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Olaparib

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https://www.readbyqxmd.com/read/28634224/igh-myc-translocation-associates-with-brca2-deficiency-and-synthetic-lethality-to-parp1-inhibitors
#1
Silvia Maifrede, Kayla Martin, Paulina Podszywalow-Bartnicka, Katherine Sullivan, Samantha K Langer, Reza Nejadi, Yashodhara Dasgupta, Michael Hulse, Daniel Gritsyuk, Margaret Nieborowska-Skorska, Lena N Lupey-Green, Huaqing Zhao, Katarzyna Piwocka, Mariusz A Wasik, Italo Tempera, Tomasz Skorski
Burkitt lymphoma/leukemia (BL) cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive BL cells accumulate a high number of potentially lethal DNA double-strand breaks (DSBs) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro...
June 20, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28631775/-innovations-in-the-treatment-of-ovarian-cancer-analysis-of-the-therapeutic-development-from-platinum-to-immunotherapy
#2
Gesuino Angius, Pierangela Sepe, Anselmo Papa, Silverio Tomao, Federica Tomao
Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin-paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease...
June 2017: Recenti Progressi in Medicina
https://www.readbyqxmd.com/read/28631738/breast-cancer-olaparib-improves-pfs
#3
Diana Romero
No abstract text is available yet for this article.
June 20, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28628639/small-molecule-inhibitors-uncover-synthetic-genetic-interactions-of-human-flap-endonuclease-1-fen1-with-dna-damage-response-genes
#4
Thomas A Ward, Peter J McHugh, Stephen T Durant
Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response...
2017: PloS One
https://www.readbyqxmd.com/read/28626402/effect-of-the-combination-of-trabectedin-and-pegylated-liposomal-doxorubicin-in-a-brca2-mutation-carrier-with-recurrent-platinum-sensitive-ovarian-cancer
#5
María Jesús Rubio Pérez
INTRODUCTION: The current standard of care for ovarian cancer is optimal cytoreduction with adjuvant chemotherapy based on a platinum/taxane combination. Although the response rate to this therapy is high, most patients ultimately relapse. Response to second-line therapy and prognosis are linked to the platinum-free interval (PFI); when both improve, the PFI increases. As a result, there is an increasing interest in the PFI extension strategies including platinum-free combinations. CASE PRESENTATION: A 50-year-old postmenopausal woman presented with ovarian serous carcinoma with peritoneal carcinomatosis...
May 2017: Case Reports in Oncology
https://www.readbyqxmd.com/read/28625312/traitement-des-rechutes-tardives-du-cancer-de-l%C3%A2-ovaire
#6
Anne Floquet, Dominique Berton-Rigaud, Gwenael Ferron, Gilles Freyer, Anne Claire Hardy-Bessard, Benoit You
Despite large improvements in treatment efficacy, the cure rate of ovarian cancer has not radically changed. Relapses both remain frequent and are still synonymous with chronic disease. Most of them are platinum-sensitive, and can be successfully treated with successive lines of chemotherapy. Surgery may have a role to play but its real impact, population selection criteria, and adequate timing still have to be established. Regarding medical treatments, the availability of new targeted therapeutics, such as bevacizumab and olaparib, complicates decision making...
May 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28625311/cancers-de-l%C3%A2-ovaire-brca-mut%C3%A3-consultation-d%C3%A2-oncog%C3%A3-n%C3%A3-tique-et-prescription-des-inhibiteurs-de-parp
#7
Laurence Gladieff, Dominique Stoppa Lyonnet, Alain Lortholary, Alexandra Leary, Catherine Genestie, Isabelle Ray-Coquard
GENETIC COUNSELING AND PARP INHIBITORS PRESCRIPTION: Upon the availability of the PARP inhibitors in relapsed ovarian carcinoma, the pathways of the oncogenetic counseling were modified. Any research for a constitutional alteration of the BRCA1 and BRCA2 genes must be accompanied by an oncogenetic counseling. BRCA testing is recommended from the diagnosis to every woman with an ovarian or fallopian tube or peritoneum of high grade adenocarcinoma, whatever the age at the diagnosis and her family history. In case of sensitive relapse or potential inclusion in a clinical trial and in the absence of preliminary constitutional research, the oncogenetic counseling is organized according to a fast track pathway and a somatic analysis can be realized in parallel...
May 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28619759/modelling-therapy-resistance-in-brca1-2-mutant-cancers
#8
Amy Dréan, Chris T Williamson, Rachel Brough, Inger Brandsma, Malini Menon, Asha Konde, Isaac Garcia-Murillas, Helen N Pemberton, Jessica Frankum, Rumana Rafiq, Nicholas Badham, James Campbell, Aditi Gulati, Nicholas C Turner, Stephen J Pettitt, Alan Ashworth, Christopher J Lord
Although PARP inhibitors target BRCA1 or BRCA2 mutant tumour cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 Whether secondary mutant tumour cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR-mutagenesis, we generated isogenic tumour cell models with secondary BRCA1 or BRCA2 mutations...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28615517/mtor-signaling-mediates-resistance-to-tankyrase-inhibitors-in-wnt-driven-colorectal-cancer
#9
Tetsuo Mashima, Yoko Taneda, Myung-Kyu Jang, Anna Mizutani, Yukiko Muramatsu, Haruka Yoshida, Ayana Sato, Noritaka Tanaka, Yoshikazu Sugimoto, Hiroyuki Seimiya
Activation of Wnt/β-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/β-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/β-catenin-dependent CRC COLO-320DM cells...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611314/olaparib-and-somatic-brca-mutations
#10
Angela George, Susana Banerjee, Stan Kaye
No abstract text is available yet for this article.
June 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28604461/chemosensitivity-of-brca1-mutated-ovarian-cancer-cells-and-established-cytotoxic-agents
#11
Caroline van Haaften, Jaap van Eendenburg, Arnoud Boot, Willem E Corver, Lucien Haans, Tom van Wezel, J Baptist Trimbos
OBJECTIVE: Serous adenocarcinomas that arise in patients with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 are initially well treatable with platinum/paclitaxel. For recurrent disease in patients with BRCA1 or BRCA2 mutations, olaparib treatment is available. To study additional therapeutic regimens, a better understanding of the cellular and molecular mechanisms of the tumors in in vitro models is important. METHODS/MATERIALS: From a high-grade serous ovarian tumor of a BRCA1 mutation carrier, we established 3 distinct cell line subclones, OVCA-TR3...
June 10, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28602780/olaparib-provides-benefit-in-metastatic-breast-cancer
#12
Manjulika Das
No abstract text is available yet for this article.
June 8, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28601509/olaparib-hydroxamic-acid-derivatives-as-dual-parp-and-hdac-inhibitors-for-cancer-therapy
#13
Zigao Yuan, Shaopeng Chen, Qinsheng Sun, Ning Wang, Dan Li, Shuangshuang Miao, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28600955/parp-activity-and-inhibition-in-fetal-and-adult-oligodendrocyte-precursor-cells-effect-on-cell-survival-and-differentiation
#14
Vito A Baldassarro, Alessandra Marchesini, Luciana Giardino, Laura Calzà
Poly (ADP-ribose) polymerase (PARP) family members are ubiquitously expressed and play a key role in cellular processes, including DNA repair and cell death/survival balance. Accordingly, PARP inhibition is an emerging pharmacological strategy for cancer and neurodegenerative diseases. Consistent evidences support the critical involvement of PARP family members in cell differentiation and phenotype maturation. In this study we used an oligodendrocyte precursor cells (OPCs) enriched system derived from fetal and adult brain to investigate the role of PARP in OPCs proliferation, survival, and differentiation...
May 30, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28587822/initial-evaluation-of-cu-64-labeled-parpi-dota-pet-imaging-in-mice-with-mesothelioma
#15
Tao Huang, Pengcheng Hu, Anna B Banizs, Jiang He
Poly(ADP-ribose) polymerase (PARP) has emerged as an important molecular target for the treatment of several oncological diseases. A couple of molecular probes based on Olaparib scaffold have been developed by incorporation of F-18 or fluorophore for positron emission tomography (PET) or optical imaging in several types of tumor. PARP has been reported overexpressed in mesothelioma. We hereby synthesized an analogue of Olaparib containing DOTA moiety and radiolabeled it with Cu-64 to evaluate its utility of PET tracer for mesothelioma...
May 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28583909/olaparib-keeps-hereditary-breast-tumors-in-check
#16
(no author information available yet)
In the phase III OlympiAD study, tumors shrank in about 60% of women with BRCA mutation-associated metastatic breast cancer who received the PARP inhibitor olaparib compared with 29% who received chemotherapy; the median time to disease progression was 7 months compared with 4.2 months, respectively. These findings are the first to demonstrate that a PARP inhibitor can improve progression-free survival in metastatic, hereditary breast cancer.
June 5, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28578601/olaparib-for-metastatic-breast-cancer-in-patients-with-a-germline-brca-mutation
#17
Mark Robson, Seock-Ah Im, Elżbieta Senkus, Binghe Xu, Susan M Domchek, Norikazu Masuda, Suzette Delaloge, Wei Li, Nadine Tung, Anne Armstrong, Wenting Wu, Carsten Goessl, Sarah Runswick, Pierfranco Conte
Background Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. Methods We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease...
June 4, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28577239/population-pharmacokinetic-analyses-of-the-effect-of-carboplatin-pretreatment-on-olaparib-in-recurrent-or-refractory-women-s-cancers
#18
Cody J Peer, Jung-Min Lee, Jeffrey Roth, Louis Rodgers, Jeffers Nguyen, Christina M Annunziata, Lori Minasian, Elise C Kohn, William D Figg
PURPOSE: Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance. METHODS: To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters...
June 2, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28569838/usp13-regulates-the-rap80-brca1-complex-dependent-dna-damage-response
#19
Yunhui Li, Kuntian Luo, Yujiao Yin, Chenming Wu, Min Deng, Lei Li, Yuping Chen, Somaira Nowsheen, Zhenkun Lou, Jian Yuan
BRCA1 regulates multiple cellular pathways that maintain genomic stability including cell cycle checkpoints, DNA repair, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis. Receptor-associated protein 80 (RAP80) helps recruit BRCA1 to double-strand breaks (DSBs) through the scaffold protein CCDC98 (Abraxas) and facilitates DNA damage response (DDR). However, the regulation of RAP80-BRCA1 complex is still unclear. Here we report that a deubiquitinase, USP13, regulates DDR by targeting RAP80...
June 1, 2017: Nature Communications
https://www.readbyqxmd.com/read/28540598/parp-inhibitors-in-prostate-cancer
#20
REVIEW
Praveen Ramakrishnan Geethakumari, Matthew J Schiewer, Karen E Knudsen, Wm Kevin Kelly
The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients...
June 2017: Current Treatment Options in Oncology
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