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Phase I study of Veliparib in combination with Cisplatin and Vinorelbine for patients with advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer

ABSTRACT: PURPOSE: Preclinically, cisplatin is synergistic with vinorelbine and the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib, and has anti-neoplastic activity in TNBC and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. PATIENTS AND METHODS: A 3+3 dose escalation design evaluated veliparib administered BID for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1,8) every 21 days, for six to ten cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. Immunohistochemistry and gene expression profiling were performed to evaluate potential predictors of response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE72795 | GEO | 2015/09/09

SECONDARY ACCESSION(S): PRJNA295080

REPOSITORIES: GEO

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Phase I study of Veliparib in combination with Cisplatin and Vinorelbine for patients with advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer

Project description:PURPOSE: Preclinically, cisplatin is synergistic with vinorelbine and the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib, and has anti-neoplastic activity in TNBC and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. PATIENTS AND METHODS: A 3+3 dose escalation design evaluated veliparib administered BID for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1,8) every 21 days, for six to ten cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. Immunohistochemistry and gene expression profiling were performed to evaluate potential predictors of response. Thirty-nine samples were assessed, six samples were run as technical duplicates. Two of the samples had a high rate of missing probes and were excluded during the normalization/pre-processing. Each sample represents a pre- or post-treatment breast cancer specimen from individual patients.

2015-09-09 | E-GEOD-72795 | biostudies-arrayexpress

IGR_Michels_PARP

Project description:Non-small cell lung cancer (NSCLC) is often treated with cisplatin (CDDP). Here, we report that two distinct poly(ADP-ribose) polymerase (PARP) inhibitors exhibited a hyperadditive combination effect with CDDP to kill NSCLC cells. A majority of CDDP-resistant cell lines and clones exhibited constitutively increased PARP expression and enzymatic activity. Cells with hyperactivated PARP initiated a DNA damage response and the intrinsic pathway of apoptosis in response to pharmacological PARP inhibition or PARP1-targeting siRNAs. Transcriptome analysis depicted an unsupervised hierarchical clustering of NSCLC cells and CDDP resistant counterparts regarding to their response to PARP inhibitors. PARP-overexpressing tumors displayed elevated levels of intracellular poly(ADP-ribose) (PAR), which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP expression itself. Thus, CDDP-resistant cancer cells develop a dependency to PARP, becoming susceptible to PARP inhibitor-induced apoptosis.

2013-10-31 | E-MTAB-1353 | biostudies-arrayexpress

Expression Analysis Upon PARP-1 or PARG Knockdown in MCF-7 Cells

Project description:Poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG) are enzymes that modify target proteins in the nucleus by the addition and removal, respectively, of ADP-ribose polymers. Although a role for PARP-1 in gene regulation has been well established, the role of PARG is less clear. To investigate how PARP-1 and PARG coordinately regulate global patterns of gene expression, we used short hairpin RNAs (shRNAs) to stably knockdown PARP-1 or PARG in MCF-7 cells, followed by expression microarray analyses.

2009-10-23 | GSE12952 | GEO

Loss of ZBTB24, a novel non-homologous end-joining protein, impairs class-switch recombination in ICF syndrome

Project description:The autosomal recessive immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite recent successes in the identification of the underlying gene defects, it is currently unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from ICF2 patients impairs non-homologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and subtype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates auto-poly(ADP-ribosyl)ation of this enzyme. The zinc finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, by binding to poly(ADP-ribose) chains ZBTB24 protects these moieties from degradation by poly(ADP-ribose) glycohydrolase (PARG). This enhances the poly(ADP-ribose)-dependent interaction between PARP1 and the LIG4/XRCC4 NHEJ complex and promotes NHEJ by facilitating the assembly of this repair complex at DNA breaks. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF syndrome.

2020-08-19 | PXD014741 | Pride

A Study of Hansoh (HS)-10502 in Patients With Advanced Solid Tumors

Project description:HS-10502 is a Poly(ADP-ribose) polymerase 1 (PARP1)-specific selective inhibitor. The purpose if this study is to assess the safety, tolerability, pharmacokinetics (PK), and efficacy of HS-10502 in subjects with homologous recombination repair (HRR) gene mutant or homologous recombination deficiency (HRD) positive advanced solid tumors.

| 9330 | ecrin-mdr-crc

Evaluation of poly (ADP) ribose polymerase (PARP) inhibitor, veliparib (ABT-888), in combination with platinum, etoposide and radiation in small cell lung cancer

Project description:Veliparib showed limited single agent cytotoxicity but selectively potentiated (≥50% reduction in IC50) cisplatin, carboplatin and etoposide in vitro in 5 of 9 SCLC cell lines. Veliparib with cisplatin, etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC=0.672; p=0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2 and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.

2014-12-31 | GSE55830 | GEO

Deletion of TIPARP increases sensitivity to dioxin-induced hepatosteatosis and lethality

Project description:The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that mediates the toxic effects of the environmental contaminant, dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD). Dioxin causes a diverse range of toxic responses, including hepatic damage and lethal wasting syndrome; however, the mechanisms of dioxin-induced toxicity are still unknown. Here we show that the loss of TCDD-inducible poly(ADP-ribose) polymerase (TIPARP; ARTD14), an ADP-ribosyltransferase and AHR repressor, increases sensitivity to dioxin-induced toxicity and lethality. Tiparp-/- mice treated with a single injection of 100 mg/kg dioxin display an accelerated lethal wasting syndrome with no Tiparp-/- mice surviving beyond day 5; all Tiparp+/+ mice survived up to 30 days post treatment. Tiparp-/- mice displayed dramatic increases in liver steatosis and hepatotoxicity. At the molecular level, TIPARP selectively ADP-ribosylates AHR, but not AHR nuclear translocator (ARNT) and the Tiparp-dependent repression of AHR is reversed by the ADP-ribosylase and macrodomain containing protein MacroD1, but not MacroD2. These results describe previously unidentified roles for Tiparp, MacroD1, and ADP-ribosylation in AHR signaling, dioxin toxicity and lethality.

2015-05-14 | GSE61534 | GEO

Comparative gene expression in adult SVZ-neurospheres neuronally differentiated under standard conditions and upon PARP1 inhibition

Project description:The relevance of DNA-dependent poly-ADP ribose production for neuronal differentiation of adult stem- and progenitor cells from the SVZ was studied. To identify genes whose up- or downregulation during neuronal differentiation requires the activity of poly-ADP-Ribosylase (PARP) 1 or 2, SVZ-derived adult neurosphere cultures were differentiated in the presence or absence of Olaparib.

2017-07-17 | GSE74314 | GEO

Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging

Project description:Cockayne syndrome (CS) is an accelerated aging disorder, caused by mutations in the CSA or CSB genes. In CSB-deficient cells, poly (ADP ribose) polymerase (PARP) is persistently activated by unrepaired DNA damage and PARP consumes and depletes cellular nicotinamide adenine dinucleotide (NAD), which leads to mitochondrial dysfunction. Here, the distribution of poly (ADP ribose) (PAR) was determined in CSB-deficient cells using ADPr-ChAP (ADP ribose-chromatin affinity purification), and the results show striking enrichment of PAR at transcription start sites (TSS), depletion of heterochromatin, and downregulation of H3K9me3-specific methyltransferases SUV39H1 and SETDB1. Induced-expression of SETDB1 in CSB-deficient cells downregulated PAR and normalized mitochondrial function. The results suggest that defects in CSB are strongly associated with loss of heterochromatin, downregulation of SETDB1, increased PAR in highly-transcribed regions, and mitochondrial dysfunction.

2019-06-22 | GSE133176 | GEO

Metabolic responses induced by DNA damage and poly (ADP-ribose) polymerase (PARP) inhibition in MCF-7 cells

Project description:Genomic instability is one of the hallmarks of cancer. Several chemotherapeutic drugs and radiotherapy induce DNA damage to prevent cancer cell replication. Cells in turn activate different DNA damage response (DDR) pathways to either repair the damage or induce cell death. These DDR pathways also elicit metabolic alterations which can play a significant role in the proper functioning of the cells. The understanding of these metabolic effects resulting from different types of DNA damage and repair mechanisms is currently lacking. In this study, we used NMR metabolomics to identify metabolic pathways which are altered in response to different DNA damaging agents. By comparing the metabolic responses in MCF-7 cells, we identified the activation of poly (ADP-ribose) polymerase (PARP) in methyl methanesulfonate (MMS)-induced DNA damage. PARP activation led to a significant depletion of NAD+. PARP inhibition using veliparib (ABT-888) was able to successfully restore the NAD+ levels in MMS-treated cells. In addition, double strand break induction by MMS and veliparib exhibited similar metabolic responses as zeocin, suggesting an application of metabolomics to classify the types of DNA damage responses. This prediction was validated by studying the metabolic responses elicited by radiation. Our findings indicate that cancer cell metabolic responses depend on the type of DNA damage responses and can also be used to classify the type of DNA damage.

2015-08-01 | MTBLS177 | MetaboLights

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