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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This research was supported by grants from the National Cancer Institute (CA199222 and CA199000), The National Health and Medical Research Council of Australia (NHMRC Fellowships APP1059804 and APP1157871), Cancer Australia and Kids’ Cancer Project (Priority-driven Collaborative Cancer Research Scheme APP1164865), Anthony Rothe Memorial Trust, Cancer Council NSW (PG16-01), Tenix Foundation, ISG Foundation, the Children’s Leukemia and Cancer Research Foundation (Perth), and Australian Postgraduate Awards from the Australian Government Department of Education and Training. Children’s Cancer Institute is affiliated with the UNSW Sydney and the Sydney Children’s Hospital Network. The authors would like to thank Raymond Yung and Lisa McDermott (CCI) for their help with experiments.
Conflict of interest
AVG is a consultant of and OC, MG, and LK are employed by Oncotartis, Inc. which developed and holds the IP on OT-82.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Somers, K., Evans, K., Cheung, L. et al. Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia. Leukemia 34, 1524–1539 (2020). https://doi.org/10.1038/s41375-019-0683-6
Signal Transduction and Targeted Therapy (2021)
OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis
Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma