{
  "abstract": "Background\n\nNeuroblastoma (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\n\nUsing 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\n\nIn 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\n\nThese 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.",
  "abstract_shown": true,
  "affiliations": [
    "Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRC, Room 1W-3816, Bethesda, MD, 20892, USA.",
    "Animal Research Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.",
    "Small Animal Imaging Program, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.",
    "Clinical Cancer Metabolism Facility, Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.",
    "Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.",
    "Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.",
    "Molecular Histopathology Laboratory, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.",
    "Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.",
    "Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.",
    "Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRC, Room 1W-3816, Bethesda, MD, 20892, USA. christine.heske@nih.gov."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 37,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sophia Varriano"
    },
    {
      "affs": [
        0
      ],
      "name": "Amy Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Abantika Chakraborty"
    },
    {
      "affs": [
        0
      ],
      "name": "Ariana E Nelson"
    },
    {
      "affs": [
        1
      ],
      "name": "Amy James"
    },
    {
      "affs": [
        1
      ],
      "name": "Kristine Isanogle"
    },
    {
      "affs": [
        2
      ],
      "name": "Nimit Patel"
    },
    {
      "affs": [
        2
      ],
      "name": "Caleb Kim"
    },
    {
      "affs": [
        0
      ],
      "name": "Unsun Lee"
    },
    {
      "affs": [
        0
      ],
      "name": "Victor J Collins"
    },
    {
      "affs": [
        0
      ],
      "name": "Grace B McKay-Corkum"
    },
    {
      "affs": [
        3
      ],
      "name": "Ye Yang"
    },
    {
      "affs": [
        4
      ],
      "name": "Xiaohu Zhang"
    },
    {
      "affs": [
        4
      ],
      "name": "Crystal McKnight"
    },
    {
      "affs": [
        4
      ],
      "name": "Kelli Wilson"
    },
    {
      "affs": [
        4
      ],
      "name": "Carleen Klumpp-Thomas"
    },
    {
      "affs": [
        4
      ],
      "name": "Michele Ceribelli"
    },
    {
      "affs": [
        4
      ],
      "name": "David Holland"
    },
    {
      "affs": [
        0
      ],
      "name": "Ming Sun"
    },
    {
      "affs": [
        3
      ],
      "name": "Gitanjali Asampille"
    },
    {
      "affs": [
        5
      ],
      "name": "Ying Wu"
    },
    {
      "affs": [
        5
      ],
      "name": "Krithika Bhuvaneshwar"
    },
    {
      "affs": [
        6
      ],
      "name": "Brad Gouker"
    },
    {
      "affs": [
        6
      ],
      "name": "Donna Butcher"
    },
    {
      "affs": [
        7
      ],
      "name": "Bhushan L Thakur"
    },
    {
      "affs": [
        0
      ],
      "name": "Arnulfo Mendoza"
    },
    {
      "affs": [
        8
      ],
      "name": "Sameer H Issaq"
    },
    {
      "affs": [
        7
      ],
      "name": "Mirit I Aladjem"
    },
    {
      "affs": [
        6
      ],
      "name": "Baktiar O Karim"
    },
    {
      "affs": [
        0
      ],
      "name": "Jack F Shern"
    },
    {
      "affs": [
        5
      ],
      "name": "Parthav Jailwala"
    },
    {
      "affs": [
        1
      ],
      "name": "Simone Difilippantonio"
    },
    {
      "affs": [
        4
      ],
      "name": "Craig J Thomas"
    },
    {
      "affs": [
        3
      ],
      "name": "Daniel R Crooks"
    },
    {
      "affs": [
        0
      ],
      "name": "Rosa Nguyen"
    },
    {
      "affs": [
        0
      ],
      "name": "Carol J Thiele"
    },
    {
      "affs": [
        9
      ],
      "name": "Christine M Heske",
      "orcid": "0000-0003-0956-6249"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dhw1xbyvz1vvq.bib",
  "cited_by": 0,
  "doi": "10.1186/s13046-026-03793-5",
  "fulltext_url": "https://europepmc.org/articles/PMC13726087",
  "id": "dhw1xbyvz1vvq",
  "issns": [
    "0392-9078",
    "1756-9966"
  ],
  "landing_url": "https://europepmc.org/article/MED/42968146",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2728|Neuroblastoma Research and Treatments"
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  "openalex": "W7172440361",
  "pdf_url": "https://europepmc.org/articles/PMC13726087?pdf=render",
  "pmcid": "PMC13726087",
  "pmid": "42968146",
  "published": "2026-08-05",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/dhw1xbyvz1vvq.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T15:20:54Z",
      "native_id": "MED:42968146",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42968146"
    },
    {
      "first_seen": "2026-11-05T12:22:30Z",
      "native_id": "PMC13726087",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s13046-026-03793-5"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Neuroblastoma Research and Treatments",
      "subfield": "neurology"
    }
  ],
  "title": "Therapeutic NAMPT inhibition reveals a targetable metabolic vulnerability in neuroblastoma.",
  "title_text": "Therapeutic NAMPT inhibition reveals a targetable metabolic vulnerability in neuroblastoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:22:07Z",
  "url": "https://research.draconitic.com/paper/dhw1xbyvz1vvq",
  "venue": "Journal of experimental & clinical cancer research : CR",
  "versions": []
}