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Olaparib

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https://www.readbyqxmd.com/read/28415784/misregulation-of-dna-damage-repair-pathways-in-hpv-positive-head-and-neck-squamous-cell-carcinoma-contributes-to-cellular-radiosensitivity
#1
Catherine M Nickson, Parisa Moori, Rachel J Carter, Carlos P Rubbi, Jason L Parsons
Patients with human papillomavirus type 16 (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy and improved survival rates in comparison to HPV-negative forms of the disease. However the cellular mechanisms responsible for this characteristic difference are unclear. Here, we have investigated the contribution of DNA damage repair pathways to the in vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positive OPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, which correlates with reduced efficiency for the repair of ionising radiation (IR)-induced DNA double strand breaks (DSB)...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28398198/functional-and-mutational-landscapes-of-brca1-for-homology-directed-repair-and-therapy-resistance
#2
Rachel W Anantha, Srilatha Simhadri, Tzeh Keong Foo, Susanna Miao, Jingmei Liu, Zhiyuan Shen, Shridar Ganesan, Bing Xia
BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance...
April 11, 2017: ELife
https://www.readbyqxmd.com/read/28395540/olaparib-for-the-treatment-of-breast-cancer
#3
Marie Robert, Jean-Sébastien Frenel, Carole Gourmelon, Anne Patsouris, Paule Augereau, Mario Campone
Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations. Areas covered: Olaparib is one of the most widely investigated PARP inhibitors...
April 11, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28394338/parp-inhibitors-enhance-replication-stress-and-cause-mitotic-catastrophe-in-mycn-dependent-neuroblastoma
#4
V Colicchia, M Petroni, G Guarguaglini, F Sardina, M Sahún-Roncero, M Carbonari, B Ricci, C Heil, C Capalbo, F Belardinilli, A Coppa, G Peruzzi, I Screpanti, P Lavia, A Gulino, G Giannini
High-risk and MYCN-amplified neuroblastomas are among the most aggressive pediatric tumors. Despite intense multimodality therapies, about 50% of these patients succumb to their disease, making the search for effective therapies an absolute priority. Due to the important functions of poly (ADP-ribose) polymerases, PARP inhibitors have entered the clinical settings for cancer treatment and are being exploited in a variety of preclinical studies and clinical trials. PARP inhibitors based combination schemes have also been tested in neuroblastoma preclinical models with encouraging results...
April 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28394191/the-parp-inhibitor-olaparib-enhances-the-cytotoxicity-of-combined-gemcitabine-busulfan-and-melphalan-in-lymphoma-cells
#5
Benigno C Valdez, Yang Li, David Murray, Yan Liu, Yago Nieto, Richard E Champlin, Borje S Andersson
The combination of gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) is a promising regimen for autologous stem-cell transplantation (SCT) for lymphomas. To further improve the efficacy of [Gem + Bu + Mel], we added poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Ola). We hypothesized that Ola would inhibit the repair of damaged DNA caused by [Gem + Bu + Mel]. Exposure of J45.01 and Toledo cell lines to IC10-20 of individual drug inhibited proliferation by 6-16%; [Gem + Bu + Mel] by 20-27%; and [Gem + Bu + Mel + Ola] by 61-67%...
April 10, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28389374/a-novel-brca1-associated-protein-1-isoform-affects-response-of-mesothelioma-cells-to-drugs-impairing-brca1-mediated-dna-repair
#6
Rossella Parrotta, Agata Okonska, Manuel Ronner, Walter Weder, Rolf Stahel, Lorenza Penengo, Emanuela Felley-Bosco
INTRODUCTION: BRCA1-associated protein-1, BAP1, is a tumor suppressor involved in multiple cellular processes such as transcriptional regulation, chromatin modification by deubiquitinating histone 2A and DNA repair. BAP1 mutations are frequent in malignant pleural mesothelioma (MPM). Our aim was to functionally characterize a newly identified isoform of BAP1 and investigate the effects of its expression on drug sensitivity in MPM. METHODS: Expression of BAP1 isoforms was detected by qPCR in MPM and normal mesothelium cell lines, tumor and non-tumor samples...
April 4, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28388551/phase-i-ib-study-of-olaparib-and-carboplatin-in-women-with-triple-negative-breast-cancer
#7
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...
March 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28388401/parp-inhibitors-for-cancer-therapy
#8
Ken Y Lin, W Lee Kraus
Rucaparib is an inhibitor of nuclear poly (ADP-ribose) polymerases (inhibition of PARP-1 > PARP-2 > PARP-3), following a similar drug, Olaparib. It disrupts DNA repair and replication pathways (and possibly transcription), leading to selective killing of cancer cells with BRCA1/2 mutations. Rucaparib is approved for recurrent ovarian cancers with germline or somatic mutations in BRCA1/2.
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28376211/rad51-degradation-role-in-oncolytic-virus-poly-adp-ribose-polymerase-inhibitor-combination-therapy-in-glioblastoma
#9
Jianfang Ning, Hiroaki Wakimoto, Cole Peters, Robert L Martuza, Samuel D Rabkin
Background: Clinical success of poly(ADP-ribose) polymerase inhibitors (PARP i ) has been limited to repair-deficient cancers and by resistance. Oncolytic herpes simplex viruses (oHSVs) selectively kill cancer cells, irrespective of mutation, and manipulate DNA damage responses (DDR). Here, we explore potential synthetic lethal-like interactions between oHSV and PARP i . Methods: The efficacy of combining PARP i , oHSV MG18L, and G47Δ in killing patient-derived glioblastoma stem cells (GSCs) was assessed using cell viability assays and Chou-Talalay synergy analysis...
March 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28376176/tumor-sequencing-and-patient-derived-xenografts-in-the-neoadjuvant-treatment-of-breast-cancer
#10
Matthew P Goetz, Krishna R Kalari, Vera J Suman, Ann M Moyer, Jia Yu, Daniel W Visscher, Travis J Dockter, Peter T Vedell, Jason P Sinnwell, Xiaojia Tang, Kevin J Thompson, Sarah A McLaughlin, Alvaro Moreno-Aspitia, John A Copland, Donald W Northfelt, Richard J Gray, Katie Hunt, Amy Conners, Richard Weinshilboum, Liewei Wang, Judy C Boughey
Background: Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown. Methods: We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies...
July 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28363999/atm-deficiency-is-associated-with-sensitivity-to-parp1-and-atr-inhibitors-in-lung-adenocarcinoma
#11
Anna Schmitt, Gero Knittel, Daniela Welcker, Tsun-Po Yang, Julie George, Michael Nowak, Uschi Leeser, Reinhard Buttner, Sven Perner, Martin Peifer, Hans Christian Reinhardt
Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib...
March 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/28347815/sigma-2-ligands-and-parp-inhibitors-synergistically-trigger-cell-death-in-breast-cancer-cells
#12
Elizabeth S McDonald, Julia Mankoff, Mehran Makvandi, Wenhua Chu, Yunxiang Chu, Robert H Mach, Chenbo Zeng
The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines...
March 24, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28346230/glutaminase-and-poly-adp-ribose-polymerase-inhibitors-suppress-pyrimidine-synthesis-and-vhl-deficient-renal-cancers
#13
Arimichi Okazaki, Paulo A Gameiro, Danos Christodoulou, Laura Laviollette, Meike Schneider, Frances Chaves, Anat Stemmer-Rachamimov, Stephanie A Yazinski, Richard Lee, Gregory Stephanopoulos, Lee Zou, Othon Iliopoulos
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis...
March 27, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28338178/the-involvement-of-senescence-induced-by-the-telomere-shortness-in-the-decline-of-osteogenic-differentiation-in-bmscs
#14
C Li, G-J Wei, L Xu, J-S Rong, S-Q Tao, Y-S Wang
OBJECTIVE: BMSC (Bone marrow mesenchymal stem cells) is an important seed cell for the repair of bone and cartilage defect in the tissue engineering. The proliferation rate and differentiation capacity of BMSCs from the old donors were less than that from young donors; however, the related mechanism remained unclear. MATERIALS AND METHODS: Sprague Dawley (SD) rats BMSCs were cultured and treated. Hydrogen peroxide (H2O2) and continual passage of BMSCs were performed to induce senescence...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28323658/changing-face-of-metastatic-prostate-cancer-the-law-of-diminishing-returns-holds-true
#15
Ulka N Vaishampayan
PURPOSE OF REVIEW: Prostate cancer presents with a multitude of faces. It ranges from localized cancers staying quiescent for many years during active surveillance to the raging diffuse liver metastases causing terminal disease. The incidence of metastatic disease is increasing. This review will highlight some of the recent developments as well as ongoing challenges of managing advanced prostate cancer. RECENT FINDINGS: Significant strides are being made in managing metastatic prostate cancer...
March 18, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28322442/systems-analysis-of-dynamic-transcription-factor-activity-identifies-targets-for-treatment-in-olaparib-resistant-cancer-cells
#16
Joseph T Decker, Eric C Hobson, Yining Zhang, Seungjin Shin, Alexandra L Thomas, Jacqueline S Jeruss, Kelly B Arnold, Lonnie D Shea
The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly (ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells...
March 21, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28280302/defective-dna-repair-mechanisms-in-prostate-cancer-impact-of-olaparib
#17
REVIEW
Francesca De Felice, Vincenzo Tombolini, Francesco Marampon, Angela Musella, Claudia Marchetti
The field of prostate oncology has continued to change dramatically. It has truly become a field that is intensely linked to molecular genetic alterations, especially DNA-repair defects. Germline breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) mutations are implicated in the highest risk of prostate cancer (PC) predisposition and aggressiveness. Poly adenosine diphosphate ribose polymerase (PARP) proteins play a key role in DNA repair mechanisms and represent a valid target for new therapies. Olaparib is an oral PARP inhibitor that blocks DNA repair pathway and coupled with BRCA mutated-disease results in tumor cell death...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28250726/parp-inhibitors-review-of-mechanisms-of-action-and-brca1-2-mutation-targeting
#18
REVIEW
Karolina N Dziadkowiec, Emilia Gąsiorowska, Ewa Nowak-Markwitz, Anna Jankowska
Poly(ADP-ribose) polymerases have shown true promise in early clinical studies due to reported activity in BRCA-associated cancers. PARP inhibitors may represent a potentially important new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. In addition, a more sophisticated understanding of the toxicity profile is required if PARP inhibitors are to be employed in the curative, rather than the palliative, setting...
December 2016: Przeglad Menopauzalny, Menopause Review
https://www.readbyqxmd.com/read/28246437/olaparib
#19
REVIEW
(no author information available yet)
No abstract text is available yet for this article.
February 2017: Australian Prescriber
https://www.readbyqxmd.com/read/28228392/idh-mutant-tumors-vulnerable-to-parp-inhibition
#20
(no author information available yet)
Several cancers, including glioma and acute myeloid leukemia, carry mutations in IDH1 or IDH2 Researchers have found that these mutations impair homologous recombination, making the tumors sensitive to PARP inhibition. They showed that one such inhibitor, olaparib, killed IDH1/2-mutant cancer cells in culture and slowed tumor growth in mice.
February 22, 2017: Cancer Discovery
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