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Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human DU145 tumor cells treated with a CDK inhibitor (Super Series)

ABSTRACT: A genomics-based approach to identify pharmacodynamic biomarkers was used for a CDK (cyclin-dependent kinase) inhibitory drug. R547 is a potent CDK inhibitor with a potent anti-proliferative effect at pharmacologically relevant doses, and is currently in Phase I clinical trials. Utilizing preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Experiment Overall Design: 52 samples were initially run, 45 passed QC and were analyzed, samples were run in 4 independent replicates and were treated with either vehicle, R547 at the IC50 concentration, R547 at the IC90, or R547 at 3 times the IC90. Samples were harvested at 2, 6, and 24 hours post treatment. Additionally, untreated time zero samples were analyzed as a further control

ORGANISM(S): Homo sapiens

SUBMITTER: James Rosinski

PROVIDER: E-GEOD-15392 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription profiling of human peripheral blood mononuclear cells treated with a CDK inhibitor

Project description:A genomics-based approach to identify pharmacodynamic biomarkers was used for a CDK (cyclin-dependent kinase) inhibitory drug. R547 is a potent CDK inhibitor with a potent anti-proliferative effect at pharmacologically relevant doses, and is currently in Phase I clinical trials. Utilizing preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Experiment Overall Design: 40 samples were initially run, 37 passed QC and were analyzed, samples were run in 6 independent replicates and were treated with either vehicle, R547 at the IC90, or R547 at 3 times the IC90. Additionally, untreated time zero samples were analyzed as a further control

2009-03-28 | E-GEOD-15389 | biostudies-arrayexpress

Transcription profiling of human HCT116 tumor cells treated with R547 a CDK inhibitor at IC50 concentration, R547 at the IC90, or R547 at 3 times the IC90m, time series design

Project description:A genomics-based approach to identify pharmacodynamic biomarkers was used for a CDK (cyclin-dependent kinase) inhibitory drug. R547 is a potent CDK inhibitor with a potent anti-proliferative effect at pharmacologically relevant doses, and is currently in Phase I clinical trials. Utilizing preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Experiment Overall Design: 77 samples were initially run, 74 passed QC and were analyzed, samples were run in 4 independent replicates and were treated with either vehicle, R547 at the IC50 concentration, R547 at the IC90, or R547 at 3 times the IC90. Samples were harvested at 1, 2, 4, 6, and 24 hours post treatment. Additionally, untreated time zero samples were analyzed as a further control

2009-03-28 | E-GEOD-15395 | biostudies-arrayexpress

HCT116 tumor cells treated with a CDK inhibitor

2009-03-26 | GSE15395 | GEO

DU145 tumor cells treated with a CDK inhibitor

2009-03-26 | GSE15392 | GEO

Peripheral blood mononuclear cells treated with a CDK inhibitor

2009-03-26 | GSE15389 | GEO

The novel BETi BI 894999 represses super-enhancer associated transcription and synergizes with CDK9 inhibition in AML by induction of apoptosis

Project description:Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood. Mechanistic studies show that BI 894999 targets super-enhancer-regulated oncogenes and other lineage-specific factors, which are involved in the maintenance of the disease state. BI 894999 is active as monotherapy in AML xenografts, and in addition leads to strongly enhanced antitumor effects in combination with CDK9 inhibitors. This treatment combination results in a marked decrease of global p-Ser2 RNA polymerase II levels and leads to rapid induction of apoptosis in vitro and in vivo. Together, these data provide a strong rationale for the clinical evaluation of BI 894999 in AML.

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Generation of a unique, comprehensive and representative Acute Myeloid Leukemia (AML) patient-derived xenograft (PDX) resource.

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Screening for blood-borne biomarkers of adiponectin action using the receptor agonist ALY688

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2024-10-30 | GSE275088 | GEO

The analysis of microRNA expression in tears of Kazakh patients with climatic droplet keratopathy in Xinjiang, China

Project description:Climatic droplet keratopathy (CDK) is characterized by increased oil-like deposits on the anterior elastic lamina and anterior stromal layer. The pathogenic mechanisms of CDK are poorly understood. Sampling corneal tissue from CDK patients is challenging. Therefore, in this study, we analyzed the microRNA (miRNA) expression profile in tear samples of CDK patients and their putative roles in CDK pathogenesis to identify possible biomarkers.

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In vitro expression in FGFR inhibitor sensitive and resistant cell lines

Project description:The challenge of developing effective pharmacodynamic biomarkers for pre-clinical and clinical testing of FGFR signalling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signalling inhibition by AZD4547, a potent inhibitor of FGF receptor 1, 2 and 3, a gene expression profiling study was performed in FGFR2 amplified drug sensitive tumour cell lines.

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