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Veliparib

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https://www.readbyqxmd.com/read/29339456/parp-inhibition-prevents-ethanol-induced-neuroinflammatory-signaling-and-neurodegeneration-in-adult-age-rat-brain-slice-cultures
#1
Nuzhath F Tajuddin, Hee-Yong Kim, Michael A Collins
Utilizing rat adult-age hippocampal-entorhinal cortical (HEC) slice cultures we examined the role of poly [ADP-ribose] polymerase (PARP) in binge ethanol's brain inflammatory and neurodegenerative mechanisms. Activated by DNA strand breaks, PARP (principally PARP1 in brain) promotes DNA repair via poly [ADP-ribose] (PAR) products, but PARP overactivation triggers regulated neuronal necrosis, e.g., parthanatos. Previously we found that brain PARP1 levels were upregulated by neurotoxic ethanol binges in adult rats and HEC slices, and PARP inhibitor PJ34 abrogated slice neurodegeneration...
January 16, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29338080/phase-1-trial-evaluating-cisplatin-gemcitabine-and-veliparib-in-2-patient-cohorts-germline-brca-mutation-carriers-and-wild-type-brca-pancreatic-ductal-adenocarcinoma
#2
Eileen M O'Reilly, Jonathan W Lee, Maeve A Lowery, Marinela Capanu, Zsofia K Stadler, Malcolm J Moore, Neesha Dhani, Hedy L Kindler, Hayley Estrella, Hannah Maynard, Talia Golan, Amiel Segal, Erin E Salo-Mullen, Kenneth H Yu, Andrew S Epstein, Michal Segal, Robin Brenner, Richard K Do, Alice P Chen, Laura H Tang, David P Kelsen
BACKGROUND: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1...
January 16, 2018: Cancer
https://www.readbyqxmd.com/read/29285982/effects-of-veliparib-on-microglial-activation-and-functional-outcomes-following-traumatic-brain-injury-in-the-rat-and-pig
#3
Karen Irvine, Robin Bishop, Seok Joon Won, Jianguo Xu, Katherine Hamel, Valerie Coppes, Pardeep Singh, Andrew Sondag, Eric Rome, Jayinee Basu, Giordano Santos, S Scott Panter, Raymond Swanson
The inflammation response induced by brain trauma can impair recovery. This response requires several hours to fully develop, and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. Here we evaluated delayed treatment with veliparib, a poly(ADP-ribose) polymerase inhibitor currently in clinical trials as a cancer therapeutic, in rats and pigs subjected to controlled cortical impact (CCI)...
December 29, 2017: Journal of Neurotrauma
https://www.readbyqxmd.com/read/29261439/targeting-androgen-receptor-and-dna-repair-in-metastatic-castration-resistant-prostate-cancer-results-from-nci-9012
#4
Maha Hussain, Stephanie Daignault-Newton, Przemyslaw W Twardowski, Costantine Albany, Mark N Stein, Lakshmi P Kunju, Javed Siddiqui, Yi-Mi Wu, Dan Robinson, Robert J Lonigro, Xuhong Cao, Scott A Tomlins, Rohit Mehra, Kathleen A Cooney, Bruce Montgomery, Emmanuel S Antonarakis, Daniel H Shevrin, Paul G Corn, Young E Whang, David C Smith, Megan V Caram, Karen E Knudsen, Walter M Stadler, Felix Y Feng, Arul M Chinnaiyan
Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response...
December 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29223478/phase-ii-trial-of-veliparib-in-patients-with-previously-treated-brca-mutated-pancreas-ductal-adenocarcinoma
#5
Maeve A Lowery, David P Kelsen, Marinela Capanu, Sloane C Smith, Jonathan W Lee, Zsofia K Stadler, Malcolm J Moore, Hedy L Kindler, Talia Golan, Amiel Segal, Hannah Maynard, Ellen Hollywood, MaryEllen Moynahan, Erin E Salo-Mullen, Richard Kinh Gian Do, Alice P Chen, Kenneth H Yu, Laura H Tang, Eileen M O'Reilly
PURPOSE: BRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC). METHODS: Patients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1-2 lines of treatment, Eastern Cooperative Oncology Group 0-2, were enrolled...
December 7, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29138343/a-phase-i-clinical-trial-of-the-poly-adp-ribose-polymerase-inhibitor-veliparib-and-weekly-topotecan-in-patients-with-solid-tumors
#6
Andrea E Wahner Hendrickson, Michael E Menefee, Lynn C Hartmann, Harry J Long, Donald W Northfelt, Joel M Reid, Felix Boakye-Agyeman, Olumide Kayode, Karen S Flatten, Maria I Harrell, Elizabeth M Swisher, Guy G Poirer, Daniel Satele, Jacob B Allred, Janet L Lensing, Alice Chen, Jiuping Jay Ji, Yiping Zhang, Charles Erlichman, Paul Haluska, Scott H Kaufmann
PURPOSE: To determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. EXPERIMENTAL DESIGN: Eligible patients had metastatic nonhematological malignancies with measurable disease...
November 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29133592/parp1-trapping-and-dna-replication-stress-enhance-radiosensitization-with-combined-wee1-and-parp-inhibitors
#7
Leslie A Parsels, David Karnak, Joshua D Parsels, Qiang Zhang, Jonathan Vélez-Padilla, Zachery R Reichert, Daniel R Wahl, Jonathan Maybaum, Mark J O'Connor, Theodore S Lawrence, Meredith A Morgan
KRAS mutations in non-small cell lung cancer (NSCLC) cause increased levels of DNA damage and replication stress, suggesting that inhibition of the DNA damage response (DDR) is a promising strategy for radiosensitization of NSCLC. This study investigates the ability of a WEE1 inhibitor (AZD1775) and a PARP inhibitor (olaparib) to radiosensitize KRAS-mutant NSCLC cells and tumors. In addition to inhibiting the DDR, these small-molecule inhibitors of WEE1 and PARP induce DNA replication stress via nucleotide exhaustion and PARP trapping, respectively...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29075104/risk-of-severe-hematologic-toxicities-in-cancer-patients-treated-with-parp-inhibitors-a-meta-analysis-of-randomized-controlled-trials
#8
Jian Xin Zhou, Li Jin Feng, Xi Zhang
PURPOSE: Hematologic toxicities, including neutropenia, thrombocytopenia, and anemia, are major adverse effects of PARP inhibitors (PARPis), but the incidence rate and overall risk has not been systematically studied. Therefore, we conducted a meta-analysis of published clinical trials to investigate the incidence and relative risks (RRs) of severe (high-grade) hematologic events in cancer patients treated with PARPis. METHODS: PubMed, Embase, and oncology conference proceedings were searched for relevant studies...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29045554/veliparib-with-temozolomide-or-carboplatin-paclitaxel-versus-placebo-with-carboplatin-paclitaxel-in-patients-with-brca1-2-locally-recurrent-metastatic-breast-cancer-randomized-phase-ii-study
#9
H S Han, V Diéras, M Robson, M Palácová, P K Marcom, A Jager, I Bondarenko, D Citrin, M Campone, M L Telli, S M Domchek, M Friedlander, B Kaufman, J E Garber, Y Shparyk, E Chmielowska, E H Jakobsen, V Kaklamani, W Gradishar, C K Ratajczak, C Nickner, Q Qin, J Qian, S P Shepherd, S J Isakoff, S Puhalla
Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, which interfere with DNA damage repair. Veliparib, a potent PARP inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer...
September 29, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28994564/targeted-therapy-for-ovarian-cancer-the-rapidly-evolving-landscape-of-parp-inhibitor-use
#10
Christine Walsh
INTRODUCTION: PARP (poly(ADP-ribose) polymerase) 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...
October 9, 2017: Minerva Ginecologica
https://www.readbyqxmd.com/read/28958991/pathway-enriched-gene-signature-associated-with-53bp1-response-to-parp-inhibition-in-triple-negative-breast-cancer
#11
Saima Hassan, Amanda Esch, Tiera Liby, Joe W Gray, Laura M Heiser
Treatment of patients with triple negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients that will most benefit from anti-PARP therapy. We determined the response of three PARP inhibitors: veliparib, olaparib, and talazoparib in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved-PARP)...
September 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28948212/dna-repair-deficiency-biomarkers-and-the-70-gene-ultra-high-risk-signature-as-predictors-of-veliparib-carboplatin-response-in-the-i-spy-2-breast-cancer-trial
#12
Denise M Wolf, Christina Yau, Ashish Sanil, Annuska Glas, Emanuel Petricoin, Julia Wulfkuhle, Tesa M Severson, Sabine Linn, Lamorna Brown-Swigart, Gillian Hirst, Meredith Buxton, Angela DeMichele, Nola Hylton, Fraser Symmans, Doug Yee, Melissa Paoloni, Laura Esserman, Don Berry, Hope Rugo, Olufunmilayo Olopade, Laura van 't Veer
Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2- patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2- patients (VC: 72 and concurrent controls: 44)...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/28938657/a-network-meta-analysis-on-the-efficacy-of-targeted-agents-in-combination-with-chemotherapy-for-treatment-of-advanced-metastatic-triple-negative-breast-cancer
#13
Long Ge, Yan Tang, Qiu-Ning Zhang, Jin-Hui Tian, Xiao-Hu Wang, Dawid Pieper, Bei Pan, Lun Li, Juan Ling, Zhi-Tong Bing, Ke-Hu Yang
OBJECTIVE: Our network meta-analysis aimed to determine the assistant efficacy of targeted therapy in combined with chemotherapy for advanced/metastatic triple-negative breast cancer (TNBC). RESULTS: A total of 15 randomized controlled trials (RCTs), involving 2,410 patients, met our inclusion criteria. Eight targeted agents involving 11 treatment arms were included. The methodological quality of included RCTs was acceptable. The results of direct comparisons showed that progression-free survival (PFS) was significantly longer with bevacizumab+chemotherapy when compared to chemotherapy alone (hazard ratio [HR] = 0...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935542/phase-i-trial-of-veliparib-a-poly-adp-ribose-polymerase-inhibitor-plus-metronomic-cyclophosphamide-in-metastatic-her2-negative-breast-cancer
#14
Jesus Anampa, Alice Chen, John Wright, Margi Patel, Christine Pellegrino, Karen Fehn, Joseph A Sparano, Eleni Andreopoulou
BACKGROUND: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. METHODS: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer...
September 1, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#15
REVIEW
Ciara C O'Sullivan, Nicole N Davarpanah, Jame Abraham, Susan E Bates
Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287)...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28893315/heterogeneous-drug-penetrance-of-veliparib-and-carboplatin-measured-in-triple-negative-breast-tumors
#16
Imke H Bartelink, Brendan Prideaux, Gregor Krings, Lisa Wilmes, Pei Rong Evelyn Lee, Pan Bo, Byron Hann, Jean-Philippe Coppé, Diane Heditsian, Lamorna Swigart-Brown, Ella F Jones, Sergey Magnitsky, Ron J Keizer, Niels de Vries, Hilde Rosing, Nela Pawlowska, Scott Thomas, Mallika Dhawan, Rahul Aggarwal, Pamela N Munster, Laura J Esserman, Weiming Ruan, Alan H B Wu, Douglas Yee, Véronique Dartois, Radojka M Savic, Denise M Wolf, Laura van 't Veer
BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS: MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice...
September 11, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28875097/sustained-long-term-maintenance-of-remission-with-single-agent-veliparib-in-recurrent-triple-negative-breast-cancer
#17
Karthik Kota, Shannon Puhalla
Triple-negative breast cancers (TNBC) have poorer outcomes than hormone positive or human epidermal growth factor receptor 2 (HER2)-positive breast cancers, with chemotherapy being the usual standard of care. Veliparib, a poly ADP-ribose polymerase (PARP) inhibitor, has been studied in both breast cancer susceptibility genes 1 and 2 (BRCA)-mutation related and sporadic cancers as a single agent and in combination with chemotherapy. Here, we describe a patient whose metastatic recurrence of TNBC was treated with combination chemotherapy and veliparib followed by maintenance single-therapy veliparib...
July 4, 2017: Curēus
https://www.readbyqxmd.com/read/28851423/the-brca1ness-signature-is-associated-significantly-with-response-to-parp-inhibitor-treatment-versus-control-in-the-i-spy-2-randomized-neoadjuvant-setting
#18
Tesa M Severson, Denise M Wolf, Christina Yau, Justine Peeters, Diederik Wehkam, Philip C Schouten, Suet-Feung Chin, Ian J Majewski, Magali Michaut, Astrid Bosma, Bernard Pereira, Tycho Bismeijer, Lodewyk Wessels, Carlos Caldas, René Bernards, Iris M Simon, Annuska M Glas, Sabine Linn, Laura van 't Veer
BACKGROUND: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. METHODS: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project...
August 25, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28837250/phase-1-study-of-veliparib-with-carboplatin-and-weekly-paclitaxel-in-japanese-patients-with-newly-diagnosed-ovarian-cancer
#19
Shin Nishio, Munetaka Takekuma, Satoshi Takeuchi, Kouichirou Kawano, Naotake Tsuda, Kazuto Tasaki, Nobutaka Takahashi, Masakazu Abe, Aki Tanaka, Takayuki Nagasawa, Tadahiro Shoji, Hao Xiong, Silpa Nuthalapati, Terri Leahy, Hideyuki Hashiba, Tsukasa Kiriyama, Philip Komarnitsky, Yasuyuki Hirashima, Kimio Ushijima
This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1-21 with carboplatin (area under the concentration-time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m(2) on days 1, 8 and 15 every 3 weeks for up to 6 21-day cycles. Dose escalation followed a 3 + 3 design to determine dose-limiting toxicities, maximum tolerated dose and the recommended phase 2 dose...
November 2017: Cancer Science
https://www.readbyqxmd.com/read/28770300/phase-i-study-of-veliparib-in-combination-with-gemcitabine
#20
Ronald Stoller, John C Schmitz, Fei Ding, Shannon Puhalla, Chandra P Belani, Leonard Appleman, Yan Lin, Yixing Jiang, Salah Almokadem, Daniel Petro, Julianne Holleran, Brian F Kiesel, R Ken Czambel, Benedito A Carneiro, Emmanuel Kontopodis, Pamela A Hershberger, Madani Rachid, Alice Chen, Edward Chu, Jan H Beumer
BACKGROUND: Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine. METHODS: Patients with advanced solid tumors received veliparib (10-40-mg PO BID) on chemotherapy weeks with gemcitabine 500-750-mg/m(2) IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle)...
August 2, 2017: Cancer Chemotherapy and Pharmacology
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