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Olaparib

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https://www.readbyqxmd.com/read/29152107/neoadjuvant-olaparib-targets-hypoxia-to-improve-radioresponse-in-a-homologous-recombination-proficient-breast-cancer-model
#1
Gerben R Borst, Ramya Kumareswaran, Hatice Yücel, Seyda Telli, Trevor Do, Trevor McKee, Gaetano Zafarana, Jos Jonkers, Marcel Verheij, Mark J O'Connor, Sven Rottenberg, Robert G Bristow
Clinical trials are studying the benefits of combining the PARP-1 inhibitor olaparib with chemotherapy and radiotherapy treatment in a variety of cancer increasing the therapeutic ratio for olaparib may come from its ability to modify the tumour microenvironment by targeting homologous recombination-deficient, hypoxic tumour clonogens, and/or increasing tumour-associated vasodilation to improve oxygenation. Herein, we investigated the effect of prolonged neoadjuvant exposure to olaparib on the tumor microenvironment using a genetically-engineered mouse p53-/- syngeneic breast cancer model, which is proficient in homology-directed DNA repair...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29152062/rapamycin-sensitizes-cancer-cells-to-growth-inhibition-by-the-parp-inhibitor-olaparib
#2
Atsushi Osoegawa, Joell J Gills, Shigeru Kawabata, Phillip A Dennis
Poly (ADP-ribose) polymerase inhibitors (PARPi) have been developed and tested in a context of combining it with double-stranded (ds) DNA repair defects or inhibitors, as PARP inhibitor impairs single-stranded (ss) DNA break repair, resulting in the activation of the dsDNA break repair machinery. Rapamycin has been widely prescribed for more than a decade and recent studies have revealed that it may inhibit dsDNA break repair. The combination of the PARP inhibitor olaparib and rapamycin synergistically inhibited cell proliferation in non-small cell lung cancer (NSCLC) cells, and even in triple negative breast cancer (TNBC) cells with BRCA1 mutations...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29150161/improved-pharmacodynamic-pd-assessment-of-low-dose-parp-inhibitor-pd-activity-for-radiotherapy-and-chemotherapy-combination-trials
#3
Rosemarie de Haan, Dick Pluim, Baukelien van Triest, Michel van den Heuvel, Heike Peulen, Damien van Berlo, Jay George, Marcel Verheij, Jan H M Schellens, Conchita Vens
BACKGROUND: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities. The aim of our study was to enable sensitive PD evaluation of PARP inhibitors for clinical sensitizer development. MATERIAL AND METHODS: PBMCs of healthy individuals and of olaparib and radiotherapy treated lung cancer patients were collected for ELISA-based PD-assays...
November 14, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/29138572/current-status-of-poly-adp-ribose-polymerase-inhibitors-and-future-directions
#4
REVIEW
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29138344/targeting-the-mycn-parp-dna-damage-response-pathway-inneuroendocrine-prostate-cancer
#5
Wei Zhang, Bo Liu, Wenhui Wu, Likun Li, Bradley M Broom, Spyridon M Basourakos, Dimitrios Korentzelos, Yang Luan, Jianxiang Wang, Guang Yang, Sanghee Park, Abul K Azad, Xuhong Cao, Jeri Kim, Paul Corn, Christopher Logothetis, Ana M Aparicio, Arul M Chinnayan, Nora M Navone, Patricia Troncoso, Timothy C Thompson
PURPOSE: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphological criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for NEPC. RESULTS: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public datasets and a panel of 28 PDX models we identified a MYCN-PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro...
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
#6
Leslie A Parsels, David Karnak, Joshua Parsels, Qiang Zhang, Jonathan Vélez-Padilla, Zachery 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/29129088/systemic-therapy-for-esophagogastric-cancer-targeted-therapies
#7
Tomas G Lyons, Geoffrey Y Ku
The poor prognosis for patients with esophagogastric cancers (EGC) has resulted in an increased focus on the use of targeted agents in this disease. Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), MET, poly (ADP-ribose) polymerase (PARP) and claudin 18.2 (CLDN18.2). Trastuzumab, an anti-Her2 antibody, was approved by the U.S. FDA in 2010 as first-line therapy in combination with chemotherapy for Her2-positive disease...
October 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/29121337/parp1-changes-from-three-dimensional-dna-damage-searching-to-one-dimensional-diffusion-after-auto-parylation-or-in-the-presence-of-ape1
#8
Lili Liu, Muwen Kong, Natalie R Gassman, Bret D Freudenthal, Rajendra Prasad, Stephanie Zhen, Simon C Watkins, Samuel H Wilson, Bennett Van Houten
PARP1-dependent poly-ADP-ribosylation (PARylation) participates in the repair of many forms of DNA damage. Here, we used atomic force microscopy (AFM) and single molecule fluorescence microscopy to examine the interactions of PARP1 with common DNA repair intermediates. AFM volume analysis indicates that PARP1 binds to DNA at nicks, abasic (AP) sites, and ends as a monomer. Single molecule DNA tightrope assays were used to follow the real-time dynamic behavior of PARP1 in the absence and presence of AP endonuclease (APE1) on AP DNA damage arrays...
November 7, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29113215/functional-analysis-of-brct-missense-mutations-in-brca1-mutated-chinese-han-familial-breast-cancer
#9
Hong Zhang, Linsen Li, Yuxia Wang, C Cameron Yin, Yuntao Xie, Xijuan Liu, Huirong Ding, Zhihua Tian, Jing Shen, Long He, Miaoran Xia, Xi Ma, Lina Wu
Breast cancer 1 (BRCA1) is one of the most common tumor suppressor genes in breast cancer. The BRCT domain of BRCA1 has been shown to have a critical role in tumor suppression. In a previous study, two de novo BRCT missense mutations of BRCA1, G1763V and L1786P were identified from Chinese females with familial breast cancer. In the present study, the function of these two novel mutations were assessed by bioinformatics analysis and a series of experiments investigating cell proliferation, cell cycle and chemotherapy combination...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29108297/phase-i-ib-study-of-olaparib-and-carboplatin-in-women-with-triple-negative-breast-cancer
#10
Jung-Min Lee, John L Hays, Victoria L Chiou, Christina M Annunziata, Elizabeth M Swisher, Maria I Harrell, Minshu Yu, Nicolas Gordon, Tristan M Sissung, Jiuping Ji, William D Figg, Lori Minasian, Stanley Lipkowitz, Bradford J Wood, James Doroshow, Elise C Kohn
PURPOSE: To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ≤ 8 cycles, with olaparib 400mg bid maintenance...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29104487/ier5-is-involved-in-dna-double-strand-breaks-repair-in-association-with-papr1-in-hela-cells
#11
Xin-Ping Yu, Yu-Mei Wu, Yang Liu, Ming Tian, Jian-Dong Wang, Ku-Ke Ding, Teng Ma, Ping-Kun Zhou
The immediate early response gene 5 (IER5) is a radiation response gene induced in a dose-independent manner, and has been suggested to be a molecular biomarker for biodosimetry purposes upon radiation exposure. Here, we investigated the function of IER5 in DNA damage response and repair. We found that interference on IER5 expression significantly decreased the efficiency of repair of DNA double-strand breaks induced by ionizing radiations in Hela cells. We found that IER5 participates in the non-homologous end-joining pathway of DNA breaks repair...
2017: International Journal of Medical Sciences
https://www.readbyqxmd.com/read/29103871/olaparib-in-combination-with-paclitaxel-in-patients-with-advanced-gastric-cancer-who-have-progressed-following-first-line-therapy-gold-a-double-blind-randomised-placebo-controlled-phase-3-trial
#12
Yung-Jue Bang, Rui-Hua Xu, Keisho Chin, Keun-Wook Lee, Se Hoon Park, Sun Young Rha, Lin Shen, Shukui Qin, Nong Xu, Seock-Ah Im, Gershon Locker, Phil Rowe, Xiaojin Shi, Darren Hodgson, Yu-Zhen Liu, Narikazu Boku
BACKGROUND: Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial. METHODS: This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy...
November 2, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29096610/therapy-response-testing-of-breast-cancer-in-a-3d-high-throughput-perfused-microfluidic-platform
#13
Henriette L Lanz, Anthony Saleh, Bart Kramer, Junmei Cairns, Chee Ping Ng, Jia Yu, Sebastiaan J Trietsch, Thomas Hankemeier, Jos Joore, Paul Vulto, Richard Weinshilboum, Liewei Wang
BACKGROUND: Breast cancer is the most common invasive cancer among women. Currently, there are only a few models used for therapy selection, and they are often poor predictors of therapeutic response or take months to set up and assay. In this report, we introduce a microfluidic OrganoPlate® platform for extracellular matrix (ECM) embedded tumor culture under perfusion as an initial study designed to investigate the feasibility of adapting this technology for therapy selection. METHODS: The triple negative breast cancer cell lines MDA-MB-453, MDA-MB-231 and HCC1937 were selected based on their different BRCA1 and P53 status, and were seeded in the platform...
November 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29091556/olaparib-for-metastatic-germline-brca-mutated-breast-cancer
#14
LETTER
Mark Robson, Carsten Goessl, Susan Domchek
New England Journal of Medicine, Volume 377, Issue 18, Page 1792-1793, November 2017.
November 2, 2017: New England Journal of Medicine
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
#15
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/29064327/the-expression-of-ape1-in-triple-negative-breast-cancer-and-its-effect-on-drug-sensitivity-of-olaparib
#16
Tianran Chen, Chuan Liu, Heng Lu, Mingzhen Yin, Changjuan Shao, Xiaoding Hu, Jiaxue Wu, Yajie Wang
Triple-negative breast cancer is a kind of breast cancer with poor prognosis and special biological behavior, which lacked endocrine therapy and targeted therapy. We investigate the effect of human APE1 (apurinic/apyrimidyl endonuclease 1), a rate-limiting enzyme of base excision repair, on the prognosis in triple-negative breast cancer and drug sensitivity of olaparib. The expression of APE1 was detected by immunohistochemistry in the triple-negative breast cancer tissues and its effect on survival of triple-negative breast cancer patients was followed...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29061656/synergistic-antiproliferative-activity-of-the-rad51-inhibitor-ibr2-with-inhibitors-of-receptor-tyrosine-kinases-and-microtubule-protein
#17
Peter J Ferguson, Mark D Vincent, James Koropatnick
Although cancer cell genetic instability contributes to characteristics that mediate tumorigenicity, it also contributes to the tumor-selective toxicity of some chemotherapy drugs. This "synthetic lethality" can be enhanced by inhibitors of DNA repair. To exploit this potential "Achilles heel", we tested the ability of a RAD51 inhibitor to potentiate the cytotoxicity of chemotherapy drugs. 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) inhibits RAD51-mediated DNA double-strand break repair but also enhances cytotoxicity of the Bcr-Abl inhibitor imatinib...
October 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29054544/-abnormalities-of-dna-repair-and-gynecological-cancers
#18
REVIEW
Aurélie Auguste, Alexandra Leary
The demonstration of frequent defects in the DNA damage response in high grade ovarian cancer has paved the way for a new therapeutic approach aimed at exploiting this unique vulnerability. The efficacy of poly (ADP) ribose polymerase inhibitors (PARPi) in patients with homologous recombination (HR) DNA repair deficient ovarian cancer (OC) resulting from a BRCA1/2 mutation has provided the proof of concept for synthetic lethality. Thus, olaparib is now approved by the EMA as maintenance therapy after response to a platinum regimen for patients with recurrent, platinum-sensitive, high-grade serous, BRCA1/2-mutated ovarian cancer...
October 17, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29053680/evaluating-in-vitro-dna-damage-using-comet-assay
#19
Yanxin Lu, Yang Liu, Chunzhang Yang
DNA damage is a common phenomenon for each cell during its lifespan, and is defined as an alteration of the chemical structure of genomic DNA. Cancer therapies, such as radio- and chemotherapy, introduce enormous amount of additional DNA damage, leading to cell cycle arrest and apoptosis to limit cancer progression. Quantitative assessment of DNA damage during experimental cancer therapy is a key step to justify the effectiveness of a genotoxic agent. In this study, we focus on a single cell electrophoresis assay, also known as the comet assay, which can quantify single and double-strand DNA breaks in vitro...
October 11, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29042365/ruxolitinib-induced-defects-in-dna-repair-cause-sensitivity-to-parp-inhibitors-in-myeloproliferative-neoplasms
#20
Margaret Nieborowska-Skorska, Silvia Maifrede, Yashodhara Dasgupta, Katherine Sullivan, Sylwia Flis, Bac Viet Le, Martyna Solecka, Elizaveta A Belyaeva, Lucia Kubovcakova, Morgan Nawrocki, Martin Kirschner, Huaqing Zhao, Josef T Prchal, Katarzyna Piwocka, Alison R Moliterno, Mariusz Wasik, Steffen Koschmieder, Tony R Green, Radek C Skoda, Tomasz Skorski
Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L) or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time primary MPN cell samples from individual patients displayed a high degree of variability in the sensitivity to these drugs...
October 17, 2017: Blood
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