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Parp inhibitor ovarian ca

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https://www.readbyqxmd.com/read/29340034/prexasertib-a-cell-cycle-checkpoint-kinases-1-and-2-inhibitor-increases-in-vitro-toxicity-of-parp-inhibition-by-preventing-rad51-foci-formation-in-brca-wild-type-high-grade-serous-ovarian-cancer
#1
Ethan Brill, Takuhei Yokoyama, Jayakumar Nair, Minshu Yu, Yeong-Ran Ahn, Jung-Min Lee
PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29327913/proteomic-analysis-of-the-downstream-signaling-network-of-parp1
#2
Yuanli Zhen, Yonghao Yu
Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is a nuclear protein that is activated upon sensing nicked DNA. Once activated, PARP1 is responsible for the synthesis of a large number of PARylated proteins and initiation of the DNA damage response (DDR) mechanisms. This observation provided the rationale for developing PARP1 inhibitors for the treatment of human malignancies...
January 12, 2018: Biochemistry
https://www.readbyqxmd.com/read/29322231/the-effect-of-food-on-the-pharmacokinetics-of-niraparib-a-poly-adp-ribose-polymerase-parp-inhibitor-in-patients-with-recurrent-ovarian-cancer
#3
Kathleen Moore, Zhi-Yi Zhang, Shefali Agarwal, Howard Burris, Manish R Patel, Vikram Kansra
PURPOSE: Niraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. In this open-label crossover study, we evaluated the effects of food on niraparib pharmacokinetics (PK) and safety. METHODS: Patients received a single 300-mg dose of niraparib either after a high-fat meal or under fasting conditions...
January 10, 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29313279/a-phase-1-study-of-parp-inhibitor-abt-767-in-advanced-solid-tumors-with-brca1-2-mutations-and-high-grade-serous-ovarian-fallopian-tube-or-primary-peritoneal-cancer
#4
Diane A J van der Biessen, Jourik A Gietema, Maja J A de Jonge, Ingrid M E Desar, Martha W den Hollander, Matthew Dudley, Martin Dunbar, Robert Hetman, Camille Serpenti, Hao Xiong, Rajendar K Mittapalli, Kirsten M Timms, Peter Ansell, Christine K Ratajczak, Stacie Peacock Shepherd, Carla M L van Herpen
Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined...
January 8, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29285388/metronomic-cyclophosphamide-induced-long-term-remission-after-recurrent-high-grade-serous-ovarian-cancer-a-case-study
#5
Leonora Wijnandina de Boo, Annelie Johanna Elisabeth Vulink, Monique Elisabeth Martina Maria Bos
Metronomic oral cyclophosphamide has gained increasing interest in recent years as a promising maintenance therapy in advanced, platinum-sensitive, high-grade serous ovarian cancer (HGSOC). Metronomic treatment with cyclophosphamide refers to the frequent, usually daily, administration of a low (oral) dose of cyclophosphamide with no prolonged drug-free breaks. Main advantages of this treatment are the effective reduction of tumour activity, oral administration in an outpatient setting, low cost and the low toxicity profile...
December 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/29283581/ratio-dependent-synergism-of-a-doxorubicin-and-olaparib-combination-in-2d-and-spheroid-models-of-ovarian-cancer
#6
Sina Eetezadi, James C Evans, Yen Ting Shen, Raquel De Souza, Micheline Piquette-Miller, Christine Allen
Ovarian cancer is the fourth leading cause of death in women in developed countries. Even though patients with the most lethal form of the disease (HGSOC; high grade serous ovarian cancer) respond well to initial treatment, they often relapse with progressively resistant disease. Inhibitors of the poly(ADP-ribose) polymerase (PARP) enzymes are a relatively new class of molecularly targeted small molecule drugs that show promise in overcoming resistance. The present study explores the combination of a DNA damaging agent, doxorubicin (DOX), with the PARP inhibitor, olaparib (OLP) in order to achieve optimal synergy of both drugs in serous ovarian cancer...
December 28, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29282716/targeting-dna-repair-the-genome-as-a-potential-biomarker
#7
REVIEW
Ksenija Nesic, Matthew Wakefield, Olga Kondrashova, Clare L Scott, Iain A McNeish
Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used both as prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next generation sequencing and improved bioinformatic analyses are revealing mutational signatures, broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes...
December 27, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29262321/bet-bromodomain-inhibition-synergizes-with-parp-inhibitor-in-epithelial-ovarian-cancer
#8
Sergey Karakashev, Hengrui Zhu, Yuhki Yokoyama, Bo Zhao, Nail Fatkhutdinov, Andrew V Kossenkov, Andrew J Wilson, Fiona Simpkins, David Speicher, Dineo Khabele, Benjamin G Bitler, Rugang Zhang
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29260919/the-development-of-parp-as-a-successful-target-for-cancer-therapy
#9
Roberto Ferrara, Francesca Simionato, Chiara Ciccarese, Elisabetta Grego, Sara Cingarlini, Roberto Iacovelli, Emilio Bria, Giampaolo Tortora, Davide Melisi
PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer...
December 20, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29251678/novel-poly-adp-ribose-polymerase-inhibitor-combination-strategies-in-ovarian-cancer
#10
Kelly E McCann
PURPOSE OF REVIEW: The recent United States Food and Drug Administration approvals of niraparib and olaparib as maintenance monotherapy for platinum-sensitive, high-grade ovarian cancers independent of BRCA status reflect a willingness to seek indications for poly-ADP-ribose polymerase (PARP) inhibitors beyond cancers with deleterious breast cancer 1 and breast cancer 2 mutations. In this review, I describe the rationale behind current PARP combination clinical trials with chemotherapies, angiogenesis inhibitors, cell cycle checkpoint inhibitors, and inhibitors of the phosphoinositide 3-kinase/AK thymoma/mechanistic target of rapamycin pathway...
February 2018: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/29251676/frontline-therapy-of-ovarian-cancer-trials-and-tribulations
#11
Jasmin Volpe, Jennifer G Filipi, Olivia R Cooper, Richard T Penson
PURPOSE OF REVIEW: The current article reviews the advances and challenges in the fight with cancer and the hope for cure, with a focus on clinical trials, at the one time with the best outcomes; first-line therapy. RECENT FINDINGS: To date there have been four great stories that bridge inception to development of new drugs in ovarian cancer: Serendipitous insight into the role of platinum, discovery of taxanes, understanding the microenvironment and angiogenesis, and following the science in the development of Poly (ADP-Ribose) Polymerase (PARP) inhibitors...
February 2018: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/29249039/advances-in-ovarian-cancer-therapy
#12
REVIEW
Alexander J Cortez, Patrycja Tudrej, Katarzyna A Kujawa, Katarzyna M Lisowska
Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials...
December 16, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29232475/front-line-therapy-of-advanced-ovarian-cancer-new-approaches
#13
J A Ledermann
Background: The 5-year survival of ovarian cancer has slowly increased but to date much of this has been due to the use of more lines of treatment rather than better first-line therapy. In this setting, there has been little improvement over the past 15 years. The introduction of new treatments to extend time to first progression and overall survival remains a key objective of clinical research. Design: The focus of research in the previous decade has been on the incorporation of anti-angiogenic therapy or dose-dense scheduling of paclitaxel (Taxol) to improve outcome...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29232464/treatment-of-recurrent-ovarian-cancer
#14
S Pignata, S C Cecere, A Du Bois, P Harter, F Heitz
Despite optimal surgery and appropriate first-line chemotherapy, ∼70%-80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29228718/increased-single-strand-annealing-rather-than-non-homologous-end-joining-predicts-hereditary-ovarian-carcinoma
#15
Miriam Deniz, Tatiana Romashova, Sarah Kostezka, Anke Faul, Theresa Gundelach, Maria Moreno-Villanueva, Wolfgang Janni, Thomas W P Friedl, Lisa Wiesmüller
Mutations in genes encoding DNA double-strand break (DSB) repair components, especially homologous recombination (HR) proteins, were found to predispose to breast and ovarian cancer. Beyond high penetrance risk gene mutations underlying monogenic defects, low risk gene mutations generate polygenic defects, enlarging the fraction of individuals with a predisposing phenotype. DSB repair dysfunction opens new options for targeted therapies; poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for BRCA-mutated and platinum-responsive ovarian cancers...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228641/brca-mutations-in-the-manifestation-and-treatment-of-ovarian-cancer
#16
REVIEW
Zimin Pan, Xing Xie
BRCA genes are important for the integrity and stability of genetic material and play key roles in repairing DNA breaks via high fidelity homologous recombination. BRCA mutations are known to predispose carriers to gynecological malignancies, accounting for a majority of hereditary OC cases. Known to be lethal, OC is difficult to detect and control. Testing for BRCA mutations is a key step in the risk assessment, prognosis, treatment and prevention of OC and current clinical guidelines recommend BRCA mutation testing for all OCs of epithelial origin...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29215764/an-evaluation-of-the-challenges-to-developing-tumour-brca1-and-brca2-testing-methodologies-for-clinical-practice
#17
Gillian Ellison, Miika Ahdesmäki, Sally Luke, Paul M Waring, Andrew Wallace, Ronnie Wright, Benno Röthlisberger, Katja Ludin, Sabine Merkelbach-Bruse, Carina Heydt, Marjolijn J L Ligtenberg, Arjen R Mensenkamp, David Gonzalez Castro, Thomas Jones, Ana Vivancos, Olga Kondrashova, Patrick Pauwels, Christine Weyn, Eric Hahnen, Jan Hauke, Richie Soong, Zhongwu Lai, Brian Dougherty, T Hedley Carr, Justin Johnson, John Mills, J Carl Barrett
Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with PARP inhibitors. Tumour BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin fixed paraffin embedded (FFPE), the tumour genome is complex and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumours to compare different approaches to identify clinically important variants within FFPE tumour DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues...
December 7, 2017: Human Mutation
https://www.readbyqxmd.com/read/29214031/parp-inhibitors-as-potential-therapeutic-agents-for-various-cancers-focus-on-niraparib-and-its-first-global-approval-for-maintenance-therapy-of-gynecologic-cancers
#18
REVIEW
Mekonnen Sisay, Dumessa Edessa
Poly (ADP-ribose) polymerases (PARPs) are an important family of nucleoproteins highly implicated in DNA damage repair. Among the PARP families, the most studied are PARP1, PARP2 and PARP 3. PARP1 is found to be the most abundant nuclear enzyme under the PARP series. These enzymes are primarily involved in base excision repair as one of the major single strand break (SSB) repair mechanisms. Being double stranded, DNA engages itself in reparation of a sub-lethal SSB with the aid of PARP. Moreover, by having a sister chromatid, DNA can also repair double strand breaks with either error-free homologous recombination or error-prone non-homologous end-joining...
2017: Gynecologic Oncology Research and Practice
https://www.readbyqxmd.com/read/29205122/parp-inhibitors-in-epithelial-ovarian-cancer
#19
Kristin N Taylor, Ramez N Eskander
Background Ovarian cancer remains the most common lethal gynecologic malignancy. The therapeutic gains with use of traditional cytotoxic chemotherapy in advanced stage disease remain limited, reflecting the need for novel therapies. Poly(ADP-ribose) polymerase (PARP) inhibitors have recently demonstrated a significant therapeutic effect in patients with recurrent, high grade serous ovarian cancer, both in the treatment of existing disease and in prolonging the disease-free interval. Objective The purpose of this article is to discuss PARP inhibitor use in patients with advanced stage ovarian cancer, and to extensively review the existing clinical literature and related patents...
December 3, 2017: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/29203787/crispr-cas9-derived-models-of-ovarian-high-grade-serous-carcinoma-targeting-brca1-pten-and-nf1-and-correlation-with-platinum-sensitivity
#20
Josephine B Walton, Malcolm Farquharson, Susan Mason, Jennifer Port, Bjorn Kruspig, Suzanne Dowson, David Stevenson, Daniel Murphy, Martin Matzuk, Jaeyeon Kim, Seth Coffelt, Karen Blyth, Iain A McNeish
Transplantable murine models of ovarian high grade serous carcinoma (HGSC) remain an important research tool. We previously showed that ID8, a widely-used syngeneic model of ovarian cancer, lacked any of the frequent mutations in HGSC, and used CRISPR/Cas9 gene editing to generate derivatives with deletions in Trp53 and Brca2. Here we have used one ID8 Trp53 -/- clone to generate further mutants, with additional mutations in Brca1, Pten and Nf1, all of which are frequently mutated or deleted in HGSC. We have also generated clones with triple deletions in Trp53, Brca2 and Pten...
December 4, 2017: Scientific Reports
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