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Niraparib

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https://www.readbyqxmd.com/read/27898364/liquid-chromatography-tandem-mass-spectrometry-assay-for-the-quantification-of-niraparib-and-its-metabolite-m1-in-human-plasma-and-urine
#1
L van Andel, Z Zhang, S Lu, V Kansra, S Agarwal, L Hughes, M M Tibben, A Gebretensae, H Rosing, J H M Schellens, J H Beijnen
Niraparib (MK-4827) is a novel poly(ADP-Ribose) polymerase (PARP) inhibitor currently investigated in phase III clinical trials to treat cancers. The development of a new drug includes the characterisation of absorption, metabolism and excretion (AME) of the compound. AME studies are a requirement of regulatory agencies and for this purpose bioanalytical assays are essential. This article describes the development and validation of a bioanalytical assay for niraparib and its carboxylic acid metabolite M1 in human plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS)...
November 19, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27866910/proteome-wide-profiling-of-clinical-parp-inhibitors-reveals-compound-specific-secondary-targets
#2
Claire E Knezevic, Gabriela Wright, Lily L Remsing Rix, Woosuk Kim, Brent M Kuenzi, Yunting Luo, January M Watters, John M Koomen, Eric B Haura, Alvaro N Monteiro, Caius Radu, Harshani R Lawrence, Uwe Rix
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively...
November 9, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27810860/niraparib-slows-ovarian-cancer-progression
#3
(no author information available yet)
Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer. Improved progression-free survival was seen regardless of the presence or absence of germline BRCA mutations, or of homologous recombination deficiency; however, patients who had these mutations or defective DNA repair did better.
November 3, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27717299/niraparib-maintenance-therapy-in-platinum-sensitive-recurrent-ovarian-cancer
#4
Mansoor R Mirza, Bradley J Monk, Jørn Herrstedt, Amit M Oza, Sven Mahner, Andrés Redondo, Michel Fabbro, Jonathan A Ledermann, Domenica Lorusso, Ignace Vergote, Noa E Ben-Baruch, Christian Marth, Radosław Mądry, René D Christensen, Jonathan S Berek, Anne Dørum, Anna V Tinker, Andreas du Bois, Antonio González-Martín, Philippe Follana, Benedict Benigno, Per Rosenberg, Lucy Gilbert, Bobbie J Rimel, Joseph Buscema, John P Balser, Shefali Agarwal, Ursula A Matulonis
Background Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. Methods In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily...
October 7, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27716873/the-current-status-of-parp-inhibitors-in-ovarian-cancer
#5
Jennifer McLachlan, Angela George, Susana Banerjee
Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach...
October 13, 2016: Tumori
https://www.readbyqxmd.com/read/27614696/in-vivo-anti-tumor-activity-of-the-parp-inhibitor-niraparib-in-homologous-recombination-deficient-and-proficient-ovarian-carcinoma
#6
Mariam M AlHilli, Marc A Becker, S John Weroha, Karen S Flatten, Rachel M Hurley, Maria I Harrell, Ann L Oberg, Matt J Maurer, Kieran M Hawthorne, Xiaonan Hou, Sean C Harrington, Sarah McKinstry, X Wei Meng, Keith M Wilcoxen, Kimberly R Kalli, Elizabeth M Swisher, Scott H Kaufmann, Paul Haluska
OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo...
September 7, 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/27141070/parp-inhibitors-in-ovarian-cancer
#7
J A Ledermann
BACKGROUND: Slow progress in improving the outcome of ovarian cancer with chemotherapy over the last decade has stimulated research into molecularly targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA repair and are specifically active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated BRCA function have HR deficiency (HRD), which is also present in a significant proportion of non-BRCA-mutated ovarian cancer...
April 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27141062/progress-in-the-treatment-of-ovarian-cancer-lessons-from-homologous-recombination-deficiency-the-first-10-years
#8
S B Kaye
For several years, a major obstacle in the systemic treatment of ovarian cancer has been the lack of a therapeutic strategy tailored to specific biomarkers present in the individual patient's tumour. However, considerable progress has been made recently through the development of drugs targeting cells deficient in the key mechanism of double-strand DNA repair, known as homologous recombination (HRD). These drugs, inhibitors of the enzyme poly (ADP) ribose polymerase (PARP), selectively kill HRD cells through a process known as tumour-selective synthetic lethality...
April 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27087632/evaluation-of-rucaparib-and-companion-diagnostics-in-the-parp-inhibitor-landscape-for-recurrent-ovarian-cancer-therapy
#9
Zachary B Jenner, Anil K Sood, Robert L Coleman
Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy...
June 2016: Future Oncology
https://www.readbyqxmd.com/read/26934368/radiosensitization-by-parp-inhibition-in-dna-repair-proficient-and-deficient-tumor-cells-proliferative-recovery-in-senescent-cells
#10
Moureq Alotaibi, Khushboo Sharma, Tareq Saleh, Lawrence F Povirk, Eric A Hendrickson, David A Gewirtz
Radiotherapy continues to be a primary modality in the treatment of cancer. In addition to promoting apoptosis, radiation-induced DNA damage can promote autophagy and senescence, both of which can theoretically function to prolong tumor survival. In this work, we tested the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiosensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population...
March 2016: Radiation Research
https://www.readbyqxmd.com/read/26513298/e7449-a-dual-inhibitor-of-parp1-2-and-tankyrase1-2-inhibits-growth-of-dna-repair-deficient-tumors-and-antagonizes-wnt-signaling
#11
Sharon McGonigle, Zhihong Chen, Jiayi Wu, Paul Chang, Donna Kolber-Simonds, Karen Ackermann, Natalie C Twine, Jue-Lon Shie, Jingzang Tao Miu, Kuan-Chun Huang, George A Moniz, Kenichi Nomoto
Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity...
December 1, 2015: Oncotarget
https://www.readbyqxmd.com/read/26438158/parp-inhibitors-sensitize-ewing-sarcoma-cells-to-temozolomide-induced-apoptosis-via-the-mitochondrial-pathway
#12
Florian Engert, Cornelius Schneider, Lilly Magdalena Weiβ, Marie Probst, Simone Fulda
Ewing sarcoma has recently been reported to be sensitive to poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for synergistic drug combinations, we tested several PARP inhibitors (talazoparib, niraparib, olaparib, veliparib) together with chemotherapeutics. Here, we report that PARP inhibitors synergize with temozolomide (TMZ) or SN-38 to induce apoptosis and also somewhat enhance the cytotoxicity of doxorubicin, etoposide, or ifosfamide, whereas actinomycin D and vincristine show little synergism. Furthermore, triple therapy of olaparib, TMZ, and SN-38 is significantly more effective compared with double or monotherapy...
December 2015: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26351319/poly-adp-ribose-polymerase-as-a-therapeutic-target-in-pediatric-diffuse-intrinsic-pontine-glioma-and-pediatric-high-grade-astrocytoma
#13
Yevgen Chornenkyy, Sameer Agnihotri, Man Yu, Pawel Buczkowicz, Patricia Rakopoulos, Brian Golbourn, Livia Garzia, Robert Siddaway, Stephie Leung, James T Rutka, Michael D Taylor, Peter B Dirks, Cynthia Hawkins
Pediatric high-grade astrocytomas (pHGA) and diffuse intrinsic pontine gliomas (DIPG) are devastating malignancies for which no effective therapies exist. We investigated the therapeutic potential of PARP1 inhibition in preclinical models of pHGA and DIPG. PARP1 levels were characterized in pHGA and DIPG patient samples and tumor-derived cell lines. The effects of PARP inhibitors veliparib, olaparib, and niraparib as monotherapy or as radiosensitizers on cell viability, DNA damage, and PARP1 activity were evaluated in a panel of pHGA and DIPG cell lines...
November 2015: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26281686/-cancer-therapy-by-parp-inhibitors
#14
REVIEW
Hiroyuki Seimiya
Poly(ADP-ribose) polymerases(PARP) synthesize the ADP-ribose polymers onto proteins and play a role in DNA repair. PARP inhibitors block the repair of single-strand breaks, which in turn gives rise to double-strand breaks during DNA replication. Thus, PARP inhibitors elicit synthetic lethality in cancer with BRCA1/2 loss-of-function mutations that hamper homologous recombination repair of double-strand breaks. Olaparib, the first-in-class PARP inhibitor, was approved for treatment of BRCA-mutated ovarian cancer in Europe and the United States in 2014...
August 2015: Nihon Rinsho. Japanese Journal of Clinical Medicine
https://www.readbyqxmd.com/read/26217019/mechanistic-dissection-of-parp1-trapping-and-the-impact-on-in-vivo-tolerability-and-efficacy-of-parp-inhibitors
#15
Todd A Hopkins, Yan Shi, Luis E Rodriguez, Larry R Solomon, Cherrie K Donawho, Enrico L DiGiammarino, Sanjay C Panchal, Julie L Wilsbacher, Wenqing Gao, Amanda M Olson, DeAnne F Stolarik, Donald J Osterling, Eric F Johnson, David Maag
UNLABELLED: Poly(ADP-ribose) polymerases (PARP1, -2, and -3) play important roles in DNA damage repair. As such, a number of PARP inhibitors are undergoing clinical development as anticancer therapies, particularly in tumors with DNA repair deficits and in combination with DNA-damaging agents. Preclinical evidence indicates that PARP inhibitors potentiate the cytotoxicity of DNA alkylating agents. It has been proposed that a major mechanism underlying this activity is the allosteric trapping of PARP1 at DNA single-strand breaks during base excision repair; however, direct evidence of allostery has not been reported...
November 2015: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/25795901/o6-1classification-of-parp-inhibitors-based-on-parp-trapping-and-catalytic-inhibition-and-rationale-for-combinations
#16
Y Pommier, J Murai
All PARP inhibitors in clinical development (veliparib, olaparib, niraparib, rucaparib, and talazoparib) are potent submicromolar competitive NAD+ inhibitors for PARP1 and PARP2, thereby blocking PARylation reactions [i.e. formation of poly(ADPribose) polymers]. In addition, PARP trapping, which determines the anticancer activity of PARP inhibitor as single agents, is drug-specific, and PARP inhibitors can be ranked according to their PARP trapping potency: talazoparib > niraparib ≈ olaparib ≈ rucaparib > veliparib...
March 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/25795872/p7-01characterization-of-148-ovarian-cancer-tumografts-avatars-using-broca-hr-deep-sequencing
#17
K Lodhia, M Becker, X Hou, K Kalli, M Harrell, K Wilcoxen, E Swisher, S Weroha, P Halsuka
Ovarian cancer is the most lethal gynecologic malignancy. Current standard of care post surgical cytoreduction is combination platinum/taxane chemotherapy, with initial response varying widely; subsets of carcinomas demonstrate resistance or sensitivity from the onset. The underlying cause of this response heterogeneity remains unknown. Patient-derived xenografts (PDX) serve as useful in vivo models to study molecular response markers and test the efficacy of targeted therapies. Our group has demonstrated a high engraftment rate (>70%) of ovarian cancer PDXs (Avatars) by injecting treatment naïve patient tumor directly into the peritoneal cavity of immunocompromised mice, in an effort to better mimic the anatomic context by which ovarian cancer naturally develops...
March 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/25761096/niraparib-a-poly-adp-ribose-polymerase-parp-inhibitor-for-the-treatment-of-tumors-with-defective-homologous-recombination
#18
Philip Jones, Keith Wilcoxen, Michael Rowley, Carlo Toniatti
Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients...
April 23, 2015: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/25758918/trapping-poly-adp-ribose-polymerase
#19
Yuqiao Shen, Mika Aoyagi-Scharber, Bing Wang
Recent findings indicate that a major mechanism by which poly(ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells...
June 2015: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/25685067/treatment-with-the-parp-inhibitor-niraparib-sensitizes-colorectal-cancer-cell-lines-to-irinotecan-regardless-of-msi-mss-status
#20
Sybil M Genther Williams, Apryle M Kuznicki, Paula Andrade, Brian M Dolinski, Cem Elbi, Ronan C O'Hagan, Carlo Toniatti
BACKGROUND: Cells with homologous recombination (HR) deficiency, most notably caused by mutations in the BRCA1 or BRCA2 genes, are sensitive to PARP inhibition. Microsatellite instability (MSI) accounts for 10-15% of colorectal cancer (CRC) and is hypothesized to lead to HR defects due to altered expression of Mre11, a protein required for double strand break (DSB) repair. Indeed, others have reported that PARP inhibition is efficacious in MSI CRC. METHODS: Here we examine the response to niraparib, a potent PARP-1/PARP-2 inhibitor currently under clinical evaluation, in MSI versus microsatellite stable (MSS) CRC cell lines in vitro and in vivo...
2015: Cancer Cell International
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