EP1108 - ECE_2149 - Nicotinamide phosphoribosyltransferase (NAMPT) inhibition—a novel metabolically-guided personalised therapy for neuroendocrine neoplasia
Year: 2026
Type: conference-abstract
Abstract: Background Tumour cells often display increased reliance on the salvage pathway for nicotinamide adenine dinucleotide (NAD⁺) production, highlighting the rate-limiting enzyme of this pathway, nicotinamide phosphoribosyltransferase (NAMPT), as a potential target for anti-cancer therapy. This study aimed to explore NAMPT inhibition as a novel therapeutic strategy for gastro-enteropancreatic (GEP) neuroendocrine tumours (NETs) and phaeochromocytomas/paragangliomas (PPGLs). Methods We investigated the effects of the NAMPT inhibitor GNE-617, and co-administration of niacin (vitamin B3), in GEP-NET/pulmonary NET and PPGL cell lines and fresh patient-derived GEP-NET/PPGL primary cultures (n = 49, including 1 neuroendocrine carcinoma [NEC] primary culture and 2 corresponding normal tissue primary cultures). We also extended our findings to pancreatic, thyroid and breast cancer cell lines. Additionally, we correlated cell viability data with NAPRT1 protein expression levels. Results We found strong significant anti-tumour effects of the NAMPT inhibitor GNE-617 in NAPRT1-deficient GEP-NET/pulmonary NET, PPGL, pancreatic, thyroid and breast cancer cell lines, and also in the GEP-NET/GEP-NEC and PPGL primary cultures. Niacin co-administration consistently rescued the NAPRT1-expressing cell lines from the anti-tumour effects of NAMPT inhibition, while having no effect in the NAPRT1-deficient cell lines. Niacin was also able to rescue 82% (22/27) of GEP-NET/GEP-NEC primary cultures and 50% (8/16) of PPGL primary cultures from the effects of NAMPT inhibition. In contrast, importantly, in 15% (4/27) of GEP-NET/GEP-NEC primary cultures and in 13% (2/16) of PPGL primary cultures, NAMPT inhibition led to strong anti-tumour effects (mean cell viability ≤60%) without tumour cell-rescue by niacin. Additionally, niacin rescued the normal tissue primary cultures from the effects of GNE-617, but not a corresponding small intestinal NET primary culture—suggesting NAPRT1-deficiency of the tumour but functional NAPRT1-expression in normal tissue. Conclusions Our results suggest that NAPRT1 expression could serve as a critical biomarker for predicting GEP-NET and PPGL tumour response to NAMPT inhibition, as well as potentially guide recommendations for niacin supplementation in patients with GEP-NETs or PPGLs. The pre-selection of patients based on this biomarker could enable precision targeted NAMPT inhibitor therapy of NAPRT1-deficient tumours, while preserving NAPRT1-expressing normal tissue with niacin co-administration.
Authors: Katharina Wang, Julia Hamati, Umberto MacCio, Julian Maurer, Lea Peischer, Astrid Reul, Elena Kuzmenko, Petra Zimmermann, Maximilian Hungbauer, Diana Vetter, José Oberholzer, Thomas Knoesel, Mercedes Robledo, Katharina Schilbach, Christine Spitzweg, Matthias Auer, Ulrike Disko, Christian Lottspeich, Felix Beuschlein, Constanze Hantel, Martin Reincke, Nicole Reisch, Ashley B Grossman, Karel Pacak, Kathrin Zitzmann, Christoph Auernhammer, Svenja Noelting
Institutions: LMU Klinikum, Ludwig-Maximilians-Universität München, University Hospital Zurich, University of Zurich, Pathologisches Institut, Spanish National Cancer Research Centre, Centre for Biomedical Network Research on Rare Diseases, The Royal Free Hospital, University of Oxford, Palacký University Olomouc
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,292
OpenAlex ID: W7213357404
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