Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

ABSTRACT: The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

PROVIDER: PRJNA1088758 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

A proof-of-concept phase 2 study of the CHK1 inhibitor prexasertib with translational study outcomes in platinum-resistant recurrent, BRCA wild-type high-grade serous ovarian carcinoma

Project description:This proof-of-concept phase 2 trial (NCT02203513) evaluated the clinical activity of the CHK1 inhibitor (CHK1i), prexasertib, in platinum-resistant (PR) recurrent high-grade serous ovarian carcinoma (HGSOC) patients without BRCA mutation. The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. 49 heavily-pretreated patients were enrolled. Among the 39 RECISTv1.1-evaluable patients, ORR was 30.7%, the median PFS was 5.8 months. Toxicity was manageable. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3, MCM7) associated with lack of clinical benefit. Subsequent preclinical experiments demonstrated synthetic lethality of POLA1 inhibition in combination with CHK1i in PR-HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

2024-02-22 | GSE249587 | GEO

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

Project description:The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

| PRJNA1088759 | ENA

A proof-of-concept phase 2 study of the CHK1 inhibitor prexasertib with translational study outcomes in platinum-resistant recurrent, BRCA wild-type high-grade serous ovarian carcinoma

Project description:A proof-of-concept phase 2 study of the CHK1 inhibitor prexasertib with translational study outcomes in platinum-resistant recurrent, BRCA wild-type high-grade serous ovarian carcinoma

| PRJNA1049777 | ENA

Effect of prexasertib on disease progression and survival in High grade serous ovarian cancer patients

Project description:The goal of this study was to compare transcription profiles of high grade serous ovarian cancer (HGSOC) patients at Day 0 and Day 15 of a single course Prexasertib treatment at 105mg/m2 intravenously over 1 hour. HGSOC patients recruited for this study were women aged 18 and older with most (79%) showing platinum resistant or refractory disease. Total RNA from patients before (Day 0, n=18) and 2 weeks after Prexasertib treatment (Day15, n=11) were prepared from frozen biopsies, and analysed using HiSeq4000 using Illumina TruSeq Stranded Total RNA Library Prep and paired-end sequencing. Data is shown as quartile normalized CPM-TMM values. Patient survival and response was monitored till end of study. Our study show that prexasertib has clinical benefit in HGSOC patients.

2020-05-02 | GSE149723 | GEO

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

Project description:The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

| S-EPMC10981752 | biostudies-literature

A pan-cancer transcriptome analysis to identify the molecular mechanism of prexasertib resistance_RNASeq

Project description:The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms which protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity. We included RNASseq data here as part of the study. Microarray data was uploaded separately.

2020-02-05 | GSE143152 | GEO

Transcriptional profiling of platinum sensitive and platinum resistant high grade serous ovarian cancer samples

Project description:This study aims at correlating changes in the transcriptional state in high grade serous epithelial ovarian cancer (HGS-EOC) to the response to therapy, in particular the insurgence of resistance to platinum-based treatment.

2020-02-11 | E-MTAB-7083 | biostudies-arrayexpress

microRNA profiling of platinum sensitive and platinum resistant high grade serous ovarian cancer samples

Project description:This study aims at correlating changes in the microRNA state in high grade serous epithelial ovarian cancer (HGS-EOC) to the response to therapy, in particular the insurgence of resistance to platinum-based treatment.

2020-02-11 | E-MTAB-7084 | biostudies-arrayexpress

A pan-cancer transcriptome analysis to identify the molecular mechanism of prexasertib resistance [microarray]

Project description:The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms which protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity. We included microarray data here as part of the study. RNAseq data was uploaded separately.

2020-02-24 | GSE143007 | GEO

RNA-seq profiling of A549 cells with sgRNA knockouts that confer prexasertib resistance

Project description:A549 cells with FOXM1 or LIN54 sgRNA knockout, which confers resistance to the CHK1 inhibitor prexasertib, were generated. These cells and control (empty vector) cells were synchronized in S phase, released for 1 hour and treated with 100 nM prexasertib or DMSO (vehicle) for 2 hours. RNA-seq profiling was performed to identify drug-induced perturbations in gene expression in these cells.

2021-02-24 | GSE154545 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data