocrine morphology and marker expression in adenocarcinoma cells, indicating that TPH1’s enzymatic activity drives NEPC development. Silencing TPH1 suppresses neuroendocrine plasticity and various aggressive behaviors of NEPC cells, including proliferation, invasion, sphere formation, and tumor xenograft growth. Mechanistically, TPH1 activates mTOR signaling through intracellular serotonin-dependent serotonylation of mTOR at glutamine 2453, leading to the induction of FOXM1 and E2F1, two master transcription factors known to confer neuroendocrine differentiation in NEPC. Additionally, pharmacological inhibition of TPH1 with the clinically available inhibitor LX1606 effectively restricts growth and neuroendocrine marker expression in multiple NEPC cell lines and patient-derived xenografts. Conclusion: These findings suggest that TPH1 is a critical driver of NEPC differentiation and growth, highlighting its potential as a promising therapeutic target for NEPC. Funding Acknowledgements: This work was supported by NIH/NCI grants R01CA279528, R37CA233658, and R01CA258634 to BJW, Department of Defense Prostate Cancer Research Program grant W81XWH-21-1-0218 to J Wei. Citation Format: jing wei, Jing Wang, jingrui chen, Chia-Hui Chen, Boyang Wu. Targeting Tryptophan Hydroxylase 1 in Neuroendocrine Prostate Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B081.