2. Academic Validation
  3. Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia

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

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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