Dataset Information

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia.

ABSTRACT: Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

SUBMITTER: Mitchell SR

PROVIDER: S-EPMC6373756 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia.

Mitchell Shaneice R SR Larkin Karilyn K Grieselhuber Nicole R NR Lai Tzung-Huei TH Cannon Matthew M Orwick Shelley S Sharma Pratibha P Asemelash Yerdanose Y Zhang Pu P Goettl Virginia M VM Beaver Larry L Mims Alice A Puduvalli Vinay K VK Blachly James S JS Lehman Amy A Harrington Bonnie B Henderson Sally S Breitbach Justin T JT Williams Katie E KE Dong Shuai S Baloglu Erkan E Senapedis William W Kirschner Karl K Sampath Deepa D Lapalombella Rosa R Byrd John C JC

Blood advances 20190201 3

Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD<sup>+</sup> and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mito ...[more]

PMID: 30692102

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Project description:Abstract BACKGROUND Current treatment of glioblastoma (GBM) with surgery and chemoRT yields an average survival of ~1.5 years, highlighting the need for more effective therapies. We have previously reported that PAK4 is a key modulator of radioresistance in GBM. Additionally, pathways that regulate differential energy metabolism in gliomas and circumvent tumor heterogeneity have recently emerged as promising therapeutic targets. We hypothesized that inhibition of NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway, a key pathway preferentially used in glioma energy metabolism, would be effective against GBM. METHODS We tested the efficacy of KPT9274, a potent first-in-class dual inhibitor of PAK4 and NAMPT, currently in human trials against solid tumors and lymphomas (NCT02702492), on NAD levels and cell viability in glioma cell lines and patient-derived glioma stem-like cells (GSC). We also examined enzyme-kinetics of various components of the NAD salvage pathway and effects of NADH rescue by nicotinamide, NMN and NAD. Lastly, we examined the biological relevance of NAMPT inhibition in glioma cells and GSC using a combination of cell adhesion, wound-healing, transwell-migration and microtubule formation assays. RESULTS Treatment with KPT9274 resulted in potent depletion of NAD in glioma cells which was rescued by nicotinamide, NMN and NAD demonstrating its specificity against NAMPT. KPT-9274 treatment resulted in potent inhibition of cell adhesion, migration, cell invasion, endothelial tube formation and proliferation in glioma cells and GSC. In vivo studies in mouse bioluminescent intracranial glioma PDX model as well as PK studies are ongoing to confirm the pre-clinical significance of targeting NAMPT in gliomas and will be presented. CONCLUSIONS Our study demonstrates a key role for NAMPT in NAD generation in gliomas as seen by the potent biological effects of KPT-9274 against these tumors and supports the potential for targeting the NAD salvage pathway as a novel therapeutic strategy for treatment of GBM.

Dataset Information

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia.

Publications

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia.

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