The Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitor, Ot-82, Exhibits In Vitro And In Vivo Efficacy Against Patient-Derived Xenograft Models Of High-Risk Acute Lymphoblastic Leukemia

Cancer cells are highly dependent on nicotinamide phosphoribosyltransferase (NAMPT) for the biosynthesis of nicotinamide adenine dinucleotide (NAD). Besides its role in energy metabolism, NAMPT influences the activity of NAD-dependent enzymes, including poly (ADP-ribose) polymerase-1 (PARP-1) and sirtuins, and thereby regulates cellular survival and stress response. Disruption of NAD synthesis through NAMPT inhibition represents a potential therapeutic strategy for treating cancer. The aim of this study was to evaluate the efficacy of the novel NAMPT inhibitor OT-82, initially isolated for its selective toxicity against a panel of adult leukemia cell lines, in a diverse panel of leukemia cell lines in vitro and pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) in vivo, and to identify potential biomarkers predictive of OT-82 response. OT-82 demonstrated low nanomolar IC50 values (0.9 – 3.4 nM) in 3 ALL and 3 acute myeloid leukemia cell lines as determined by resazurin reduction assays. In vivo efficacy of OT-82 (40 mg/kg x 3 days x 3 weeks, p.o.) was evaluated as a single agent against pediatric ALL PDXs, including B-cell precursor ALL (n = 3), Philadelphia chromosome (Ph) positive ALL (n = 2), Ph-like ALL (n = 2), T-cell ALL (n = 3), and early T-cell precursor ALL (n = 3) in immune deficient (NSG) mice. Response to treatment was assessed by time to event or stringent objective response criteria modeled after the clinical setting. OT-82 was well tolerated, significantly increased event-free survival (EFS) relative to control mice in 11/13 ALL PDXs, and elicited objective responses in 11/13 (85%) PDXs [3 Partial Responses, 4 Complete Responses (CRs) and 4 Maintained CRs (MCRs)]. Analysis of basal protein expression revealed elevated levels of poly (ADP-ribosyl)ated (PARylated) PARP-1 in 4/5 responders versus 0/2 non-responders. In vitro studies examining various chemotherapeutic agents used for childhood leukemia showed synergy between cytarabine (AraC) and OT-82 in an ALL cell line. In an OT-82 sensitive Mixed Lineage Leukemia (MLL) PDX, treatment with AraC (25 mg/kg x 5 days x 2 weeks, i.p.) and OT-82 (40 mg/kg x 3 days x 2 weeks, p.o.) significantly increased EFS compared to OT-82 (P Citation Format: Kathryn Evans, Tara Pritchard, Michelle J. Henderson, Klaartje Somers, Mawar Karsa, Leanna Cheung, Raymond Yung, Stephen W. Erickson, Lioubov Korotchkina, Olga Chernova, Andrei Gudkov, Malcolm A. Smith, Richard B. Lock. The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, OT-82, exhibits in vitro and in vivo efficacy against patient-derived xenograft models of high-risk acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1942. doi:10.1158/1538-7445.AM2017-1942