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Parp inhibitor ovarian ca

Alexander Reinthaller
Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the formation and progression of ovarian cancer. Several well-designed phase II and III trials studied the efficacy of antiangiogenic agents in advanced ovarian cancer. The results of these trials demonstrated significantly prolonged progression-free survival when antiangiogenic agents were used as a maintenance therapy. To date, no effect on overall survival could be ascertained. The most widely studied antiangiogenic agent, bevacizumab - a monoclonal humanized antibody against vascular endothelial growth factor - was effective in all phases of the disease (first-line therapy, platinum-sensitive and platinum-resistant recurrence)...
2016: Memo
Luc Dirix, Helen Swaisland, Henk M W Verheul, Sylvie Rottey, Karin Leunen, Guy Jerusalem, Christian Rolfo, Dorte Nielsen, L Rhoda Molife, Rebecca Kristeleit, Judith de Vos-Geelen, Morten Mau-Sørensen, Patricia Soetekouw, Carla van Herpen, Anitra Fielding, Karen So, Wendy Bannister, Ruth Plummer
PURPOSE: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. METHODS: Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors...
October 10, 2016: Clinical Therapeutics
G E Konecny, R S Kristeleit
Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC...
October 13, 2016: British Journal of Cancer
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
Jennifer McLachlan, Angela George, Susana Banerjee
ABSTRACTRecent 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...
September 24, 2016: Tumori
Aiste McCormick, Peter Donoghue, Michelle Dixon, Richard O'Sullivan, Rachel Louise O'Donnell, James Murray, Angelika Kaufmann, Nicola J Curtin, Richard J Edmondson
PURPOSE: DNA damage defects are common in ovarian cancer and can be used to stratify treatment. Although most work has focussed on Homologous Recombination (HR), DNA double strand breaks are repaired primarily by non-homologous end joining (NHEJ). Defects in NHEJ have been shown to contribute to genomic instability and have been associated with the development of chemoresistance. EXPERIMENTAL DESIGN: NHEJ was assessed in a panel of ovarian cancer cell lines and 47 primary ascitic derived ovarian cancer cultures, by measuring the ability of cell extracts to end-join linearized plasmid monomers into multimers...
October 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Elizabeth H Stover, Panagiotis A Konstantinopoulos, Ursula A Matulonis, Elizabeth M Swisher
Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly- (ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents...
September 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rowan E Miller, Jonathan A Ledermann
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition...
September 2016: Clinical Advances in Hematology & Oncology: H&O
Shan Su, Xueyan Lin, Ning Ding, Hong Zhang, Qinghua Zhang, Yumei Ding, Xiaoman Hou, Yongjie Tian
BACKGROUND: To assess the effects of the poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor PJ34 and ERK1/2 inhibitor U0126 on the proliferation and epithelial mesenchymal transitions (EMT) of cisplatin resistant ovarian cancer SKOV-3 cells. METHODS: Proliferation of SKOV-3 cells was evaluated using a 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyl tetrazolium bromide assay with PJ34 and U0126 treatment. Expression changes of E-cadherin and vimentin with PJ34 and U0126 treatment was examined using Western blot and quantitative PCR...
August 2, 2016: Pharmacological Reports: PR
Jung-Min Lee, Cody J Peer, Minshu Yu, Lauren Amable, Nicolas Gordon, Christina M Annunziata, Nicole Houston, Andrew K L Goey, Tristan M Sissung, Bernard Parker, Lori Minasian, Victoria Chiou, Robert F Murphy, Brigitte C Widemann, William D Figg, Elise C Kohn
PURPOSE: Our preclinical studies showed the PARP inhibitor, olaparib prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic/pharmacodynamic (PK/PD) effects, safety and activity of the combination. PATIENTS AND METHODS: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200mg bid, days1-7) in a 3+3 dose escalation with carboplatin AUC4 or 5 q21 days, up to eight cycles, followed by olaparib maintenance...
September 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Stephen Murata, Catherine Zhang, Nathan Finch, Kevin Zhang, Loredana Campo, Eun-Kyoung Breuer
Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use in BRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized...
2016: BioMed Research International
Anselmo Papa, Davide Caruso, Martina Strudel, Silverio Tomao, Federica Tomao
BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors...
2016: Journal of Translational Medicine
Jonathan A Ledermann, Philipp Harter, Charlie Gourley, Michael Friedlander, Ignace Vergote, Gordon Rustin, Clare Scott, Werner Meier, Ronnie Shapira-Frommer, Tamar Safra, Daniela Matei, Anitra Fielding, Stuart Spencer, Philip Rowe, Elizabeth Lowe, Darren Hodgson, Mika A Sovak, Ursula Matulonis
BACKGROUND: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm). METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system...
September 8, 2016: Lancet Oncology
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
Ruoxi Hong, Fei Ma, Weimin Zhang, Xiying Yu, Qing Li, Yang Luo, Changjun Zhu, Wei Jiang, Binghe Xu
BACKGROUND: Mutations in DNA damage response factors BRCA1 and BRCA2 confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors in breast and ovarian cancers. BRCA1/BRCA2-defective tumors can exhibit resistance to PARP inhibitors via multiple mechanisms, one of which involves loss of 53BP1. Deficiency in the DNA damage response factor ataxia-telangiectasia mutated (ATM) can also sensitize tumors to PARP inhibitors, raising the question of whether the presence or absence of 53BP1 can predict sensitivity of ATM-deficient breast cancer to these inhibitors...
2016: BMC Cancer
Vijayalakshmi Kari, Wael Yassin Mansour, Sanjay Kumar Raul, Simon J Baumgart, Andreas Mund, Marian Grade, Hüseyin Sirma, Ronald Simon, Hans Will, Matthias Dobbelstein, Ekkehard Dikomey, Steven A Johnsen
The CHD1 gene, encoding the chromo-domain helicase DNA-binding protein-1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double-strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of CtIP to chromatin and subsequent end resection during DNA DSB repair. Our data support a role for CHD1 in opening the chromatin around the DSB to facilitate the recruitment of homologous recombination (HR) proteins. Consequently, depletion of CHD1 specifically affects HR-mediated DNA repair but not non-homologous end joining...
September 5, 2016: EMBO Reports
Yoko Katsuki, Minoru Takata
Hereditary breast and ovarian cancer (HBOC) syndrome and a rare childhood disorder Fanconi anemia (FA) are caused by homologous recombination (HR) defects, and some of the causative genes overlap. Recent studies in this field have led to the exciting development of PARP inhibitors as novel cancer therapeutics and have clarified important mechanisms underlying genome instability and tumor suppression in HR-defective disorders. In this review, we provide an overview of the basic molecular mechanisms governing HR and DNA crosslink repair, highlighting BRCA2, and the intriguing relationship between HBOC and FA...
October 2016: Endocrine-related Cancer
Márton Zs Enyedi, Gábor Jaksa, Lajos Pintér, Farkas Sükösd, Zoltán Gyuris, Adrienn Hajdu, Erika Határvölgyi, Katalin Priskin, Lajos Haracska
The development of breast and ovarian cancer is strongly connected to the inactivation of the BRCA1 and BRCA2 genes by different germline and somatic alterations, and their diagnosis has great significance in targeted tumor therapy, since recently approved PARP inhibitors show high efficiency in the treatment of BRCA-deficient tumors. This raises the need for new diagnostic methods that are capable of performing an integrative mutation analysis of the BRCA genes not only from germline DNA but also from formalin-fixed and paraffin-embedded (FFPE) tumor samples...
August 12, 2016: Oncotarget
Josephine Walton, Julianna Blagih, Darren Ennis, Elaine Leung, Suzanne Dowson, Malcolm Farquharson, Laura A Tookman, Clare Orange, Dimitris Athineos, Susan Mason, David Stevenson, Karen Blyth, Douglas Strathdee, Frances R Balkwill, Karen Vousden, Michelle Lockley, Iain A McNeish
There is a need for transplantable murine models of ovarian high-grade serous carcinoma (HGSC) with regard to mutations in the human disease to assist investigations of the relationships between tumor genotype, chemotherapy response, and immune microenvironment. In addressing this need, we performed whole-exome sequencing of ID8, the most widely used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400× with 90% exons sequenced >50×. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, and Rb1), and p53 remained transcriptionally active...
October 15, 2016: Cancer Research
Xia Ding, Arnab Ray Chaudhuri, Elsa Callen, Yan Pang, Kajal Biswas, Kimberly D Klarmann, Betty K Martin, Sandra Burkett, Linda Cleveland, Stacey Stauffer, Teresa Sullivan, Aashish Dewan, Hanna Marks, Anthony T Tubbs, Nancy Wong, Eugen Buehler, Keiko Akagi, Scott E Martin, Jonathan R Keller, André Nussenzweig, Shyam K Sharan
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2(cko/ko) mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2(ko/ko) cells...
August 8, 2016: Nature Communications
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