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Science (New York, N.Y.) Nov 2018The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic α-syn causes...
The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.
Topics: Animals; Benzimidazoles; Brain; Cell Death; Dopaminergic Neurons; Enzyme Activation; Gene Knockout Techniques; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Parkinson Disease; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Recombinant Proteins; alpha-Synuclein
PubMed: 30385548
DOI: 10.1126/science.aat8407 -
ACS Medicinal Chemistry Letters May 2023Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and...
Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also supports their application as neuroprotective agents since PARP overactivation compromises the mitochondrial homeostasis by consumption of NAD reserves, leading to an increase in reactive oxygen and nitrogen species and a spike in intracellular Ca levels. Herein, we present the synthesis and preliminary evaluation of new mitochondria-targeting PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance potential neuroprotective properties without impairing the repair of damaged DNA in the nucleus.
PubMed: 37197461
DOI: 10.1021/acsmedchemlett.3c00065 -
Gynecologic Oncology Feb 2022In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian... (Randomized Controlled Trial)
Randomized Controlled Trial
Impact of veliparib, paclitaxel dosing regimen, and germline BRCA status on the primary treatment of serous ovarian cancer - an ancillary data analysis of the VELIA trial.
OBJECTIVE
In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status.
METHODS
Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status.
RESULTS
1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCAwt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n = 211) and gBRCAwt (n = 902) subgroups.
CONCLUSIONS
DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Carcinoma, Ovarian Epithelial; Drug Administration Schedule; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Hereditary Breast and Ovarian Cancer Syndrome; Humans; Induction Chemotherapy; Maintenance Chemotherapy; Middle Aged; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Paclitaxel; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Young Adult
PubMed: 34930617
DOI: 10.1016/j.ygyno.2021.12.012 -
Annals of Oncology : Official Journal... Sep 2020In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of... (Review)
Review
BACKGROUND
In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm.
DESIGN
We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need.
RESULTS
Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety.
CONCLUSIONS
PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority.
Topics: Carcinoma, Ovarian Epithelial; Clinical Trials as Topic; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 32569725
DOI: 10.1016/j.annonc.2020.06.004 -
Cell Nov 2020Strategies for installing authentic ADP-ribosylation (ADPr) at desired positions are fundamental for creating the tools needed to explore this elusive post-translational...
Strategies for installing authentic ADP-ribosylation (ADPr) at desired positions are fundamental for creating the tools needed to explore this elusive post-translational modification (PTM) in essential cellular processes. Here, we describe a phospho-guided chemoenzymatic approach based on the Ser-ADPr writer complex for rapid, scalable preparation of a panel of pure, precisely modified peptides. Integrating this methodology with phage display technology, we have developed site-specific as well as broad-specificity antibodies to mono-ADPr. These recombinant antibodies have been selected and characterized using multiple ADP-ribosylated peptides and tested by immunoblotting and immunofluorescence for their ability to detect physiological ADPr events. Mono-ADPr proteomics and poly-to-mono comparisons at the modification site level have revealed the prevalence of mono-ADPr upon DNA damage and illustrated its dependence on PARG and ARH3. These and future tools created on our versatile chemical biology-recombinant antibody platform have broad potential to elucidate ADPr signaling pathways in health and disease.
Topics: ADP-Ribosylation; Amino Acid Sequence; Antibodies; Benzimidazoles; Carrier Proteins; Cell Line, Tumor; Cell Surface Display Techniques; DNA Damage; Glycoside Hydrolases; Histones; Humans; Nuclear Proteins; Phosphates; Phosphoric Monoester Hydrolases; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Recombinant Proteins; Serine; Tyrosine
PubMed: 33186521
DOI: 10.1016/j.cell.2020.09.055 -
Journal of Clinical Oncology : Official... Nov 2021Squamous non-small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Squamous non-small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with conventional chemotherapy for advanced sqNSCLC (NCT02106546).
PATIENTS AND METHODS
Patients age ≥ 18 years with untreated, advanced sqNSCLC were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg twice daily (twice a day) or placebo twice a day for up to six cycles. The primary end point was overall survival (OS) in the veliparib arm versus the control arm in current smokers, based on phase II findings. Archival tumor samples were provided for biomarker analysis using a 52-gene expression histology classifier (LP52).
RESULTS
Overall, 970 patients were randomly assigned to carboplatin and paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were current smokers. There was no significant OS benefit with veliparib in current smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95% CI, 0.744 to 1.101; = .266). In the overall population, OS favored veliparib; median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with no difference in progression-free survival (median 5.6 months per arm). In patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib in the LP52-positive population (median 14.0 9.6 months; HR, 0.66; 95% CI, 0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were observed in the experimental arm.
CONCLUSION
In current smokers with advanced sqNSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carboplatin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Clinical Decision-Making; Female; Gene Expression Profiling; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Patient Selection; Progression-Free Survival; Smokers; Time Factors; Transcriptome
PubMed: 34436928
DOI: 10.1200/JCO.20.03318 -
European Journal of Cancer (Oxford,... Mar 2024In the BROCADE3 study, the addition of veliparib to carboplatin plus paclitaxel resulted in a significant improvement in progression-free survival (PFS) compared with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the BROCADE3 study, the addition of veliparib to carboplatin plus paclitaxel resulted in a significant improvement in progression-free survival (PFS) compared with placebo plus carboplatin and paclitaxel, in patients with germline BRCA1 or BRCA2 (BRCA1/2)-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We now report final overall survival (OS) data.
METHODS
BROCADE3 is a randomized phase 3 study that enrolled patients with BRCA1/2-mutated, HER2-negative advanced breast cancer who received ≤ 2 prior lines of chemotherapy for metastatic disease. Patients were randomized 2:1 to carboplatin and paclitaxel, dosed with either veliparib or matching placebo. OS was a secondary endpoint.
RESULTS
In the intention-to-treat population (N = 509), 337 patients were randomized to receive veliparib and 172 to placebo. Median OS was 32.4 months vs 28.2 months (hazard ratio, 0.916; 95% CI, 0.736-1.140; P = .434). The updated safety data for veliparib are consistent with those reported in the primary analysis; the addition of veliparib was generally well tolerated.
CONCLUSIONS
Final OS data indicate that the PFS improvement shown in the primary analysis did not translate into an OS benefit. The long survival times observed in both arms suggest that combination therapy with paclitaxel and carboplatin provides clinical benefit in the population of patients with BRCA1/2-mutated metastatic breast cancer.
Topics: Humans; Female; Breast Neoplasms; Carboplatin; Paclitaxel; BRCA1 Protein; BRCA2 Protein; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles
PubMed: 38309017
DOI: 10.1016/j.ejca.2024.113580 -
Annals of Oncology : Official Journal... Mar 2022In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio... (Randomized Controlled Trial)
Randomized Controlled Trial
Veliparib monotherapy following carboplatin/paclitaxel plus veliparib combination therapy in patients with germline BRCA-associated advanced breast cancer: results of exploratory analyses from the phase III BROCADE3 trial.
BACKGROUND
In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P = 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported.
PATIENTS AND METHODS
Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days -2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases.
RESULTS
A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo).
CONCLUSIONS
Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Carboplatin; Female; Germ Cells; Humans; Paclitaxel
PubMed: 34861374
DOI: 10.1016/j.annonc.2021.11.018 -
Science (New York, N.Y.) Apr 2020The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although...
The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.
Topics: Allosteric Regulation; Benzimidazoles; Cell Line, Tumor; DNA Breaks; DNA Damage; Humans; Isoindoles; Neoplasms; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Protein Domains
PubMed: 32241924
DOI: 10.1126/science.aax6367 -
Journal of Translational Medicine Mar 2017The O -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard...
BACKGROUND
The O -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM.
METHODS
The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors.
RESULTS
The combination of veliparib and RT inhibited colony formation in the majority of PDCLs tested. The PDCL, RN1 showed significantly reduced levels of the homologous repair protein, Mre11 and a heightened response to PARP inhibition measured by increased apoptosis and decreased colony formation. The oral administration of veliparib (12.5 mg/kg, twice daily for 5 days in a 28-day treatment cycle) in combination with whole brain RT (4 Gy) induced apoptosis (Tunel staining) and decreased cell proliferation (Ki67 staining) in a PDX of MGMT unmethylated GBM. Significantly longer survival times of the PDX treated with the combination treatment were recorded compared to RT only or veliparib only.
CONCLUSIONS
Our results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.
Topics: Animals; Apoptosis; Benzimidazoles; Brain Neoplasms; Cell Line, Tumor; Combined Modality Therapy; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Disease Models, Animal; Female; Glioblastoma; Humans; Mice, Nude; Survival Analysis; Tumor Suppressor Proteins
PubMed: 28314386
DOI: 10.1186/s12967-017-1164-1