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

Mitchell, Shaneice; Larkin, Karilyn; Grieselhuber, Nicole R.; Lai, Tzung Huei; Cannon, Matthew; Orwick, Shelley; Sharma, Pratibha; Asemelash, Yerdanose; Zhang, Pu; Goettl, Virginia M.; Beaver, Larry; Mims, Alice S.; Puduvalli, Vinay K.; Blachly, James S.; Lehman, Amy; Harrington, Bonnie K.; Henderson, Sally E.; Breitbach, Justin; Williams, Katie; Dong, Shuai; Baloglu, Erkan; Senapedis, William; Kirschner, Karl N.; Sampath, Deepa; Lapalombella, Rosa; Byrd, John C.

doi:10.1182/bloodadvances.2018024182

Cited by 47 publications

(40 citation statements)

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“…Earlier studies from our group and others have demonstrated remarkable anti-tumor activity of KPT-9274 in solid (breast, colon, and kidney) and hematologic (NHL, CLL, and MM) tumor xenograft models [25][26][27][28]. Our group has also demonstrated the activity of KPT-9274 in PDAC xenograft in vivo [29].…”

Section: Kpt-9274 Shows Single Agent Anti-tumor Activity In Pnetsupporting

confidence: 64%

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

Mpilla

Aboukameel

Muqbil

et al. 2019

Cancers

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Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation.

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Section: Kpt-9274 Shows Single Agent Anti-tumor Activity In Pnetsupporting

confidence: 64%

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

Mpilla

Aboukameel

Muqbil

et al. 2019

Cancers

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“…MGG119, MGG152, BT142 primary glioblastoma cell lines; HT1080, 30T and SW1353 chondrosarcoma cell lines; SNU484, SNU668, SNU1750, MKN1 and Hs746T gastric cancer cell lines which have mutations in IDH1 [7][8][9], were sensitive to NAMPT inhibition. NAMPT inhibitors not only have shown promising effect as single-agent therapy, but were also found to sensitize other modalities of cancer treatment in both in vitro and in vivo experiments [45,[55][56][57], as shown in Tables 2 and 3. As preclinical studies with NAMPT showed encouraging results [73][74][75], the clinical efficacy and safety of NAMPT inhibitors has been tested in cancer patients.…”

Section: Therapeutic Role Of Nampt In Cancermentioning

confidence: 99%

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

et al. 2020

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Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers.

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“…In addition to Ewing sarcoma, recent insights have revealed that other pediatric cancers may also be susceptible to NAMPT inhibition. Preclinical models of pediatric hematologic malignancies, including B-and T-cell leukemias (112,113), and AML (114,115) underwent growth inhibition upon treatment with single agent NAMPT inhibitors. Models of pediatric HGG, including diffuse pontine gliomas (DIPG) were also sensitive to inhibition of NAMPT, which may be mediated by genetic silencing of compensatory enzymes (116).…”

Section: Nicotinamide Adenine Dinucleotide (Nad + ) Metabolismmentioning

confidence: 99%

Targeting metabolic dependencies in pediatric cancer

Issaq

Heske

2020

Current Opinion in Pediatrics

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Purpose of Review: In an attempt to identify potential new therapeutic targets, efforts to describe the metabolic features unique to cancer cells are increasingly being reported. While current standard of care regimens for several pediatric malignancies incorporate agents that target tumor metabolism, these drugs have been part of the therapeutic landscape for decades. More recent research has focused on the identification and targeting of new metabolic vulnerabilities in pediatric cancers. The purpose of this review is to describe the most recent translational findings in the metabolic targeting of pediatric malignancies. Recent Findings: Across multiple pediatric cancer types, dependencies on a number of key metabolic pathways have emerged through study of patient tissue samples and preclinical modeling. Among the potentially targetable vulnerabilities are glucose metabolism via glycolysis, oxidative phosphorylation, amino acid and polyamine metabolism, and NAD + metabolism. While few agents have yet to move forward into clinical trials for pediatric cancer patients, the robust and promising preclinical data that has been generated suggests that future clinical trials should rationally test metabolically-targeted agents for relevant disease populations. Summary: Recent advances in our understanding of the metabolic dependencies of pediatric cancers represent a source of potential new therapeutic opportunities for these diseases.

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

Cited by 47 publications

References 50 publications

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

Targeting metabolic dependencies in pediatric cancer

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