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ACUTE LYMPHOBLASTIC LEUKEMIA

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

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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Fig. 1: OT-82 potently decreases the viability of leukemia cell lines and pediatric ALL PDX cells.
Fig. 2: OT-82 decreases intracellular NAD+ levels culminating in apoptosis induction in leukemia cells.
Fig. 3: OT-82 induces regressions in vivo in a broad panel of pediatric ALL PDX models.
Fig. 4: OT-82 reduces NAD+, ATP and serum visfatin levels and inhibits PARP-1 in ALL PDXs in vivo.
Fig. 5: OT-82 potentiates currently used therapies for pediatric high-risk ALL.
Fig. 6: Determinants of response to OT-82.

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Acknowledgements

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.

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KS, KE, LC, AK, MK, TP, AB, AE, HF, LJ, SM, OC, LK, and MG conducted the experiments. KS, KE, LC, MK, HF, LJ, LK, BT, and SWE analyzed the data. CM performed the analysis of the RNA sequencing and SNP data. URK provided guidance and access to the cell lines and patient material used in the study. KS, KE, LJ, AG, OC, MDN, MH, RBL, and MJH conceived the project and designed the experiments. MAS provided support with study design. KS wrote the manuscript under the guidance of MJH, MDN, MH, and RBL who critically reviewed the manuscript. KE assisted in manuscript preparation. All authors reviewed the manuscript.

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Correspondence to Michelle J. Henderson.

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AVG is a consultant of and OC, MG, and LK are employed by Oncotartis, Inc. which developed and holds the IP on OT-82.

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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

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