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Cancer Medicine Dec 2014Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of...
Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥ 50% reduction in IC50 ) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. 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.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Cell Line, Tumor; Chemoradiotherapy; Cisplatin; Drug Synergism; Etoposide; Humans; In Vitro Techniques; Lung Neoplasms; Mice; Mice, Nude; Poly(ADP-ribose) Polymerase Inhibitors; Random Allocation; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays
PubMed: 25124282
DOI: 10.1002/cam4.317 -
Journal of Clinical Oncology : Official... Jul 2020
Topics: Adenocarcinoma; Benzimidazoles; Cisplatin; Deoxycytidine; Fanconi Anemia Complementation Group N Protein; Germ Cells; Humans; Mutation; Pancreas; Gemcitabine
PubMed: 32407214
DOI: 10.1200/JCO.20.00833 -
ACS Chemical Biology Oct 2018The poly(ADP-ribose) polymerase (PARP) family of enzymes plays a crucial role in cellular and molecular processes including DNA damage detection and repair and...
The poly(ADP-ribose) polymerase (PARP) family of enzymes plays a crucial role in cellular and molecular processes including DNA damage detection and repair and transcription; indeed, PARP inhibitors are under clinical evaluation as chemotherapeutic adjuncts given their capacity to impede genomic DNA repair in tumor cells. Conversely, overactivation of PARP can lead to NAD depletion, mitochondrial energy failure, and cell death. Since PARP activation facilitates genomic but impedes mitochondrial DNA repair, nonselective PARP inhibitors are likely to have opposing effects in these cellular compartments. Herein, we describe the synthesis and evaluation of the mitochondria-targeting PARP inhibitor, XJB-veliparib. Attachment of the hemigramicidin S pentapeptide isostere for mitochondrial targeting using a flexible linker at the primary amide site of veliparib did not disrupt PARP affinity or inhibition. XJB-veliparib was effective at low nanomolar concentrations (10-100 nM) and more potent than veliparib in protection from oxygen-glucose deprivation (OGD) in primary cortical neurons. Both XJB-veliparib and veliparib (10 nM) preserved mitochondrial NAD after OGD; however, only XJB-veliparib prevented release of NAD into cytosol. XJB-veliparib (10 nM) appeared to inhibit poly(ADP-ribose) polymer formation in mitochondria and preserve mitochondrial cytoarchitecture after OGD in primary cortical neurons. After 10 nM exposure, XJB-veliparib was detected by LC-MS in mitochondria but not nuclear-enriched fractions in neurons and was observed in mitoplasts stripped of the outer mitochondrial membrane obtained from HT22 cells. XJB-veliparib was also effective at preventing glutamate-induced HT22 cell death at micromolar concentrations. Importantly, in HT22 cells exposed to HO to produce DNA damage, XJB-veliparib (10 μM) had no effect on nuclear DNA repair, in contrast to veliparib (10 μM) where DNA repair was retarded. XJB-veliparib and analogous mitochondria-targeting PARP inhibitors warrant further evaluation in vitro and in vivo, particularly in conditions where PARP overactivation leads to mitochondrial energy failure and maintenance of genomic DNA integrity is desirable, e.g., ischemia, oxidative stress, and radiation exposure.
Topics: Animals; Benzimidazoles; Cell Death; Cell Line; DNA Repair; Mice; Mitochondria; NAD; Neurons; Neuroprotective Agents; Oligopeptides; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Rats, Sprague-Dawley
PubMed: 30184433
DOI: 10.1021/acschembio.8b00423 -
Cancer Chemotherapy and Pharmacology Feb 2019Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in...
PURPOSE
Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design.
METHODS
Population pharmacokinetic analysis was performed using Phoenix NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CL), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival.
RESULTS
A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CL and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure.
CONCLUSIONS
Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure-safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure-efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit-risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Leukemia, Myeloid, Acute; Male; Maryland; Middle Aged; Models, Statistical; Mucositis; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Temozolomide; Tissue Distribution; Young Adult
PubMed: 30456480
DOI: 10.1007/s00280-018-3731-4 -
Oncology Letters Oct 2020Epithelial ovarian cancer (EOC) has a poor prognosis. Since the introduction of paclitaxel as antineoplastic agent >20 years ago, only a few phase III randomized trials... (Review)
Review
Epithelial ovarian cancer (EOC) has a poor prognosis. Since the introduction of paclitaxel as antineoplastic agent >20 years ago, only a few phase III randomized trials have shown challenging data regarding different therapeutic options for facing its aggressive clinical course and granting active therapies to patients. Different studies have shown the utility of poly(ADP-ribose) polymerase (PARP) inhibitors in women with EOC with or without mutations, both germline and somatic. Three PARP inhibitors, olaparib, rucaparib and niraparib, have been recently approved by the Food and Drug Administration for clinical use in EOC patients, though with different clinical indications and profiles of toxicity, while two other molecules, veliparib and talazoparib, are still under clinical investigation. The aim of the present paper is to evaluate the current status of PARP inhibitors in terms of molecular activity, pharmacodynamic properties and clinical applications.
PubMed: 32831909
DOI: 10.3892/ol.2020.11951 -
Cancer Chemotherapy and Pharmacology Apr 2020Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents...
Phase I and pharmacokinetic study of veliparib, a PARP inhibitor, and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up.
OBJECTIVE
Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients.
METHODS
Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1-14 with PLD 40 mg/mg on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added.
RESULTS
44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID.
CONCLUSIONS
The RP2D is 200 mg veliparib BID on days 1-14 with 40 mg/m PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Doxorubicin; Female; Follow-Up Studies; Genital Neoplasms, Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Glycols; Prognosis; Survival Rate; Tissue Distribution; Triple Negative Breast Neoplasms
PubMed: 32055930
DOI: 10.1007/s00280-020-04030-2 -
Minerva Ginecologica Apr 2018Poly(ADP-ribose) polymerase (PARP) inhibitors are a targeted therapy option for ovarian cancer. The goal of this review was to organize and summarize the clinical trials... (Review)
Review
INTRODUCTION
Poly(ADP-ribose) polymerase (PARP) inhibitors are a targeted therapy option for ovarian cancer. The goal of this review was to organize and summarize the clinical trials evaluating PARP inhibitor therapy in ovarian cancer as monotherapy, maintenance therapy after partial or complete remission to therapy or as a part of a combination regimen.
EVIDENCE ACQUISITION
PubMed, ClinicalTrials.gov, data from the United States Food and Drug Administration (US FDA) and proceedings from scientific conferences were searched for published and unpublished data pertaining to clinical trials and approvals of PARP inhibitor use in ovarian cancer.
EVIDENCE SYNTHESIS
There have been 36 published phase 1, 2 and 3 studies evaluating the use of olaparib, niraparib, veliparib and rucaparib in ovarian cancer. Olaparib and rucaparib have been approved by the US FDA as monotherapy for advanced recurrent ovarian cancer. Niraparib and olaparib have been approved by the US FDA for maintenance therapy after partial or complete remission in recurrent ovarian cancer. There are currently ten phase 3 trials evaluating PARP inhibitors at various timepoints in ovarian cancer therapy including at the time of primary adjuvant therapy, as maintenance therapy after primary chemotherapy, as monotherapy for recurrent cancer and as maintenance therapy after chemotherapy for recurrence.
CONCLUSIONS
The landscape of PARP inhibitor use for ovarian cancer is rapidly evolving and PARP inhibitors have become more available as a targeted therapy option for ovarian cancer treatment.
Topics: Antineoplastic Agents; Female; Humans; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Remission Induction; Time Factors
PubMed: 28994564
DOI: 10.23736/S0026-4784.17.04152-1 -
Cancers Jun 2023Among ovarian cancer patients with mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib,... (Review)
Review
Prevalence of Homologous Recombination Deficiency in First-Line PARP Inhibitor Maintenance Clinical Trials and Further Implication of Personalized Treatment in Ovarian Cancer.
Among ovarian cancer patients with mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib, niraparib, veliparib, and rucaparib has been proven in a number of clinical trials. mutation and HRD are currently indicated for PARP inhibitor maintenance treatment in ovarian cancer. HRD diagnostic tests examine various components, resulting in different HRD status definitions and, as a result, different treatment decisions. A number of HRD diagnostic tests exist, but test results provided by different companies may differ as they use different methods and different cutoffs. HRD prevalence difference was shown between PARP inhibitor maintenance trials. It is important to select an appropriate method that can present accurate HRD phenotypes to predict sensitivity to PARP inhibitors so that patients who are most likely to benefit from treatment are selected. Additionally, in the subset data of the PARP inhibitor maintenance trials, there was a difference in HRD prevalence by race as higher HRD prevalence in Japanese and Chinese ovarian cancer patients was shown. Further large-scale investigations on racial differences in HRD prevalence are needed and this may contribute to changes in determining the treatment plan and personalized treatment in ovarian cancer patients.
PubMed: 37370704
DOI: 10.3390/cancers15123095 -
Neuro-oncology Jun 2020A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly...
BACKGROUND
A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series.
METHODS
Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity.
RESULTS
Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively.
CONCLUSION
Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG.
TRIAL REGISTRATION
NCT01514201.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Brain Neoplasms; Brain Stem Neoplasms; Child; Glioma; Humans; Temozolomide
PubMed: 32009149
DOI: 10.1093/neuonc/noaa016 -
Therapeutic Advances in Medical Oncology 2021To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative,...
Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline / mutations and hormone receptor status from the phase-3 BROCADE3 trial.
PURPOSE
To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline (g)-associated breast cancer defined by hormone receptor (HR) and g/ mutation status.
PATIENTS AND METHODS
In this phase-3, double-blind, placebo-controlled trial, patients ( = 509) with advanced HER2-negative breast cancer and g mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and g mutation status were prespecified.
RESULTS
In the intention-to-treat population, there were similar proportions of patients with g g mutations (51% 49%) and HR+ disease triple-negative breast cancer (TNBC) (52% 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), = 0.013; TNBC: 16.6 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), = 0.052; g: 14.2 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), = 0.073; g: 14.6 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% 15.3%; TNBC, 40.4% 25.0%) and 3 years (HR+, 17.5% 8.6%; TNBC, 35.3% 13.0%) in all subgroups. g status () did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile.
CONCLUSION
Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by g g mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the g g and HR+ TNBC subgroups.
TRIAL REGISTRATION
NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.
PubMed: 34917174
DOI: 10.1177/17588359211059601