A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia

Yee, Karen; Chen, Hsiao-Wei T.; Hedley, David W.; Chow, Sue; Brandwein, Joseph; Schuh, Andre C.; Schimmer, Aaron D.; Gupta, Vikas; Sanfelice, Deborah; Johnson, Tara; Le, Lisa W.; Arnott, Jamie; Bray, Mark R.; Sidor, Carolyn; Minden, Mark D.

doi:10.1007/s10637-016-0375-2

Cited by 25 publications

(11 citation statements)

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“…In vitro experiments revealed that ENMD-2076 induces a G2/M checkpoint block and cell death, alone or in combination with radiosensitisation [136]. Phase I trials showed that ENMD-2076 is a lowcytotoxicity compound in patients affected with relapsed or refractory acute myeloid leukaemia, or chronic myelomonocytic leukaemia [137]. To date, several Phase II trials are ongoing.…”

Section: Enmd-2076mentioning

confidence: 99%

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

Bertolin

Tramier

2019

Cell. Mol. Life Sci.

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AURKA is a serine/threonine kinase overexpressed in several cancers. Originally identified as a protein with multifaceted roles during mitosis, improvements in quantitative microscopy uncovered several nonmitotic roles as well. In physiological conditions, AURKA regulates cilia disassembly, neurite extension, cell motility, DNA replication and senescence programs. In cancer-like contexts, AURKA actively promotes DNA repair, it acts as a transcription factor, promotes cell migration and invasion, and it localises at mitochondria to regulate mitochondrial dynamics and ATP production. Here we review the non-mitotic roles of AURKA, and its partners outside of cell division. In addition, we make an insight on how structural data and quantitative fluorescence microscopy allowed to understand AURKA activation and its interaction with new substrates, highlighting future developments in fluorescence microscopy needed to better understand AURKA functions in vivo. Last, we will recapitulate the most significant AURKA inhibitors currently in clinical trials, and we will explore how the non-mitotic roles of the kinase may provide new insights to ameliorate current pharmacological strategies against AURKA overexpression.

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Section: Enmd-2076mentioning

confidence: 99%

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

Bertolin

Tramier

2019

Cell. Mol. Life Sci.

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“…The anti-leukemic effect of Aurora kinase inhibitors was reported via inducing mitochondrial impairment [45], cell cycle arrest [46] etc. Preliminary clinical studies have been conducted to validate the e cacy and safety of Aurora kinase inhibitors in AML [47][48][49]. Although the association of TP53 mutation and AURKA expression has been rarely studied previously for AML, it was explored in solid tumors with high frequency of TP53 variants, including adrenocortical carcinoma [50], pancreatic cancer [51], head and neck cancer [52], hepatocellular carcinoma [53] and ovarian cancer [54].…”

Section: Discussionmentioning

confidence: 99%

The Landscape of Gene Co-Expression Modules Correlating with Prognostic Genetic Abnormalities in AML

Guo

Gao

et al. 2020

Preprint

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Background: The heterogenous cytogenetic and molecular variations were harbored by AML patients, some of which are related with AML pathogenesis and clinical outcomes. We aimed to uncover the intrinsic expression profiles correlating with prognostic genetic abnormalities by WGCNA.Methods: We downloaded the clinical and expression dataset from BeatAML, TCGA and GEO database. Using R (version 4.0.2) and ‘WGCNA’ package, the co-expression modules correlating with the ELN2017 prognostic markers were identified (R2 ≥ 0.4, p < 0.01). ORA detected the enriched pathways for the key co-expression modules. The patients in TCGA cohort were randomly assigned into the training set (50%) and testing set (50%). The LASSO penalized regression analysis was employed to build the prediction model, fitting OS to the expression level of hub genes by ‘glmnet’ package. Then the testing and 2 independent validation sets (GSE12417 and GSE37642) were used to validate the diagnostic utility and accuracy of the model. Results: A total of 37 gene co-expression modules and 973 hub genes were identified for the BeatAML cohort. We found that 3 modules were significantly correlated with genetic markers (the ‘lightyellow’ module for NPM1 mutation, the ‘saddlebrown’ module for RUNX1 mutation, the ‘lightgreen’ module for TP53 mutation). ORA revealed that the ‘lightyellow’ module was mainly enriched in DNA-binding transcription factor activity and activation of HOX genes. The ‘saddlebrown’ module was enriched in immune response process. And the ‘lightgreen’ module was predominantly enriched in mitosis cell cycle process. The LASSO- regression analysis identified 6 genes (NFKB2, NEK9, HOXA7, APRC5L, FAM30A and LOC105371592) with non-zero coefficients. The risk score generated from the 6-gene model, was associated with ELN2017 risk stratification, relapsed disease, and prior MDS history. The 5-year AUC for the model was 0.822 and 0.824 in the training and testing sets, respectively. Moreover, the diagnostic utility of the model was robust when it was employed in 2 validation sets (5-year AUC 0.743-0.79).Conclusions: We established the co-expression network signature correlated with the ELN2017 recommended prognostic genetic abnormalities in AML. The 6-gene prediction model for AML survival was developed and validated by multiple datasets.

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“…Previous in vivo experiments demonstrated ENMD-2076 induces regression or complete inhibition in tumor xenograft models including colorectal cancer, breast cancer and multiple myeloma [39]. Several Phase I and II clinical trials involving ENMD-2076 showed that it is a promising antitumor drug in dealing with ovarian cancer, multiple myeloma, etc [41–43]. However, the antitumor activity of ENMD-2076 against glioblastoma has not been evaluated.…”

Section: Discussionmentioning

confidence: 99%

Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats

Zhong

Bai

et al. 2019

Aging

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Background: Glioblastoma is the most common type of malignant brain tumor. Bioinformatics technology and structure biology were effectively and systematically used to identify specific targets in malignant tumors and screen potential drugs.Results: GBM patients have higher AURKA and KDR mRNA expression compared with normal samples. Then, we identified a small molecular compound, ENMD-2076, could effectively inhibit Aurora kinase A and VEGFR-2 (encoded by KDR) activities. ENMD-2076 is predicted without toxic properties and also has absorption and gratifying brain/blood barrier penetration ability. Further results demonstrated that ENMD-2076 could significantly inhibit GBM cell lines proliferation and vitality, it also suppressed GBM cells migration and invasion. ENMD-2076 induced glioblastoma cell cycle arrest in G2-M phase and apoptosis by inhibiting PI3K/AKT/mTOR signaling pathways. Additionally, ENMD-2076 prolonged the median survival time of tumor-bearing rats and restrained growth rate of tumor volume in vivo.Conclusions: Our findings reveal that ENMD-2076 is a promising drug in dealing with glioblastoma and have a perspective application.Methods: We show that AURKA and KDR genes are hub driver genes in glioblastoma with bioinformatics technology including WGCNA analysis, PPI network, GO, KEGG analysis and GSEA analysis. After identifying a compound via virtual screening analysis, further experiments were carried out to examine the anti-glioblastoma activities of the compound in vivo and in vitro.

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A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia

Cited by 25 publications

References 50 publications

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

The Landscape of Gene Co-Expression Modules Correlating with Prognostic Genetic Abnormalities in AML

Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats

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