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https://www.readbyqxmd.com/read/28925391/ezh2-contributes-to-the-response-to-parp-inhibitors-through-its-parp-mediated-poly-adp-ribosylation-in-breast-cancer
#1
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
#2
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...
September 7, 2017: Biochimie
https://www.readbyqxmd.com/read/28884397/brca1-gene-function-and-deficiency
#3
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
#4
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
#5
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
#6
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...
August 3, 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
#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...
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
#8
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...
June 27, 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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28546758/distinct-implications-of-different-brca-mutations-efficacy-of-cytotoxic-chemotherapy-parp-inhibition-and-clinical-outcome-in-ovarian-cancer
#12
REVIEW
Robert L Hollis, Michael Churchman, Charlie Gourley
Approximately a fifth of ovarian carcinoma (OC) is associated with inherited germline mutations, most commonly in the DNA repair genes BRCA1 or BRCA2 (BRCA). BRCA1- and BRCA2-associated OCs have historically been described as a single subgroup of OC that displays a distinct set of characteristics termed the "BRCAness" phenotype. The hallmarks of this phenotype are superior clinical outcome and hypersensitivity to platinum-based chemotherapy and poly-(ADP-ribose) polymerase (PARP) inhibitors. However, growing evidence suggests that BRCA1- and BRCA2-associated OCs display distinct characteristics, most notably in long-term patient survival...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28540821/enhancing-radiosensitisation-of-brca2-proficient-and-brca2-deficient-cell-lines-with-hyperthermia-and-parp1-i
#13
Arlene L Oei, Vidhula R Ahire, C M van Leeuwen, Rosemarie Ten Cate, Lukas J A Stalpers, Johannes Crezee, H Petra Kok, Nicolaas A P Franken
Poly(ADP-ribose)polymerase1 (PARP1) is an important enzyme in regulating DNA replication. Inhibition of PARP1 can lead to collapsed DNA forks which subsequently causes genomic instability, making DNA more susceptible in developing fatal DNA double strand breaks. PARP1-induced DNA damage is generally repaired by homologous recombination (HR), in which BRCA2 proteins are essential. Therefore, BRCA2-deficient tumour cells are susceptible to treatment with PARP1-inhibitors (PARP1-i). Recently, BRCA2 was shown to be down-regulated by hyperthermia (HT) temporarily, and this consequently inactivated HR for several hours...
May 19, 2017: International Journal of Hyperthermia
https://www.readbyqxmd.com/read/28536297/androgen-receptor-inhibitor-induced-brcaness-and-parp-inhibition-are-synthetically-lethal-for-castration-resistant-prostate-cancer
#14
Likun Li, Styliani Karanika, Guang Yang, Jiangxiang Wang, Sanghee Park, Bradley M Broom, Ganiraju C Manyam, Wenhui Wu, Yong Luo, Spyridon Basourakos, Jian H Song, Gary E Gallick, Theodoros Karantanos, Dimitrios Korentzelos, Abul Kalam Azad, Jeri Kim, Paul G Corn, Ana M Aparicio, Christopher J Logothetis, Patricia Troncoso, Timothy Heffernan, Carlo Toniatti, Hyun-Sung Lee, Ju-Seog Lee, Xuemei Zuo, Wenjun Chang, Jianhua Yin, Timothy C Thompson
Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as "BRCAness" and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients...
May 23, 2017: Science Signaling
https://www.readbyqxmd.com/read/28508305/recent-advances-in-targeting-dna-repair-pathways-for-the-treatment-of-ovarian-cancer-and-their-clinical-relevance
#15
REVIEW
Katsutoshi Oda, Michihiro Tanikawa, Kenbun Sone, Mayuyo Mori-Uchino, Yutaka Osuga, Tomoyuki Fujii
Poly (ADP-ribose) polymerase (PARP) inhibitors have attracted much attention as one of the major molecular-targeted therapeutics for inhibiting DNA damage response. The PARP inhibitor, olaparib, has been clinically applied for treating certain recurrent ovarian cancer patients with BRCA1/2 mutations in Europe and the United States. It was also designated on 24 March 2017 as an orphan drug in Japan for similar clinical indications. In this review, we discuss (i) the prevalence of BRCA1/2 mutations in ovarian cancer, (ii) clinical trials of PARP inhibitors in ovarian cancer, (iii) genetic counseling for hereditary breast and ovarian cancer patients, and (iv) non-BRCA genes that may be associated with homologous recombination deficiency...
August 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28500233/nanoformulation-of-olaparib-amplifies-parp-inhibition-and-sensitizes-pten-tp53-deficient-prostate-cancer-to-radiation
#16
Anne L van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John G Clohessy, G Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar
The use of PARP inhibitors in combination with radiation therapy is a promising strategy to locally enhance DNA-damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation-sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of Olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28497333/next-generation-sequencing-based-genomic-profiling-of-brain-metastases-of-primary-ovarian-cancer-identifies-high-number-of-brca-mutations
#17
S Balendran, S Liebmann-Reindl, A S Berghoff, T Reischer, N Popitsch, C B Geier, L Kenner, P Birner, B Streubel, M Preusser
Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSight Rapid Capture Kit in combination with a cancer specific enrichment kit covering 94 genes...
July 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28429680/the-inhibitory-effects-of-hydamtiq-a-novel-parp-inhibitor-on-growth-in-human-tumor-cell-lines-with-defective-dna-damage-response-pathways
#18
Enrico Mini, Ida Landini, Laura Lucarini, Andrea Lapucci, Cristina Napoli, Gabriele Perrone, Renato Tassi, Emanuela Masini, Flavio Moroni, Stefania Nobili
The poly(ADP-ribose) polymerase (PARP) enzymes play key roles in the regulation of cellular processes (e.g. DNA damagerepair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells with dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP1 activity.The aim of this study was to evaluate the growth inhibitory effects of a novel PARPI, HYDAMTIQ, on human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil...
April 20, 2017: Oncology Research
https://www.readbyqxmd.com/read/28427225/enhancing-synthetic-lethality-of-parp-inhibitor-and-cisplatin-in-brca-proficient-tumour-cells-with-hyperthermia
#19
Arlene L Oei, Caspar M van Leeuwen, Vidhula R Ahire, Hans M Rodermond, Rosemarie Ten Cate, Anneke M Westermann, Lukas J A Stalpers, Johannes Crezee, H Petra Kok, Przemek M Krawczyk, Roland Kanaar, Nicolaas A P Franken
BACKGROUND: Poly-(ADP-ribose)-polymerase1 (PARP1) is involved in repair of DNA single strand breaks. PARP1-inhibitors (PARP1-i) cause an accumulation of DNA double strand breaks, which are generally repaired by homologous recombination (HR). Therefore, cancer cells harboring HR deficiencies are exceptionally sensitive to PARP1-i. For patients with HR-proficient tumors, HR can be temporarily inhibited by hyperthermia, thereby inducing synthetic lethal conditions in every tumor type. Since cisplatin is successfully used combined with hyperthermia (thermochemotherapy), we investigated the effectiveness of combining PARP1-i with thermochemotherapy...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423528/level-of-fact-defines-the-transcriptional-landscape-and-aggressive-phenotype-of-breast-cancer-cells
#20
Daria Fleyshman, Laura Prendergast, Alfiya Safina, Geraldine Paszkiewicz, Mairead Commane, Kelsey Morgan, Kristopher Attwood, Katerina Gurova
Although breast cancer (BrCa) may be detected at an early stage, there is a shortage of markers that predict tumor aggressiveness and a lack of targeted therapies. Histone chaperone FACT, expressed in a limited number of normal cells, is overexpressed in different types of cancer, including BrCa. Recently, we found that FACT expression in BrCa correlates with markers of aggressive BrCa, which prompted us to explore the consequences of FACT inhibition in BrCa cells with varying levels of FACT.FACT inhibition using a small molecule or shRNA caused reduced growth and viability of all BrCa cells tested...
March 28, 2017: Oncotarget
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