Therapeutic NAMPT inhibition reveals a targetable metabolic vulnerability in neuroblastoma.
10 affiliations
- 1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRC, Room 1W-3816, Bethesda, MD, 20892, USA.
- 2Animal Research Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
- 3Small Animal Imaging Program, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
- 4Clinical Cancer Metabolism Facility, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- 5Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
- 6Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
- 7Molecular Histopathology Laboratory, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
- 8Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- 9Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- 10Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRC, Room 1W-3816, Bethesda, MD, 20892, USA. [email protected].
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 proliferation and viability across multiple molecularly diverse NB models in an on-target manner. Mechanistically, NAMPT inhibition resulted in rapid depletion of NAD⁺ and ATP, disruption of energy metabolism, accumulation of DNA damage, and induction of irreversible non-apoptotic cellular death. In vivo, OT-82 was well tolerated and produced marked antitumor activity, including tumor regressions in orthotopic NB models, including several with regional liver metastases. Pharmacodynamic analysis confirmed intratumoral NAD⁺ depletion during treatment, demonstrating on-target pathway inhibition in vivo.Conclusions
These findings identify NB as a highly NAMPT inhibitor-sensitive pediatric solid tumor and establish NAMPT-dependent NAD⁺ biosynthesis as a targetable metabolic vulnerability in this disease. By integrating an unbiased discovery screen with mechanistic and orthotopic in vivo validation using clinically relevant inhibitors, this study provides a strong translational rationale for clinical investigation of NAMPT inhibitors in NB.
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BibTeX
@article{varriano2026therapeutic,
title = {{Therapeutic NAMPT inhibition reveals a targetable metabolic vulnerability in neuroblastoma.}},
author = {Sophia Varriano and Amy Yu and Abantika Chakraborty and Ariana E Nelson and Amy James and Kristine Isanogle and Nimit Patel and Caleb Kim and Unsun Lee and Victor J Collins and Grace B McKay-Corkum and Ye Yang and Xiaohu Zhang and Crystal McKnight and Kelli Wilson and Carleen Klumpp-Thomas and Michele Ceribelli and David Holland and Ming Sun and Gitanjali Asampille and Ying Wu and Krithika Bhuvaneshwar and Brad Gouker and Donna Butcher and Bhushan L Thakur and Arnulfo Mendoza and Sameer H Issaq and Mirit I Aladjem and Baktiar O Karim and Jack F Shern and Parthav Jailwala and Simone Difilippantonio and Craig J Thomas and Daniel R Crooks and Rosa Nguyen and Carol J Thiele and Christine M Heske},
journal = {Journal of experimental \& clinical cancer research : CR},
year = {2026},
month = aug,
doi = {10.1186/s13046-026-03793-5},
url = {https://europepmc.org/article/MED/42968146},
note = {CC BY},
}
RIS
TY - JOUR
TI - Therapeutic NAMPT inhibition reveals a targetable metabolic vulnerability in neuroblastoma.
AU - Sophia Varriano
AU - Amy Yu
AU - Abantika Chakraborty
AU - Ariana E Nelson
AU - Amy James
AU - Kristine Isanogle
AU - Nimit Patel
AU - Caleb Kim
AU - Unsun Lee
AU - Victor J Collins
AU - Grace B McKay-Corkum
AU - Ye Yang
AU - Xiaohu Zhang
AU - Crystal McKnight
AU - Kelli Wilson
AU - Carleen Klumpp-Thomas
AU - Michele Ceribelli
AU - David Holland
AU - Ming Sun
AU - Gitanjali Asampille
AU - Ying Wu
AU - Krithika Bhuvaneshwar
AU - Brad Gouker
AU - Donna Butcher
AU - Bhushan L Thakur
AU - Arnulfo Mendoza
AU - Sameer H Issaq
AU - Mirit I Aladjem
AU - Baktiar O Karim
AU - Jack F Shern
AU - Parthav Jailwala
AU - Simone Difilippantonio
AU - Craig J Thomas
AU - Daniel R Crooks
AU - Rosa Nguyen
AU - Carol J Thiele
AU - Christine M Heske
PY - 2026
DA - 2026/08/05
JO - Journal of experimental & clinical cancer research : CR
DO - 10.1186/s13046-026-03793-5
UR - https://europepmc.org/article/MED/42968146
AB - 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 proliferation and viability across multiple molecularly diverse NB models in an on-target manner. Mechanistically, NAMPT inhibition resulted in rapid depletion of NAD⁺ and ATP, disruption of energy metabolism, accumulation of DNA damage, and induction of irreversible non-apoptotic cellular death. In vivo, OT-82 was well tolerated and produced marked antitumor activity, including tumor regressions in orthotopic NB models, including several with regional liver metastases. Pharmacodynamic analysis confirmed intratumoral NAD⁺ depletion during treatment, demonstrating on-target pathway inhibition in vivo.Conclusions These findings identify NB as a highly NAMPT inhibitor-sensitive pediatric solid tumor and establish NAMPT-dependent NAD⁺ biosynthesis as a targetable metabolic vulnerability in this disease. By integrating an unbiased discovery screen with mechanistic and orthotopic in vivo validation using clinically relevant inhibitors, this study provides a strong translational rationale for clinical investigation of NAMPT inhibitors in NB.
SN - 0392-9078
SN - 1756-9966
ER -