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https://www.readbyqxmd.com/read/29792535/does-the-poly-adp-ribose-polymerase-inhibitor-veliparib-merit-further-study-for-cancer-associated-weight-loss-observations-and-conclusions-from-60-prospectively-treated-patients
#1
Jason D Doles, Kelly A Hogan, Jennifer O'Connor, Andrea E Wahner Hendrickson, Olivia Huston, Aminah Jatoi
BACKGROUND: More than 80% of patients with advanced cancer develop weight loss. Because preclinical data suggest poly (ADP-ribose) polymerase (PARP) inhibitors can treat this weight loss, this study was undertaken to explore the PARP inhibitor veliparib for this indication. OBJECTIVE: The current study was undertaken to analyze prospectively gathered data on weight in cancer patients on PARP inhibitors. DESIGN/SETTING: The current study relied on a previously published, prospectively conducted phase 1 single institution trial that combined veliparib and topotecan (NCT01012817) as antineoplastic therapy for advanced cancer patients...
May 24, 2018: Journal of Palliative Medicine
https://www.readbyqxmd.com/read/29733524/safety-and-pharmacokinetics-of-veliparib-extended-release-in-patients-with-advanced-solid-tumors-a-phase-i-study
#2
Theresa L Werner, Jasgit Sachdev, Elizabeth M Swisher, Martin Gutierrez, Muaiad Kittaneh, Mark N Stein, Hao Xiong, Martin Dunbar, Danielle Sullivan, Philip Komarnitsky, Mark McKee, Antoinette R Tan
The poly(ADP-ribose) polymerase-1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended-release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib-ER up to 800 mg once daily or 600 mg twice daily. Dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28-day cycles)...
May 7, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29675979/senescent-cells-re-engineered-to-express-spd-1-for-inhibiting-pd-1-pd-l1-as-a-vaccination-approach-against-breast-cancer
#3
Zehong Chen, Kang Hu, Lieting Feng, Ruxiong Su, Nan Lai, Zike Yang, Shijun Kang
Various types of vaccines have been proposed as approaches for prevention or delay of the onset of cancer by boosting the endogenous immune system. We previously developed a senescent-cell-based vaccine, induced by radiation and veliparib, as a preventive and therapeutic tool against triple-negative breast cancer. However, the PD-1/PD-L1 pathway was found to play an important role in vaccine failure. Hence, we further developed sPD1-expressing senescent cells to overcome PD-L1/PD1-mediated immune suppression while vaccinating to promote dendritic cells (DCs) maturity, thereby amplifying T cell activation...
April 20, 2018: Cancer Science
https://www.readbyqxmd.com/read/29664016/the-evolving-landscape-of-predictive-biomarkers-of-response-to-parp-inhibitors
#4
Anish Thomas, Junko Murai, Yves Pommier
Poly(ADP-ribose) polymerase inhibitors (PARPis) are DNA-damaging agents that trap PARP-DNA complexes and interfere with DNA replication. Three PARPis - olaparib, niraparib, and rucaparib - were recently approved by the FDA for the treatment of breast and ovarian cancers. These PARPis, along with 2 others (talazoparib and veliparib), are being evaluated for their potential to treat additional malignancies, including prostate cancers. While lack of PARP-1 confers high resistance to PARPis, it has not been established whether or not the levels of PARP-1 directly correlate with tumor response...
May 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29592880/trastuzumab-resistant-her2-breast-cancer-cells-retain-sensitivity-to-poly-adp-ribose-polymerase-parp-inhibition
#5
Monica E Wielgos, Zhuo Zhang, Rajani Rajbhandari, Tiffiny S Cooper, Ling Zeng, Andres Forero, Francisco J Esteva, C Kent Osborne, Rachel Schiff, Albert F LoBuglio, Susan E Nozell, Eddy S Yang
HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ breast cancer cells to poly (ADP-Ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR) deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2+ trastuzumab resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity...
March 28, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29579325/a-phase-2-study-of-the-parp-inhibitor-veliparib-plus-temozolomide-in-patients-with-heavily-pretreated-metastatic-colorectal-cancer
#6
Michael J Pishvaian, Rebecca S Slack, Wei Jiang, A Ruth He, Jimmy J Hwang, Amy Hankin, Karen Dorsch-Vogel, Divyesh Kukadiya, Louis M Weiner, John L Marshall, Jonathan R Brody
BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA-damaging agents such as temozolomide. The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects. METHODS: A single-arm, open-label, phase 2 study was performed to investigate the disease control rate (DCR) after 2 cycles of veliparib plus temozolomide in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies...
March 26, 2018: Cancer
https://www.readbyqxmd.com/read/29558281/concurrent-veliparib-with-chest-wall-and-nodal-radiotherapy-in-patients-with-inflammatory-or-locoregionally-recurrent-breast-cancer-the-tbcrc-024-phase-i-multicenter-study
#7
Reshma Jagsi, Kent A Griffith, Jennifer R Bellon, Wendy A Woodward, Janet K Horton, Alice Ho, Felix Y Feng, Corey Speers, Beth Overmoyer, Michael Sabel, Anne F Schott, Lori Pierce
Purpose Locoregional control for inflammatory breast cancers and chest wall recurrences is suboptimal, which has motivated interest in radiosensitization to intensify therapy. Preclinical studies have suggested a favorable therapeutic index when poly (ADP-ribose) polymerase inhibitors are used as radiosensitizers; clinical investigation is necessary to establish appropriate dosing and confirm safety. Patients and Methods We conducted a multi-institutional phase I study of veliparib and concurrent radiotherapy (RT) to the chest wall and regional lymph nodes in 30 patients with inflammatory or locally recurrent breast cancer after complete surgical resection...
May 1, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29527010/a-phase-1-dose-escalation-study-of-veliparib-with-bimonthly-folfiri-in-patients-with-advanced-solid-tumours
#8
Jordan Berlin, Ramesh K Ramanathan, John H Strickler, Deepa S Subramaniam, John Marshall, Yoon-Koo Kang, Robert Hetman, Matthew W Dudley, Jiewei Zeng, Caroline Nickner, Hao Xiong, Philip Komarnitsky, Stacie Peacock Shepherd, Herbert Hurwitz, Heinz-Josef Lenz
BACKGROUND: Veliparib is a potent poly(ADP-ribose) polymerase inhibitor. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib combined with various FOLFIRI regimens in patients with solid tumours. METHODS: Patients received veliparib (10-270 mg BID, days 1-5, 15-19) and FOLFIRI (days 1-3, 15-17) in three regimens containing 5-fluorouracil 2,400 mg/m2 : irinotecan 150 mg/m2 and folinic acid 400 mg/m2 (part 1); irinotecan 180 mg/m2 , folinic acid 400 mg/m2 , and 5-fluorouracil 400 mg/m2 bolus (part 2), or irinotecan 180 mg/m2 (part 3)...
April 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29512470/parp-inhibitors-in-ovarian-cancer
#9
Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Sofia Genta, Massimo Aglietta, Anna Sapino, Giorgio Valabrega
BACKGROUND: Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. OBJECTIVES: To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis...
March 5, 2018: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/29501363/addition-of-the-parp-inhibitor-veliparib-plus-carboplatin-or-carboplatin-alone-to-standard-neoadjuvant-chemotherapy-in-triple-negative-breast-cancer-brightness-a-randomised-phase-3-trial
#10
Sibylle Loibl, Joyce O'Shaughnessy, Michael Untch, William M Sikov, Hope S Rugo, Mark D McKee, Jens Huober, Mehra Golshan, Gunter von Minckwitz, David Maag, Danielle Sullivan, Norman Wolmark, Kristi McIntyre, Jose J Ponce Lorenzo, Otto Metzger Filho, Priya Rastogi, W Fraser Symmans, Xuan Liu, Charles E Geyer
BACKGROUND: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer...
April 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29352572/phase-i-combination-study-of-the-parp-inhibitor-veliparib-plus-carboplatin-and-gemcitabine-in-patients-with-advanced-ovarian-cancer-and-other-solid-malignancies
#11
Heidi J Gray, Katherine Bell-McGuinn, Gini F Fleming, Mihaela Cristea, Hao Xiong, Danielle Sullivan, Yan Luo, Mark D McKee, Wijith Munasinghe, Lainie P Martin
OBJECTIVE: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. METHODS: In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m2 on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy...
March 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29339456/parp-inhibition-prevents-ethanol-induced-neuroinflammatory-signaling-and-neurodegeneration-in-rat-adult-age-brain-slice-cultures
#12
Nuzhath Tajuddin, Hee-Yong Kim, Michael A Collins
Using 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 the 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...
April 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
#13
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...
April 1, 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
#14
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
#15
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...
April 1, 2018: 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
#16
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...
January 2018: 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
#17
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, Jake Allred, Janet L Lensing, Alice Chen, Jiuping Ji, Yiping Zang, Charles Erlichman, Paul Haluska, Scott H Kaufmann
Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II 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 nonhematologic malignancies with measurable disease...
February 15, 2018: 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
#18
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...
February 2018: 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
#19
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
#20
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 inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase 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...
January 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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