Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours

Schöffski, Patrick; Jones, Suzanne F.; Dumez, Herlinde; Infante, Jeffrey R.; Mieghem, Elke Van; Fowst, Camilla; Gerletti, Paola; Xu, Huiping; Jakubczak, John L.; English, Patricia A.; Pierce, Kristen J.; Burris, Howard A.

doi:10.1016/j.ejca.2011.07.008

Cited by 46 publications

(28 citation statements)

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“…The modulation of PLGF demonstrated preclinically for ABT-348 in this article has been observed previously in responses to therapy with antiangiogenic agents, leading to the incorporation of the assay for this protein as a biomarker into the clinical development multitargeted kinase inhibitors (Bass et al, 2010). Inhibition of histone H3 phosphorylation, as reported in the current study, has been used as a clinical biomarker of Aurora inhibition (Schöffski et al, 2011). Taken together, these assays should provide useful tools to help guide future clinical assessment of ABT-348 with the goal of defining its therapeutic utility and tolerability.…”

Section: Discussionmentioning

confidence: 62%

Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families

Glaser

Magoc

et al. 2012

J Pharmacol Exp Ther

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ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.

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Section: Discussionmentioning

confidence: 62%

Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families

Glaser

Magoc

et al. 2012

J Pharmacol Exp Ther

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“…AURKA, a protein-associated PC, is a member of a family of serine/threonine kinases that plays a well-established role in promoting cell cycle and assembly of the mitotic spindle 21,22. High expression of AURKA is implicated for poor prognosis of many types of cancer including BLCA 23–26. In clear cell renal cell carcinomas, reduced AURKA levels can induce a significant increase in PC formation 27.…”

Section: Discussionmentioning

confidence: 99%

Analysis of potential genes associated with primary cilia in bladder cancer

Du¹,

Lü²,

Sheng³

et al. 2018

CMAR

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BackgroundDysfunction of primary cilia (PC), which could influence cell cycle and modulate cilia-related signaling transduction, has been reported in several cancers. However, there is no evidence of their function in bladder cancer (BLCA). This study was performed to investigate the presence of PC in BLCA and to explore the potential molecular mechanisms underlying the PC in BLCA.Patients and methodsThe presence of PC was assessed in BLCA and adjacent non-cancerous tissues. The gene expression dataset GSE52519 was employed to obtain differentially expressed genes (DEGs) associated with PC. The mRNA expression of the DEGs were confirmed by Gene Expression Profiling Interactive Analysis. The DEGs properties and pathways were analyzed by Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Genomatix software was used to predict putative transcription factor binding sites (TFBS) in the promoter region of DEGs, and the transcription factors were achieved according to the shared TFBS, which were supported by the ChIP-Sequence data.ResultsPC were found to be reduced in BLCA tissue samples in this study. Seven DEGs were observed to be associated with PC, and gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that these DEGs exhibited the properties and functions of PC, and that the Hedgehog signaling pathway probably participated in the pathogenesis and progression of BLCA. The mRNA expression of the seven DEGs in 404 BLCA and 28 normal tissue samples were analyzed, and five DEGs including CENPF, STIL, AURKA, STK39 and OSR1 were identified. Five TFBS including CREB, E2FF, EBOX, ETSF and HOXF in the promoter region of five DEGs were calculated and the transcription factors were obtained according to the shared TFBS.ConclusionPC were found to be reduced in BLCA, and the potential molecular mechanisms of PC in BLCA helped to provide novel diagnosis and therapeutic targets for BLCA.

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“…Histone H3 phosphorylation, which is associated with Aurora-B activity, has also been evaluated as a pharmacodynamic marker in phase I trials. [88-90] The degree of mitotic cell chromosome alignment and spindle bipolarity has been evaluated as well, and these are less apparent after treatment with MLN8054, a preclinical Aurora-A inhibitor. [59] Blockade of Aurora kinase activity triggers p53-mediated apoptosis in cells containing wild type p53, while loss of p53 upregulates Aurora-A.…”

Section: Concepts For Future Trials Of Combination Strategies Involvimentioning

confidence: 99%

Aurora kinases in head and neck cancer

Mehra¹,

Serebriiskii²,

Burtness³

et al. 2013

The Lancet Oncology

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Summary Controlled activation of the Aurora kinases regulates mitotic progression in normal cells. Overexpression and hyperactivation of the Aurora-A and -B kinases play a leading role in tumorigenesis, inducing aneuploidy and genomic instability. In squamous cell carcinomas of the head and neck (SCCHN), overexpression of Aurora-A is associated with decreased survival, and reduction of Aurora-A and -B expression inhibits SCCHN cell growth and increases apoptosis. In this article, we provide a basic overview of the biological functions of Aurora kinases in normal cells and in cancer, and review both small studies and high throughput datasets that implicate Aurora-A, particularly, in the pathogenesis of SCCHN. Early phase clinical trials are beginning to evaluate the activity of small molecule inhibitors of the Aurora kinases. We summarize the state of current trials evaluating Aurora inhibitors in SCCHN, and discuss rational directions for future drug combination trials and biomarkers for use with Aurora-inhibiting agents.

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Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours

Cited by 46 publications

References 10 publications

Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families

Preclinical Characterization of ABT-348, a Kinase Inhibitor Targeting the Aurora, Vascular Endothelial Growth Factor Receptor/Platelet-Derived Growth Factor Receptor, and Src Kinase Families

Analysis of potential genes associated with primary cilia in bladder cancer

Aurora kinases in head and neck cancer

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