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

  • Leukemia. 2020 Jun;34(6):1524-1539. doi: 10.1038/s41375-019-0683-6.
Klaartje Somers   #  1 ,  Kathryn Evans   #  1 ,  Leanna Cheung  1 ,  Mawar Karsa  1 ,  Tara Pritchard  1 ,  Angelika Kosciolek  1 ,  Angelika Bongers  1 ,  Ali El-Ayoubi  1 ,  Helen Forgham  1  2 ,  Shiloh Middlemiss  1 ,  Chelsea Mayoh  1 ,  Luke Jones  1 ,  Mahima Gupta  3 ,  Ursula R Kees  4 ,  Olga Chernova  3 ,  Lioubov Korotchkina  3 ,  Andrei V Gudkov  3  5 ,  Stephen W Erickson  6 ,  Beverly Teicher  7 ,  Malcolm A Smith  7 ,  Murray D Norris  1  8 ,  Michelle Haber  1 ,  Richard B Lock   #  1 ,  Michelle J Henderson   #  9
Affiliations
  • 1. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
  • 2. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for NanoMedicine, UNSW Australia, Sydney, NSW, Australia.
  • 3. Oncotartis, Inc, Buffalo, NY, USA.
  • 4. Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.
  • 5. Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
  • 6. RTI International, Research Triangle Park, NC, USA.
  • 7. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
  • 8. UNSW Centre for Childhood Cancer Research, Sydney, NSW, Australia.
  • 9. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia. [email protected].
  • # Contributed equally.
PMID: 31848452 DOI: 10.1038/s41375-019-0683-6
Abstract

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.

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