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https://www.readbyqxmd.com/read/29138572/current-status-of-poly-adp-ribose-polymerase-inhibitors-and-future-directions
#1
REVIEW
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29109859/candidate-synthetic-lethality-partners-to-parp-inhibitors-in-the-treatment-of-ovarian-clear-cell-cancer
#2
Naoki Kawahara, Kenji Ogawa, Mika Nagayasu, Mai Kimura, Yoshikazu Sasaki, Hiroshi Kobayashi
Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies...
November 2017: Biomedical Reports
https://www.readbyqxmd.com/read/29042365/ruxolitinib-induced-defects-in-dna-repair-cause-sensitivity-to-parp-inhibitors-in-myeloproliferative-neoplasms
#3
Margaret Nieborowska-Skorska, Silvia Maifrede, Yashodhara Dasgupta, Katherine Sullivan, Sylwia Flis, Bac Viet Le, Martyna Solecka, Elizaveta A Belyaeva, Lucia Kubovcakova, Morgan Nawrocki, Martin Kirschner, Huaqing Zhao, Josef T Prchal, Katarzyna Piwocka, Alison R Moliterno, Mariusz Wasik, Steffen Koschmieder, Tony R Green, Radek C Skoda, Tomasz Skorski
Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L) or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time primary MPN cell samples from individual patients displayed a high degree of variability in the sensitivity to these drugs...
October 17, 2017: Blood
https://www.readbyqxmd.com/read/29040190/novel-therapeutics-for-ovarian-cancer-the-11th-biennial-rivkin-center-ovarian-cancer-research-symposium
#4
Neil Johnson, John B Liao
OBJECTIVE: The aim of this study was to summarize developments in novel therapeutics for ovarian cancer presented at the Ovarian Cancer Research Symposium held at the University of Washington. METHODS: A symposium of the leaders in ovarian cancer research was convened to present and discuss current advances and future directions in ovarian cancer research. RESULTS: The fourth session was held on September 13, 2016, and focused on Novel Therapeutics for Ovarian Cancer...
October 17, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/29020822/trabectedin-mechanism-of-action-and-platinum-resistance-molecular-rationale
#5
Isabelle Ray-Coquard
Trabectedin presents a complex mode of action affecting key cell biology processes in tumor cells and in the tumor microenvironment. In ovarian cancer patients with a platinum treatment-free interval of 6-12 months treated with trabectedin + pegylated liposomal doxorubicin (PLD) or single-agent PLD, and retreated with platinum after relapse, overall survival was significantly prolonged in the trabectedin + PLD group. Mechanisms by which trabectedin restores tumor sensitivity to platinum include its interaction with components of the nucleotide excision repair machinery in tumor cells and inhibition of inflammatory mediators such as IL-6 in the tumor microenvironment...
October 11, 2017: Future Oncology
https://www.readbyqxmd.com/read/28981380/astrocytes-promote-progression-of-breast-cancer-metastases-to-the-brain-via-a-kiss1-mediated-autophagy
#6
Natalya Kaverina, Anton V Borovjagin, Zaira Kadagidze, Anatoly Baryshnikov, Maria Baryshnikova, Dmitry Malin, Dhimankrishhna Ghosh, Nameeta Shah, Danny R Welch, Patrik Gabikian, Apollon Karseladze, Charles Cobbs, Ilya V Ulasov
Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development. KISS1 expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12...
October 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28978184/poly-adp-ribose-polymerase-inhibitors-as-radiosensitizers-a-systematic-review-of-pre-clinical-and-clinical-human-studies
#7
REVIEW
Paul Lesueur, François Chevalier, Jean-Baptiste Austry, Waisse Waissi, Hélène Burckel, Georges Noël, Jean-Louis Habrand, Yannick Saintigny, Florence Joly
BACKGROUND: Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28977823/intraductal-cisplatin-treatment-in-a-brca-associated-breast-cancer-mouse-model-attenuates-tumor-development-but-leads-to-systemic-tumors-in-aged-female-mice
#8
Jolien S de Groot, Paul J van Diest, Miranda van Amersfoort, Eva J Vlug, Xiaojuan Pan, Natalie D Ter Hoeve, Hilde Rosing, Jos H Beijnen, Sameh A Youssef, Alain de Bruin, Jos Jonkers, Elsken van der Wall, Patrick W B Derksen
BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1-associated breast cancer may be local prophylactic treatment via the nipple. Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935542/phase-i-trial-of-veliparib-a-poly-adp-ribose-polymerase-inhibitor-plus-metronomic-cyclophosphamide-in-metastatic-her2-negative-breast-cancer
#9
Jesus Anampa, Alice Chen, John Wright, Margi Patel, Christine Pellegrino, Karen Fehn, Joseph A Sparano, Eleni Andreopoulou
BACKGROUND: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. METHODS: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer...
September 1, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/28925391/ezh2-contributes-to-the-response-to-parp-inhibitors-through-its-parp-mediated-poly-adp-ribosylation-in-breast-cancer
#10
H Yamaguchi, Y Du, K Nakai, M Ding, S-S Chang, J L Hsu, J Yao, Y Wei, L Nie, S Jiao, W-C Chang, C-H Chen, Y Yu, G N Hortobagyi, M-C Hung
Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells...
September 18, 2017: Oncogene
https://www.readbyqxmd.com/read/28890386/co-targeting-c-met-and-dna-double-strand-breaks-dsbs-therapeutic-strategies-in-brca-mutated-gastric-carcinomas
#11
REVIEW
Chrysovalantou Mihailidou, Michalis V Karamouzis, Dimitrios Schizas, Athanasios G Papavassiliou
Gastric cancer (GC) is a threatening malignancy characterized by heterogeneity. Current therapies use DNA damaging agents, for example, chemotherapeutic agents and ionizing radiation (IR). However, a significant portion of GC patients develops therapeutic resistance to DNA damage response (DDR) - inducing agents. An important mechanism is the stimulation of the c-MET RTK, which is a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), which facilitates cell survival by boosting DNA damage repair pathways and via escaping cell cycle arrest...
November 2017: Biochimie
https://www.readbyqxmd.com/read/28884397/brca1-gene-function-and-deficiency
#12
REVIEW
Miho Takaoka, Yoshio Miki
The BRCA1 protein, a hereditary breast and ovarian cancer-causing gene product, is known as a multifunctional protein that performs various functions in cells. It is well known, along with BRCA 2, to cause hereditary breast and ovarian cancer, but here we will specifically focus on BRCA1. We introduce the mechanism and the latest report on homologous recombination repair, replication, involvement in checkpoint regulation, transcription, chromatin remodeling, and cytoplasmic function (centrosome regulation, apoptosis, selective autophagy), and consider the possibility of carcinogenesis from inhibition of the intracellular functions in each...
September 7, 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28831388/a-new-network-based-strategy-for-predicting-the-potential-mirna-mrna-interactions-in-tumorigenesis
#13
Jiwei Xue, Fanfan Xie, Junmei Xu, Yuan Liu, Yu Liang, Zhining Wen, Menglong Li
MicroRNA (miRNA) plays an important role in the degradation and inhibition of mRNAs and is a kind of essential drug targets for cancer therapy. To facilitate the clinical cancer research, we proposed a network-based strategy to identify the cancer-related miRNAs and to predict their targeted genes based on the gene expression profiles. The strategy was validated by using the data sets of acute myeloid leukemia (AML), breast invasive carcinoma (BRCA), and kidney renal clear cell carcinoma (KIRC). The results showed that in the top 20 miRNAs ranked by their degrees, 90...
2017: International Journal of Genomics
https://www.readbyqxmd.com/read/28829366/understanding-resistance-mechanisms-and-expanding-the-therapeutic-utility-of-parp-inhibitors
#14
REVIEW
Joline S J Lim, David S P Tan
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility...
August 22, 2017: Cancers
https://www.readbyqxmd.com/read/28770827/discovery-of-potent-2-4-difluoro-linker-poly-adp-ribose-polymerase-1-inhibitors-with-enhanced-water-solubility-and-in-vivo-anticancer-efficacy
#15
Wen-Hua Chen, Shan-Shan Song, Ming-Hui Qi, Xia-Juan Huan, Ying-Qing Wang, Hualiang Jiang, Jian Ding, Guo-Bin Ren, Ze-Hong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3...
November 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28723660/poly-adp-ribose-polymerase-inhibitors-as-radiosensitizers-a-systematic-review-of-pre-clinical-and-clinical-human-studies
#16
REVIEW
Paul Lesueur, François Chevalier, Jean-Baptiste Austry, Waisse Waissi, Hélène Burckel, Georges Noël, Jean-Louis Habrand, Yannick Saintigny, Florence Joly
BACKGROUND: Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality...
July 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28692916/discovery-mechanism-and-metabolism-studies-of-2-3-difluorophenyl-linker-containing-parp1-inhibitors-with-enhanced-in%C3%A2-vivo-efficacy-for-cancer-therapy
#17
Wenhua Chen, Ne Guo, Minghui Qi, Haiying Dai, Minghuang Hong, Longfei Guan, Xiajuan Huan, Shanshan Song, Jinxue He, Yingqing Wang, Yong Xi, Xinying Yang, Yanyan Shen, Yi Su, Yiming Sun, Yinglei Gao, Yi Chen, Jian Ding, Yun Tang, Guobin Ren, Zehong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1...
September 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28644128/intraductal-cisplatin-treatment-in-a-brca-associated-breast-cancer-mouse-model-attenuates-tumor-development-but-leads-to-systemic-tumors-in-aged-female-mice
#18
Jolien S de Groot, Paul J van Diest, Miranda van Amersfoort, Eva J Vlug, Xiaojuan Pan, Natalie D Ter Hoeve, Hilde Rosing, Jos H Beijnen, Sameh A Youssef, Alain de Bruin, Jos Jonkers, Elsken van der Wall, Patrick W B Derksen
BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1-associated breast cancer may be local prophylactic treatment via the nipple.Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer...
June 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28605876/e2f8-confers-cisplatin-resistance-to-er-breast-cancer-cells-via-transcriptionally-activating-mastl
#19
Jianjun Tian, Yuting Lin, Jianhua Yu
MASTL (microtubule-associated serine/threonine kinase-like) is a critical kinase modulating mitotic entry. In this study, we investigated the mechanism of its dysregulation in breast cancer and its involvement in cisplatin resistance in ER+ breast cancer cells. Data mining in Kaplan-Meier Plotter showed that high MASTL expression was associated with worse distant metastasis free survival (DMFS) and relapse free survival (RFS) in ER+ breast cancer patients. In TCGA breast cancer cohort (TCGA-BRCA), MASTL was strongly co-upregulated with E2F8...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28574821/the-effect-of-thermal-dose-on-hyperthermia-mediated-inhibition-of-dna-repair-through-homologous-recombination
#20
Nathalie van den Tempel, Charlie Laffeber, Hanny Odijk, Wiggert A van Cappellen, Gerard C van Rhoon, Martine Franckena, Roland Kanaar
Hyperthermia has a number of biological effects that sensitize tumors to radiotherapy in the range between 40-44 °C. One of these effects is heat-induced degradation of BRCA2 that in turn causes reduced RAD51 focus formation, which results in an attenuation of DNA repair through homologous recombination. Prompted by this molecular insight into how hyperthermia attenuates homologous recombination, we now quantitatively explore time and temperature dynamics of hyperthermia on BRCA2 levels and RAD51 focus formation in cell culture models, and link this to their clonogenic survival capacity after irradiation (0-6 Gy)...
July 4, 2017: Oncotarget
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