Predictor RIO TNBC
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001002805 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:In this study, samples fom a window study of the PARP inhibitor rucaparib in patients with primary triple negative or BRCA1/2 related breast cancer (RIO trial) will be investigated. Samples will undergo whole genome sequence and analysis, including use of HR Predict. .
This dataset contains all the data available for this study on 2019-04-03.
| EGAD00001004894 | EGA
Project description:Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary endpoint, decreased Ki67, occurs in 12% of TNBC. Multiple different approaches identify HR deficiency in the majority of TNBC, 69% with the mutational-signature-based HRDetect assay. Cancers with mutational signatures of HR deficiency have a functional defect in HR. Following rucaparib treatment there is no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identify activity of rucaparib in cancers with mutation-signatures of HR deficiency, with rucaparib inducing expression of interferon response genes in HR deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.
| EGAS00001004405 | EGA
Project description:Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage responsefactor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice, and rescues HR deficiency, as measured by hypersensitivity to PARP (polyADPribose polymerase) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA cross-link repair that is distinct from HR. Disruption of the non-homologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi Anemia pathway for ICL repair. Brca1 therefore has two separate roles in ICL repair, whereas FANCD2 provides a key activity that can not be bypassed by ablation of 53BP1 or Ku. B cells were stimulated to undergo class switch recombination in vitro. Chromatin from B cells was harvested 72 hours post-stimulation and used for RPA ChIP to study the extent of resection of DNA DSBs.
2012-09-30 | E-GEOD-35698 | biostudies-arrayexpress
Project description:To detect the off-target effects of PARP inhibition, a quantitative mass spectrometry-based proteomic analysis was conducted of a BRCA1-mutated HGSOC cell line treated with low doses of two PARPi, Niraparib and Rucaparib.
2022-04-15 | PXD027177 | Pride
Project description:Sister chromatid exchanges (SCEs) are a product of joint DNA molecules resolution, and are considered to require homologous recombination (HR). Canonical HR factors BRCA1, BRCA2 and RAD51 were indeed essential for SCE induction in response to irradiation-induced DNA breaks. By contrast, replication-blocking agents, including PARP inhibitors, induced SCEs independently of BRCA1, BRCA2 or RAD51. HR-independent SCEs were associated with incomplete DNA replication, as evidenced by post-replicative single-stranded DNA (ssDNA) accumulation and enrichment of PARP inhibitor-induced SCEs at common fragile sites (CFSs). Importantly, PARP-induced DNA lesions were transmitted into mitosis, pointing towards SCEs originating from mitotic processing of underreplicated DNA. We found polymerase theta to be associated to mitotic DNA lesions, to be required for SCE formation and to prevent chromosome fragmentation upon PARP inhibition in HR-defective cells. Combined, our data show that replication-blocking agents lead to underreplicated DNA in mitosis, which is processed into SCEs independently of canonical HR factors.
2023-03-11 | PXD028670 | Pride
Project description:Inhibitors of nuclear poly(ADP-ribose) polymerase (PARP) enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes.
2019-10-01 | GSE136155 | GEO
Project description:In this study a collection of core biopsies from breast cancer patients receiving neoadjuvant chemotherapy as part of the ChemoNEAR trial will be investigated. The study is intended to detect early acquired resistance in women with diagnosed breast carcinoma. Samples will undergo whole genome sequencing and analysis, including use of HR Predict.
| EGAS00001002806 | EGA
Project description:The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially these harboring BRCA1/2 mutations. The cancer associated BRCA1/2 mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting accumulation of toxic DSBs. Unfortunately, PARP inhibitor (PARPi) resistance is common and develops through multiple mechanisms. Restoration of HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we undertook an unbiased approach with a CRISPR-pooled library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and confirmed its loss-of-function led to the PARPi resistance in BRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi. Taken together, our study identified a novel gene whose loss of function conferred resistance to PARPi, providing new insight into signaling pathways that contribute to acquired resistance in BRCA1-mutated breast and ovarian cancers.
2023-05-31 | GSE205221 | GEO
Project description:Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage responsefactor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice, and rescues HR deficiency, as measured by hypersensitivity to PARP (polyADPribose polymerase) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA cross-link repair that is distinct from HR. Disruption of the non-homologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi Anemia pathway for ICL repair. Brca1 therefore has two separate roles in ICL repair, whereas FANCD2 provides a key activity that can not be bypassed by ablation of 53BP1 or Ku.
2012-09-30 | GSE35698 | GEO
Project description:Inhibitors of PARP (PARPis) represent the first clinically approved anticancer agents targeting the DNA damage response. They have been approved as monotherapy and/or in combination and maintenance settings in different tumor types, including high-grade ovarian carcinomas. Their efficacy was first underlined in cells with functional inactivation of BRCA1 and BRCA2 genes and this strong preclinical evidence prompted their clinical development in tumors with BRCA1/BRCA2 mutations. It was later demonstrated that PARPis were very effective in tumors displaying deficiency in homologous recombination (HR) repair beyond BRCA1 and BRCA2 loss of function. In addition, evidence from randomized clinical trials supports their efficacy also in tumors with intact HR repair, although to a lesser extent.
2023-09-14 | E-MTAB-13055 | biostudies-arrayexpress