Therapeutic NAMPT inhibition reveals a targetable metabolic vulnerability in neuroblastoma

作者：Sophia Varriano, Amy Yu, Abantika Chakraborty, Ariana E. Nelson, Amy E. James, Kristine A. Isanogle, Nimit L. Patel, Caleb Kim, Unsun Lee, Victor J. Collins, Grace B. McKay-Corkum, Ye Yang, Xiaohu Zhang, Crystal G. McKnight, Kelli M. Wilson, Carleen A. Klumpp-Thomas, Michele Ceribelli, David O. Holland, Ming Sun, Gitanjali Asampille, Ying Wu, Krithika Bhuvaneshwar, Brad A. Gouker, Donna O. Butcher, Bhushan L. Thakur, Arnulfo Mendoza, Sameer H. Issaq, Mirit I. Aladjem, Baktiar O. Karim, Jack F. Shern, Parthav Jailwala, Simone Difilippantonio, Craig J. Thomas, Daniel R. Crooks, Rosa Nguyen, Carol J. Thiele, Christine M. Heske · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2026 · DOI：10.1186/s13046-026-03793-5 · 研究领域：Sirtuins and Resveratrol in Medicine、PARP inhibition in cancer therapy、Biochemical and Molecular Research

Abstract Background Neuroblastoma (NB) remains a major cause of pediatric cancer mortality for which new therapeutic strategies are needed. Exploitation of reprogrammed metabolic pathways offers an opportunity for cell-type specific anticancer therapeutics. To identify pediatric solid tumors with an enhanced susceptibility to targeting the nicotinamide adenine dinucleotide (NAD + ) salvage pathway, we performed an unbiased high-throughput screen of over 200 cancer cell line models using inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme in the NAD + salvage pathway. Our analysis identified NB as one of the most sensitive solid tumor types, prompting further investigation of NAMPT inhibition as a potential therapeutic strategy in this disease. Methods Using two early phase clinical NAMPT inhibitors (OT-82 and KPT-9274), we validated screen results using assays of proliferation and survival in a panel of molecularly diverse NB cell lines. Effects on proliferation, survival, NAD + abundance, adenosine triphosphate (ATP) levels, and energy-related metabolites were quantified, and downstream consequences of NAD + -consuming enzymatic pathways were examined. Tolerability, antitumor activity and pharmacodynamic effects of OT-82 were evaluated in three orthotopic NB mouse models. Results In the drug screen, NB models ranked among the most sensitive pediatric solid tumor cells lines to NAMPT inhibition. OT-82 and KPT-9274 potently suppressed prolife...