Recent advances of targeting nicotinamide phosphoribosyltransferase (NAMPT) for cancer drug discovery

He, Ting; Wang, Lin; Wang, Tianyu; Yang, Jiamei; Zheng, Shuai; Tong, Jinyi; Jiang, Sheng; Zhang, Xiangyu; Zhang, Kuojun

doi:10.1016/j.ejmech.2023.115607

Cited by 14 publications

(7 citation statements)

References 147 publications

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“…Although Daporinad displayed promising preclinical outcomes, it lacked consistent tumor response in clinical trials for chronic lymphocytic leukemia B cells [61], melanoma [62], and cutaneous T-cell lymphoma [63]. Efforts to widen the therapeutic window and enhance NAMPT inhibitors' efficacy include identifying predictive response biomarkers and developing second-generation NAMPT inhibitors [70]. Furthermore, recent research highlighted the potential interplay between the microbiota and the efficacy of NAMPT inhibitors [71,72].…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Gonzalez,

Pérez Küper,

Garcia Fallit

et al. 2024

Preprint

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Purpose Glioblastoma (GBM) remains a formidable challenge in oncology due to its invasiveness and resistance to treatment, i.e. surgery, radiotherapy, and chemotherapy with temozolomide. This study aimed to develop and validate an integrated model to predict the sensitivity of GBM to alternative chemotherapeutics and to identify novel candidate drugs and combinations for the treatment of GBM. Methods We utilized the drug sensitivity response data of 272 compounds from CancerRxTissue, a validated predictive model, to identify drugs with therapeutic potential for GBM. Using the IC50, we selected 'potentially effective' drugs among those predicted to be blood-brain barrier permeable via in silico algorithms. We ultimately selected drugs with targets overexpressed and associated with worse prognosis in GBM for experimental in vitro validation. Results The workflow proposed predicted that GBM is more sensitive to Etoposide and Cisplatin, in comparison with Temozolomide, effects that were validated in vitro in a set of GBM cellular models. Using this workflow, we identified a set of 5 novel drugs to which GBM would exhibit high sensitivity and selected Daporinad, a blood-brain barrier permeant NAMPT inhibitor, for further preclinical in vitro evaluation, which aligned with the in silico prediction. Conclusion Our results suggest that this workflow could be useful to select potentially effective drugs and combinations for GBM, according to the molecular characteristics of the tumor. This comprehensive workflow, which integrates computational prowess with experimental validation, could constitute a simple tool for identifying and validating compounds with potential for drug repurposing in GBM and other tumors.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Gonzalez,

Pérez Küper,

Garcia Fallit

et al. 2024

Preprint

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“…We thus propose that the combination of chemotherapy with INSR inhibitors and NAMPT inhibitors could represent a promising treatment strategy for early chemoresistant HGSOC patients. The inhibitors of NAMPT and INSR have undergone extensive development and clinical testing (58,59). Previous research has demonstrated that the combination of a NAMPT inhibitor and chemotherapy resulted in a better prognosis than chemotherapy alone in mice with HGSOC (60), holds promise for further improving the therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer

Gu,

He,

et al. 2024

Preprint

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Chemoresistance has long been a significant but unresolved issue in the treatment of various cancers, including the most deadly gynecological cancer, the high-grade serous ovary cancer (HGSOC). In this study, single nuclei transcriptome analyses were utilized to identify key cells and core networks for chemoresistance in HGSOC patients with different early responses to platinum-based chemotherapy at the single-cell level. Biomarkers for chemoresistance were also screened using bulk transcriptome data from independent cohorts with larger sample sizes. A total of 62,482 single cells from six samples were analyzed, revealing that chemoresistant cancer cells (Epithelial cells_0) pre-existed within individual patient before treatment. Two network modules formed with hub genes such as hormone-related genes (ESR1 and AR), insulin-related genes (INSR and IGF1R), and CTNNB1, were significantly overexpressed in these cells in the chemoresistant patient. BMP1 and TPM2 could be promise biomarkers in identifying chemoresistant patients before chemotherapy using bulk transcriptome data. Additionally, chemotherapy-induced fibroblasts (Fibroblasts_01_after) emerged as key stromal cells for chemoresistance. One network module containing one subnetwork formed by cholesterol biosynthesis-related genes and one subnetwork formed by cancer-related genes such as STAT3 and MYC, was significantly overexpressed in these cells in the chemoresistant patient. Notably, the NAMPT-INSR was the most prioritized ligand-receptor pair for cells interacting with Fibroblasts_01_after cells and Epithelial cells_0 cells to drive the up-regulation of their core genes, including IL1R1, MYC and INSR itself. Our findings deepen the understandings about mechanisms of early chemoresistance in HGSOC patients.

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“…NAD is closely related to many important life processes such as cell metabolism, aging, apoptosis, DNA damage and repair. Nicotinamide phosphoribosyltransferase (NAMPT) is the speed limit of NAD biosynthesis enzyme, several studies have found that NAMPT expressed in all kinds of tumor tissue, It may participate in signal transduction related to cell carcinogenesis and affect cell metabolism through NAD pathway, which may lead to the occurrence and progression of cancer 31 . The p21-activated kinases 1(PAK1) has been shown to be a downstream node of multiple oncogenic signaling pathways that promote tumor changes.Venu et al demonstrated that PAK1 and its activation state have the ability to progress toward a more aggressive phenotype in gliomas 32 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing explores the evolution of the ecosystem from leukoplakia to head and neck squamous cell carcinoma

Wang,

Guan,

Zheng

2024

Sci Rep

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It has been found that progression from leukoplakia to head and neck squamous cell carcinoma (HNSCC) is a long-term process that may involve changes in the multicellular ecosystem. We acquired scRNA-seq samples information from gene expression omnibus and UCSC Xena database. The BEAM function was used to construct the pseudotime trajectory and analyze the differentially expressed genes in different branches. We used the ssGSEA method to explore the correlation between each cell subgroup and survival time, and obtained the cell subgroup related to prognosis. During the progression from leukoplakia to HNSCC, we found several prognostic cell subgroups, such as AURKB + epithelial cells, SFRP1 + fibroblasts, SLC7A8 + macrophages, FCER1A + CD1C + dendritic cells, and TRGC2 + NK/T cells. All cell subgroups had two different fates, one tending to cell proliferation, migration, and enhancement of angiogenesis capacity, and the other tending to inflammatory immune response, leukocyte chemotaxis, and T cell activation. Tumor-promoting genes such as CD163 and CD209 were highly expressed in the myeloid cells, and depletion marker genes such as TIGIT, LAG3 were highly expressed in NK/T cells. Our study may provide a reference for the molecular mechanism of HNSCC and theoretical basis for the development of new therapeutic strategies.

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Recent advances of targeting nicotinamide phosphoribosyltransferase (NAMPT) for cancer drug discovery

Cited by 14 publications

References 147 publications

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Identification and validation of drugs for repurposing in Glioblastoma: a computational and experimental workflow

Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer

Single-cell RNA sequencing explores the evolution of the ecosystem from leukoplakia to head and neck squamous cell carcinoma

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