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1.
Cancers (Basel) ; 11(3)2019 Mar 13.
Article in English | MEDLINE | ID: mdl-30871186

ABSTRACT

Dysfunctional homologous recombination DNA repair (HRR), frequently due to BRCA mutations, is a determinant of sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi). In cultures of ovarian cancer cells, we have previously shown that HRR function, based upon RAD51 foci quantification, correlated with growth inhibition ex vivo induced by rucaparib (a PARPi) and 12-month survival following platinum chemotherapy. The aim of this study was to determine the feasibility of measuring HRR dysfunction (HRD) in other tumours, in order to estimate the frequency and hence wider potential of PARPi. A total of 24 cultures were established from ascites sampled from 27 patients with colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, mesothelioma, and non-epithelial ovarian cancers; 8 were HRD. Cell growth following continuous exposure to 10 µM of rucaparib was lower in HRD cultures compared to HRR-competent (HRC) cultures. Overall survival in the 10 patients who received platinum-based therapy was marginally higher in the 3 with HRD ascites (median overall survival of 17 months, range 10 to 90) compared to the 7 patients with HRC ascites (nine months, range 1 to 55). HRR functional assessment in primary cultures, from several tumour types, revealed that a third are HRD, justifying the further exploration of PARPi therapy in a broader range of tumours.

2.
Cancer Discov ; 7(6): 620-629, 2017 06.
Article in English | MEDLINE | ID: mdl-28242752

ABSTRACT

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.


Subject(s)
Antineoplastic Agents/therapeutic use , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Neoplasms/drug therapy , Phthalazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Female , Germ-Line Mutation , Humans , Leukocytes, Mononuclear/enzymology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/enzymology , Neoplasms/genetics , Phthalazines/administration & dosage , Phthalazines/adverse effects , Phthalazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/blood , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Treatment Outcome , Young Adult
3.
Oncotarget ; 6(41): 43978-91, 2015 Dec 22.
Article in English | MEDLINE | ID: mdl-26539646

ABSTRACT

In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors.We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 - 190052 pmol PAR/106 cells) compared to that seen in healthy volunteer lymphocytes (2451 - 7519 pmol PAR/106 cells). PARP activity was associated with PARP1 protein expression and endogenous PAR levels. PARP activity was not associated with p53 or ATM loss, Binet stage, IGHV mutational status or survival, but correlated with Bcl-2 and Rel A (an NF-kB subunit). Levels of 8-hydroxy-2'-deoxyguanosine in DNA (a marker of oxidative damage) were not associated with PAR levels or PARP activity. The potent PARP inhibitor, talazoparib (BMN 673), inhibited CD40L-stimulated proliferation of CLL cells at nM concentrations, independently of Binet stage or p53/ATM function.PARP activity is highly variable in CLL and correlates with stress-induced proteins. Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Phthalazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Adult , Area Under Curve , Biomarkers, Tumor , DNA Damage/drug effects , Enzyme-Linked Immunosorbent Assay , Female , Humans , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Male , Middle Aged , Poly (ADP-Ribose) Polymerase-1 , ROC Curve , Sensitivity and Specificity
4.
Oncotarget ; 6(32): 32396-409, 2015 Oct 20.
Article in English | MEDLINE | ID: mdl-26486089

ABSTRACT

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure.Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs.Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine.


Subject(s)
Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , DNA Damage , DNA Repair , Glioblastoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Sulfones/pharmacology , Animals , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , CHO Cells , Cell Line, Tumor , Computational Biology , Cricetinae , Cricetulus , DNA Repair/genetics , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , DNA-Activated Protein Kinase/genetics , DNA-Activated Protein Kinase/metabolism , Databases, Genetic , Dose-Response Relationship, Drug , G2 Phase Cell Cycle Checkpoints/drug effects , Gene Expression Profiling/methods , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Glioblastoma/enzymology , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Molecular Targeted Therapy , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction/drug effects , Time Factors , Transfection
5.
Cell Cycle ; 11(24): 4650-60, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23187806

ABSTRACT

The relationships between the kinetochore and checkpoint control remain unresolved. Here, we report the characterization of the in vivo behavior of Cdc20 and Mad2 and the relevant spindle assembly checkpoint (SAC) functions in the neuroblasts of a Drosophila Mps1 weak allele (ald (B4-2) ). ald (B4-2) third instar larvae brain samples contain only around 16% endogenous Mps1 protein, and the SAC function is abolished. However, this does not lead to rapid anaphase onset and mitotic exit, in contrast to the loss of Mad2 alone in a mad2 (EY) mutant. The level of GFP-Cdc20 recruitment to the kinetochore is unaffected in ald (B4-2) neuroblasts, while the level of GFP-Mad2 is reduced to just about 20%. Cdc20 and Mad2 display only monophasic exponential kinetics at the kinetochores. The ald (B4-2) heterozygotes expressed approximately 65% of normal Mps1 protein levels, and this is enough to restore the SAC function. The kinetochore recruitment of GFP-Mad2 in response to SAC activation increases by around 80% in heterozygotes, compared with just about 20% in ald (B4-2) mutant. This suggests a correlation between Mps1 levels and Mad2 kinetochore localization and perhaps the existence of a threshold level at which Mps1 is fully functional. The failure to arrest the mitotic progression in ald (B4-2) neuroblasts in response to colchicine treatment suggests that when Mps1 levels are low, approximately 20% of normal GFP-Mad2, alongside normal levels of GFP-Cdc20 kinetochore recruitments, is insufficient for triggering SAC signal propagation.


Subject(s)
Cell Cycle Proteins/metabolism , Drosophila Proteins/metabolism , Kinetochores/metabolism , M Phase Cell Cycle Checkpoints/physiology , Protein Serine-Threonine Kinases/metabolism , Animals , Cdc20 Proteins , Cell Cycle Proteins/genetics , Drosophila Proteins/genetics , Drosophila melanogaster , Heterozygote , M Phase Cell Cycle Checkpoints/genetics , Mad2 Proteins , Protein Serine-Threonine Kinases/genetics
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