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https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#1
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/28916476/pharmacologic-ascorbate-induces-neuroblastoma-cell-death-by-hydrogen-peroxide-mediated-dna-damage-and-reduction-in-cancer-cell-glycolysis
#2
Enlong Ma, Ping Chen, Heather M Wilkins, Tao Wang, Russell H Swerdlow, Qi Chen
An ascorbate-mediated production of oxidative stress has been shown to retard tumor growth. Subsequent glycolysis inhibition has been suggested. Here, we further define the mechanisms relevant to this observation. Ascorbate was cytotoxic to human neuroblastoma cells through the production of H2O2, which led to ATP depletion, inhibited GAPDH, and non-apoptotic and non-autophagic cell death. The mechanism of cytotoxicity is different when PARP-dependent DNA repair machinery is active or inhibited. Ascorbate-generated H2O2 damaged DNA, activated PARP, depleted NAD+, and reduced glycolysis flux...
September 12, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28895177/a-novel-use-for-olaparib-for-treatment-of-metastatic-castration-recurrent-prostate-cancer
#3
Grace A Martin, Adrienne H Chen, Kinjal Parikh
Although mortality from prostate cancer has declined over the past 20 years as a result of early detection and treatment, the 5-year survival rate for men with prostate cancer who develop metastatic disease is only 29%. Current treatment options for metastatic castration-recurrent prostate cancer (mCRPC) are associated with toxicity and a limited durable response; therefore, additional lines of efficacious and minimally toxic therapy are needed. Olaparib, a poly(adenosine 5'-diphosphate) ribose polymerase (PARP) inhibitor, received United States Food and Drug Administration breakthrough therapy designation in January 2016 for the treatment of patients with BRCA1/2 or ATM gene-mutated mCRPC based on results of a compelling phase II trial of olaparib in patients with advanced castration resistant prostate cancer (TOPARP-A)...
September 12, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28886696/inhibition-of-pi3k-akt-mtor-pathway-sensitizes-endometrial-cancer-cell-lines-to-parp-inhibitors
#4
Charles-André Philip, Ido Laskov, Marie-Claude Beauchamp, Maud Marques, Oreekha Amin, Joanna Bitharas, Roy Kessous, Liron Kogan, Tahira Baloch, Walter H Gotlieb, Amber Yasmeen
BACKGROUND: Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70-80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair. METHODS: Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay...
September 8, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28886273/parpi-potentiates-with-current-conventional-therapy-in-mll-leukemia
#5
Lu Zhao, Chi Wai Eric So
Acute myeloid leukemias driven by MLL fusion proteins are commonly associated with poor prognosis and refractory treatment. Here, we provide evidence that olaparib can potentiate sensitivity of MLL leukemia cells to conventional chemotherapy and DNMT inhibitors offering new potential therapeutic strategies for MLL rearranged leukemias Using the primary mouse leukemia cells and human MLL-AF9 leukemic cell line, we demonstrate that treatment of MLL-AF9 leukemic cells with DNMT inhibitors or chemotherapies in combination with olaparib results in significant reduction in colony formation or cell growth while the single agent treatments had little impacts...
September 8, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28846114/identification-of-translationally-controlled-tumor-protein-in-promotion-of-dna-homologous-recombination-repair-in-cancer-cells-by-affinity-proteomics
#6
Y Li, H Sun, C Zhang, J Liu, H Zhang, F Fan, R A Everley, X Ning, Y Sun, J Hu, J Liu, J Zhang, W Ye, X Qiu, S Dai, B Liu, H Xu, S Fu, S P Gygi, C Zhou
Translationally controlled tumor protein(TCTP) has been implicated in the regulation of apoptosis, DNA repair and drug resistance. However, the underlying molecular mechanisms are poorly defined. To better understand the molecular mechanisms underlying TCTP involved in cellular processes, we performed an affinity purification-based proteomic profiling to identify proteins interacting with TCTP in human cervical cancer HeLa cells. We found that a group of proteins involved in DNA repair are enriched in the potential TCTP interactome...
August 28, 2017: Oncogene
https://www.readbyqxmd.com/read/28841282/synthetic-lethality-triggered-by-combining-olaparib-with-brca2-rad51-disruptors
#7
Federico Falchi, Elisa Giacomini, Tiziana Masini, Nicolas Boutard, Lorenza Di Ianni, Marcella Manerba, Fulvia Farabegoli, Lara Rossini, Janet Robertson, Saverio Minucci, Isabella Pallavicini, Giuseppina Di Stefano, Marinella Roberti, Roberto Pellicciari, Andrea Cavalli
In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways...
September 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28830922/deletion-of-11q-in-neuroblastomas-drives-sensitivity-to-parp-inhibition
#8
Elena Sanmartín, Lisandra Muñoz, Marta Piqueras, J Antoni Sirerol, Pablo Berlanga, Adela Cañete, Victoria Castel, Jaime Font de Mora
PURPOSE: Despite advances in multimodal therapy, neuroblastomas with hemizygous deletion in chromosome 11q (20-30%) undergo consecutive recurrences with poor outcome. We hypothesized that patients with 11q loss may share a druggable molecular target(s) that can be exploited for a precision medicine strategy to improve treatment outcome. EXPERIMENTAL DESIGN: SNP arrays were combined with next generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma aetiology...
August 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28829871/olaparib-increased-survival-in-metastatic-breast-cancer
#9
Anita Slomski
No abstract text is available yet for this article.
August 22, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28829762/characterisation-of-the-novel-deleterious-rad51c-p-arg312trp-variant-and-prioritisation-criteria-for-functional-analysis-of-rad51c-missense-changes
#10
Javier Gayarre, Paloma Martín-Gimeno, Ana Osorio, Beatriz Paumard, Alicia Barroso, Victoria Fernández, Miguel de la Hoya, Alejandro Rojo, Trinidad Caldés, José Palacios, Miguel Urioste, Javier Benítez, María J García
BACKGROUND: Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. METHODS: To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation...
August 22, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28823141/targeted-therapy-of-ovarian-cancer-including-immune-check-point-inhibitor
#11
REVIEW
Jin Young Kim, Chi Heum Cho, Hong Suk Song
Epithelial ovarian cancer is the eighth most common cause of cancer-related deaths in women because most patients present with advanced stage disease at the time of diagnosis. Although cytoreductive surgery and platinum-based chemotherapy remain the gold standards of treatment, the recurrence rate of ovarian cancer remains high. Attempts to improve this standard two-drug chemotherapy by adding a third cytotoxic drug have failed to affect either progression-free survival or overall survival and have resulted in an increase in toxic side effects...
September 2017: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/28812596/targeted-therapies-solo2-confirms-olaparib-maintenance-in-ovarian-cancer
#12
Lisa Hutchinson
No abstract text is available yet for this article.
October 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28806493/olaparib-a-clinically-used-poly-adp-ribose-polymerase-inhibitor-protects-against-oxidant-induced-cardiac-myocyte-death-in-vitro-and-improves-cardiac-contractility-during-early-phase-after-heart-transplantation-in-a-rat-model-in-vivo
#13
Sevil Korkmaz-Icöz, Bartosz Szczesny, Michela Marcatti, Shiliang Li, Mihály Ruppert, Felix Lasitschka, Sivakkanan Loganathan, Csaba Szabo, Gábor Szabó
BACKGROUND AND PURPOSE: Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) have recently been approved for human use for oncological indications. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effect of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in-vivo model of cardiac transplantation. EXPERIMENTAL APPROACH: H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen-peroxide (H2 O2 ) or with glucose-oxidase (GOx, which generates H2 O2 in the tissue culture medium)...
August 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28792849/olaparib-for-metastatic-breast-cancer-in-patients-with-a-germline-brca-mutation
#14
(no author information available yet)
No abstract text is available yet for this article.
August 9, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28790402/h-ferritin-nanocaged-olaparib-a-promising-choice-for-both-brca-mutated-and-sporadic-triple-negative-breast-cancer
#15
S Mazzucchelli, M Truffi, F Baccarini, M Beretta, L Sorrentino, M Bellini, M A Rizzuto, R Ottria, A Ravelli, P Ciuffreda, D Prosperi, F Corsi
Poly(ADP-ribose) polymerase (PARP) inhibitors represent a promising strategy toward the treatment of triple-negative breast cancer (TNBC), which is often associated to genomic instability and/or BRCA mutations. However, clinical outcome is controversial and no benefits have been demonstrated in wild type BRCA cancers, possibly due to poor drug bioavailability and low nuclear delivery. In the attempt to overcome these limitations, we have developed H-Ferritin nanoformulated olaparib (HOla) and assessed its anticancer efficacy on both BRCA-mutated and non-mutated TNBC cells...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790064/atm-deficiency-generating-genomic-instability-sensitizes-pancreatic-ductal-adenocarcinoma-cells-to-therapy-induced-dna-damage
#16
Lukas Perkhofer, Anna Schmitt, Maria Carolina Romero Carrasco, Michaela Ihle, Stephanie Hampp, Dietrich Alexander Ruess, Elisabeth Hessmann, Ronan Russell, André Lechel, Ninel Azoitei, Qiong Lin, Stefan Liebau, Meike Hohwieler, Hanibal Bohnenberger, Marina Lesina, Hana Algül, Laura Gieldon, Evelin Schröck, Jochen Gaedcke, Martin Wagner, Lisa Wiesmüller, Bence Sipos, Thomas Seufferlein, Hans Christian Reinhardt, Pierre-Olivier Frappart, Alexander Kleger
Pancreatic adenocarcinomas (PDAC) harbour recurrent functional mutations of the master DNA damage response kinase ATM which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements and deregulated DNA integrity checkpoints, reminiscent of human PDAC...
August 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/28780754/fda-approval-of-parp-inhibitors-and-the-impact-on-genetic-counseling-and-genetic-testing-practices
#17
Kathryn M Buchtel, Kristen J Vogel Postula, Shelly Weiss, Carmen Williams, Mario Pineda, Scott M Weissman
In December 2014, the FDA approved olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) for ovarian cancer patients who have failed three or more lines of chemotherapy and have a germline BRCA1/2 mutation identified through a companion diagnostic test (BRACAnalysis CDx™ (CDx™)) offered exclusively by Myriad Genetic Laboratories. This study explored the impact of PARPi/CDx™ on genetic counselors' (GCs) counseling and testing practices. One hundred twenty three GCs responded to an online survey regarding pre- and post-FDA approval referral patterns, testing strategies/influences, and anecdotal experiences with insurance coverage of PARPi for BRCA1/2 positive patients through a non-CDx™ platform...
August 5, 2017: Journal of Genetic Counseling
https://www.readbyqxmd.com/read/28780018/acute-myeloid-leukemia-after-olaparib-treatment-in-metastatic-castration-resistant-prostate-cancer
#18
Jason Zhu, Matthew Tucker, Endi Wang, Joel S Grossman, Andrew J Armstrong, Daniel J George, Tian Zhang
No abstract text is available yet for this article.
July 14, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28770827/discovery-of-potent-2-4-difluoro-linker-poly-adp-ribose-polymerase-1-inhibitors-with-enhanced-water-solubility-and-in-vivo-anticancer-efficacy
#19
Wen-Hua Chen, Shan-Shan Song, Ming-Hui Qi, Xia-Juan Huan, Ying-Qing Wang, Hualiang Jiang, Jian Ding, Guo-Bin Ren, Ze-Hong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3...
August 3, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28759753/inhibition-of-rad51-sensitizes-breast-cancer-cells-with-wild-type-pten-to-olaparib
#20
Qian Zhao, Jiawei Guan, Zhiwei Zhang, Jian Lv, Yulu Wang, Likun Liu, Qi Zhou, Weifeng Mao
PTEN is a tumor suppressor gene well characterized as a phosphatase. However, more evidences demonstrate PTEN functions in DNA repair independent of its phosphatase activity, which affects the efficacy of DNA damage anti-tumoral drugs in treating cancer cells with PTEN variations. Using BT549 breast cancer cells, we studied the roles of PTEN in DNA repair and in sensitization of breast cancer cells to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor. Comet assay showed PTEN promoted DNA repair. PTEN-deficient BT549 cells are sensitive to olaparib, which shows the synthetic lethality between PTEN and PARP1...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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