Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia

Klaartje Somers, Kathryn Evans, Leanna Cheung, Mawar Karsa, Tara Pritchard, Angelika Kosciolek, Angelika Bongers, Ali El-Ayoubi, Helen Forgham, Shiloh Middlemiss, Chelsea Mayoh, Luke Jones, Mahima Gupta, Ursula R. Kees, Olga Chernova, Lioubov Korotchkina, Andrei V. Gudkov, Stephen W. Erickson, Beverly Teicher, Malcolm A. SmithMurray D. Norris, Michelle Haber, Richard B. Lock, Michelle J. Henderson

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


The prognosis for children diagnosed with high-risk acute lymphoblastic leukemia (ALL) remains suboptimal, and more potent and less toxic treatments are urgently needed. We investigated the efficacy of a novel nicotinamide phosphoribosyltransferase inhibitor, OT-82, against a panel of patient-derived xenografts (PDXs) established from high-risk and poor outcome pediatric ALL cases. OT-82 was well-tolerated and demonstrated impressive single agent in vivo efficacy, achieving significant leukemia growth delay in 95% (20/21) and disease regression in 86% (18/21) of PDXs. In addition, OT-82 enhanced the efficacy of the established drugs cytarabine and dasatinib and, as a single agent, showed similar efficacy as an induction-type regimen combining three drugs used to treat pediatric ALL. OT-82 exerted its antileukemic action by depleting NAD+ and ATP, inhibiting the NAD+-requiring DNA damage repair enzyme PARP-1, increasing mitochondrial ROS levels and inducing DNA damage, culminating in apoptosis induction. OT-82 sensitivity was associated with the occurrence of mutations in major DNA damage response genes, while OT-82 resistance was characterized by high expression levels of CD38. In conclusion, our study provides evidence that OT-82, as a single agent, and in combination with established drugs, is a promising new therapeutic strategy for a broad spectrum of high-risk pediatric ALL for which improved therapies are urgently needed.

Original languageEnglish
Pages (from-to)1524-1539
Number of pages16
Issue number6
Publication statusPublished - 1 Jun 2020


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