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Background <p>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<sup>+</sup>) 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<sup>+</sup> 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.</p> Methods <p>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<sup>+</sup> abundance, adenosine triphosphate (ATP) levels, and energy-related metabolites were quantified, and downstream consequences of NAD<sup>+</sup>-consuming enzymatic pathways were examined. Tolerability, antitumor activity and pharmacodynamic effects of OT-82 were evaluated in three orthotopic NB mouse models.</p> Results <p>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<sup>+</sup> 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<sup>+</sup> depletion during treatment, demonstrating on-target pathway inhibition in vivo.</p> Conclusions <p>These findings identify NB as a highly NAMPT inhibitor-sensitive pediatric solid tumor and establish NAMPT-dependent NAD<sup>+</sup> 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.</p>

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Therapeutic NAMPT inhibition reveals a targetable metabolic vulnerability in neuroblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Sophia Varriano,
  • Amy Yu,
  • Abantika Chakraborty,
  • Ariana E. Nelson,
  • Amy James,
  • Kristine Isanogle,
  • Nimit Patel,
  • Caleb Kim,
  • Unsun Lee,
  • Victor J. Collins,
  • Grace B. McKay-Corkum,
  • Ye Yang,
  • Xiaohu Zhang,
  • Crystal McKnight,
  • Kelli Wilson,
  • Carleen Klumpp-Thomas,
  • Michele Ceribelli,
  • David Holland,
  • Ming Sun,
  • Gitanjali Asampille,
  • Ying Wu,
  • Krithika Bhuvaneshwar,
  • Brad Gouker,
  • Donna 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

摘要

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.