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Olaparib

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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/29339456/parp-inhibition-prevents-ethanol-induced-neuroinflammatory-signaling-and-neurodegeneration-in-adult-age-rat-brain-slice-cultures
#2
Nuzhath F Tajuddin, Hee-Yong Kim, Michael A Collins
Utilizing rat adult-age hippocampal-entorhinal cortical (HEC) slice cultures we examined the role of poly [ADP-ribose] polymerase (PARP) in binge ethanol's brain inflammatory and neurodegenerative mechanisms. Activated by DNA strand breaks, PARP (principally PARP1 in brain) promotes DNA repair via poly [ADP-ribose] (PAR) products, but PARP overactivation triggers regulated neuronal necrosis, e.g., parthanatos. Previously we found that brain PARP1 levels were upregulated by neurotoxic ethanol binges in adult rats and HEC slices, and PARP inhibitor PJ34 abrogated slice neurodegeneration...
January 16, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29339439/idh1-2-mutations-sensitize-acute-myeloid-leukemia-to-parp-inhibition-and-this-is-reversed-by-idh1-2-mutant-inhibitors
#3
Remco J Molenaar, Tomas Radivoyevitch, Yasunobu Nagata, Mohammed Khurshed, Bartlomiej Przychodzen, Hideki Makishima, Mingjiang Xu, Fonnet E Bleeker, Johanna W Wilmink, Hetty Carraway, Sudipto Mukherjee, Mikkael A Sekeres, Cornelis J F Van Noorden, Jaroslaw P Maciejewski
PURPOSE: Somatic mutations in IDH1/2 occur in ~20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increases in DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known. EXPERIMENTAL DESIGN: Well-characterized primary IDH1MUT, IDH2MUT and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation and PARP inhibitors...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29327913/proteomic-analysis-of-the-downstream-signaling-network-of-parp1
#4
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/29327849/olaparib-for-metastatic-germline-brca-mutated-breast-cancer
#5
Mark Robson, Carsten Goessl, Susan Domchek
No abstract text is available yet for this article.
November 2, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29327848/olaparib-for-metastatic-germline-brca-mutated-breast-cancer
#6
Steven Narod, Christopher M Booth, William D Foulkes
No abstract text is available yet for this article.
November 2, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29326071/a-rapid-fluorescent-method-for-the-real-time-measurement-of-poly-adp-ribose-polymerase-1-activity
#7
T A Kurgina, R O Anarbaev, M V Sukhanova, O I Lavrik
Poly(ADP-ribose) polymerase 1 (PARP1) is a key enzyme that regulates important cellular processes, including DNA repair. PARP1 binds to a DNA damage site and synthesizes poly(ADP-ribose) chains (PARs), which serve as a signal of DNA damage for other DNA repair enzymes. PARP1 is a recognized target for the development of anti-cancer drugs. In this work, a method is developed that makes it possible to investigate the complex formation of PARP1 with DNA as well as its dissociation by detecting the fluorescence anisotropy of this complex during the poly(ADP-ribose) synthesis...
January 8, 2018: Analytical Biochemistry
https://www.readbyqxmd.com/read/29325860/brca2-reversion-mutation-associated-with-acquired-resistance-to-olaparib-in-estrogen-receptor-positive-breast-cancer-detected-by-genomic-profiling-of-tissue-and-liquid-biopsy
#8
Erica L Gornstein, Sara Sandefur, Jon H Chung, Laurie M Gay, Oliver Holmes, Rachel L Erlich, Salil Soman, L Katherine Martin, Andrea V Rose, Philip J Stephens, Jeffrey S Ross, Vincent A Miller, Siraj M Ali, Sibel Blau
No abstract text is available yet for this article.
December 21, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29321523/integrative-genomic-and-transcriptomic-analysis-of-leiomyosarcoma
#9
Priya Chudasama, Sadaf S Mughal, Mathijs A Sanders, Daniel Hübschmann, Inn Chung, Katharina I Deeg, Siao-Han Wong, Sophie Rabe, Mario Hlevnjak, Marc Zapatka, Aurélie Ernst, Kortine Kleinheinz, Matthias Schlesner, Lina Sieverling, Barbara Klink, Evelin Schröck, Remco M Hoogenboezem, Bernd Kasper, Christoph E Heilig, Gerlinde Egerer, Stephan Wolf, Christof von Kalle, Roland Eils, Albrecht Stenzinger, Wilko Weichert, Hanno Glimm, Stefan Gröschel, Hans-Georg Kopp, Georg Omlor, Burkhard Lehner, Sebastian Bauer, Simon Schimmack, Alexis Ulrich, Gunhild Mechtersheimer, Karsten Rippe, Benedikt Brors, Barbara Hutter, Marcus Renner, Peter Hohenberger, Claudia Scholl, Stefan Fröhling
Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism...
January 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29313488/replication-study-systematic-identification-of-genomic-markers-of-drug-sensitivity-in-cancer-cells
#10
John P Vanden Heuvel, Ewa Maddox, Samar W Maalouf, Elizabeth Iorns, Rachel Tsui, Alexandria Denis, Nicole Perfito, Timothy M Errington
In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Vanden Heuvel et al., 2016), that described how we intended to replicate selected experiments from the paper 'Systematic identification of genomic markers of drug sensitivity in cancer cells' (Garnett et al., 2012). Here we report the results. We found Ewing's sarcoma cell lines, overall, were more sensitive to the PARP inhibitor olaparib than osteosarcoma cell lines; however, while the effect was in the same direction as the original study (Figure 4C; Garnett et al...
January 9, 2018: ELife
https://www.readbyqxmd.com/read/29285242/roscovitine-strongly-enhances-the-effect-of-olaparib-on-radiosensitivity-for-hpv-neg-but-not-for-hpv-pos-hnscc-cell-lines
#11
Frank Ziemann, Steve Seltzsam, Kristin Dreffke, Stefanie Preising, Andrea Arenz, Florentine S B Subtil, Thorsten Rieckmann, Rita Engenhart-Cabillic, Ekkehard Dikomey, Andrea Wittig
At present, advanced stage human Papillomavirus (HPV) negative and positive head and neck squamous cell carcinoma (HNSCC) are treated by intense multimodal therapy that includes radiochemotherapy, which are associated with relevant side effects. Patients with HPV positive tumors possess a far better prognosis than those with HPV negative cancers. Therefore, new therapeutic strategies are needed to improve the outcome especially of the latter one as well as quality of life for all HNSCC patients. Here we tested whether roscovitine, an inhibitor of cyclin-dependent kinases (CDKs), which hereby also blocks homologous recombination (HR), can be used to enhance the radiation sensitivity of HNSCC cell lines...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29283581/ratio-dependent-synergism-of-a-doxorubicin-and-olaparib-combination-in-2d-and-spheroid-models-of-ovarian-cancer
#12
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/29274141/acquired-resistance-of-pten-deficient-cells-to-parp-inhibitor-and-ara-c-mediated-by-53bp1-loss-and-samhd1-overexpression
#13
Yu-Ting Wang, Bo Yuan, Hua-Dong Chen, Lin Xu, Yu-Nan Tian, Ao Zhang, Jin-Xue He, Ze-Hong Miao
With increasing uses of PARP inhibitors (PARPis) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the PTEN-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46~71.78-fold) to all 5 PARPis including niraparib and rucaparib and showed higher degrees of resistance to the PARPis to which the parental cells were more sensitive...
December 22, 2017: Cancer Science
https://www.readbyqxmd.com/read/29262321/bet-bromodomain-inhibition-synergizes-with-parp-inhibitor-in-epithelial-ovarian-cancer
#14
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/29251678/novel-poly-adp-ribose-polymerase-inhibitor-combination-strategies-in-ovarian-cancer
#15
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/29250202/asco-2017-highlights-in-breast-cancer
#16
REVIEW
Rupert Bartsch, Elisabeth Bergen
At the 2017 ASCO Annual Meeting, several pertinent studies in the field of breast cancer were presented and some are deemed as being potentially practice changing. BrighTNess was the first phase III study to investigate the addition of carboplatin to standard neoadjuvant chemotherapy in triple-negative breast cancer; while toxicity was increased in the experimental group, a significantly higher pathologic complete remission (pCR) rate was observed as well suggesting that adding carboplatin to neoadjuvant anthracycline, cyclophosphamide and taxane-containing regimens is efficacious in otherwise healthy patients...
2017: Memo
https://www.readbyqxmd.com/read/29248130/guidance-statement-on-brca1-2-tumor-testing-in-ovarian-cancer-patients
#17
REVIEW
Ettore Capoluongo, Gillian Ellison, José Antonio López-Guerrero, Frederique Penault-Llorca, Marjolijn J L Ligtenberg, Susana Banerjee, Christian Singer, Eitan Friedman, Birgid Markiefka, Peter Schirmacher, Reinhard Büttner, Christi J van Asperen, Isabelle Ray-Coquard, Volker Endris, Suzanne Kamel-Reid, Natalie Percival, Jane Bryce, Benno Röthlisberger, Richie Soong, David Gonzalez de Castro
The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer...
June 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/29232464/treatment-of-recurrent-ovarian-cancer
#18
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/29227281/targeting-mcl-1-enhances-dna-replication-stress-sensitivity-to-cancer-therapy
#19
Guo Chen, Andrew T Magis, Ke Xu, Dongkyoo Park, David S Yu, Taofeek K Owonikoko, Gabriel L Sica, Sarah W Satola, Suresh S Ramalingam, Walter J Curran, Paul W Doetsch, Xingming Deng
DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ...
December 11, 2017: Journal of Clinical Investigation
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
#20
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
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