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https://www.readbyqxmd.com/read/27716873/the-current-status-of-parp-inhibitors-in-ovarian-cancer
#1
Jennifer McLachlan, Angela George, Susana Banerjee
Recent advances in our understanding of the molecular biology of epithelial ovarian cancer have led to the development of a number of targeted therapies, including poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Early studies have shown significant efficacy for PARP inhibitors in patients with germline BRCA1/2 mutations. It has become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this therapeutic approach...
October 13, 2016: Tumori
https://www.readbyqxmd.com/read/27708213/resistance-to-parp-inhibitors-by-slfn11-inactivation-can-be-overcome-by-atr-inhibition
#2
Junko Murai, Ying Feng, Guoying K Yu, Yuanbin Ru, Sai-Wen Tang, Yuqiao Shen, Yves Pommier
Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models...
September 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27676009/slfn11-is-necessary-for-single-agent-sensitivity-to-talazoparib-a-potent-parp-inhibitor-but-not-for-radiosensitization-in-small-cell-lung-cancer-sclc-cell-lines-and-patient-derived-xenografts-pdx
#3
B H Lok, Y Feng, E E Gardner, G K Yu, Y K Ru, N Riaz, E deStanchina, S N Powell, Y J Shen, J T Poirier, C M Rudin
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/27447864/osteosarcoma-cells-with-genetic-signatures-of-brcaness-are-susceptible-to-the-parp-inhibitor-talazoparib-alone-or-in-combination-with-chemotherapeutics
#4
Florian Engert, Michal Kovac, Daniel Baumhoer, Michaela Nathrath, Simone Fulda
We recently discovered mutation signatures reminiscent of BRCA deficiency in the vast majority of a set of primary osteosarcomas (OS). In the current study, we therefore investigated the sensitivity of a panel of OS cell lines to the poly(ADP)-ribose polymerase (PARP) inhibitor talazoparib alone and in combination with several chemotherapeutic drugs (i.e. temozolomide (TMZ), SN-38, doxorubicin, cisplatin, methotrexate (MTX), etoposide/carboplatin). Here, we identified an association between homologous recombination (HR) repair deficiency and the response of OS cell lines to talazoparib...
July 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27440269/parp-inhibitor-activity-correlates-with-slfn11-expression-and-demonstrates-synergy-with-temozolomide-in-small-cell-lung-cancer
#5
Benjamin H Lok, Eric E Gardner, Valentina E Schneeberger, Andy Ni, Patrice Desmeules, Natasha Rekhtman, Elisa de Stanchina, Beverly A Teicher, Nadeem Riaz, Simon N Powell, John T Poirier, Charles M Rudin
PURPOSE: PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy. EXPERIMENTAL DESIGN: Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, was analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6...
July 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27087632/evaluation-of-rucaparib-and-companion-diagnostics-in-the-parp-inhibitor-landscape-for-recurrent-ovarian-cancer-therapy
#6
Zachary B Jenner, Anil K Sood, Robert L Coleman
Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy...
June 2016: Future Oncology
https://www.readbyqxmd.com/read/27064363/histone-deacetylase-inhibitors-decrease-nhej-both-by-acetylation-of-repair-factors-and-trapping-of-parp1-at-dna-double-strand-breaks-in-chromatin
#7
Carine Robert, Pratik K Nagaria, Nisha Pawar, Adeoluwa Adewuyi, Ivana Gojo, David J Meyers, Philip A Cole, Feyruz V Rassool
Histone deacetylase inhibitors (HDACi) induce acetylation of histone and non-histone proteins, and modulate the acetylation of proteins involved in DNA double-strand break (DSB) repair. Non-homologous end-joining (NHEJ) is one of the main pathways for repairing DSBs. Decreased NHEJ activity has been reported with HDACi treatment. However, mechanisms through which these effects are regulated in the context of chromatin are unclear. We show that pan-HDACi, trichostatin A (TSA), causes differential acetylation of DNA repair factors Ku70/Ku80 and poly ADP-ribose polymerase-1 (PARP1), and impairs NHEJ...
June 2016: Leukemia Research
https://www.readbyqxmd.com/read/27055253/activation-of-the-pi3k-mtor-pathway-following-parp-inhibition-in-small-cell-lung-cancer
#8
Robert J Cardnell, Ying Feng, Seema Mukherjee, Lixia Diao, Pan Tong, C Allison Stewart, Fatemeh Masrorpour, YouHong Fan, Monique Nilsson, Yuqiao Shen, John V Heymach, Jing Wang, Lauren A Byers
Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options. We previously found that PARP is overexpressed in SCLC and that targeting PARP reduces cell line and tumor growth in preclinical models. However, SCLC cell lines with PI3K/mTOR pathway activation were relatively less sensitive to PARP inhibition. In this study, we investigated the proteomic changes in PI3K/mTOR and other pathways that occur following PAPR inhibition and/or knockdown in vitro and in vivo. Using reverse-phase protein array, we found the proteins most significantly upregulated following treatment with the PARP inhibitors olaparib and rucaparib were in the PI3K/mTOR pathway (p-mTOR, p-AKT, and pS6) (p≤0...
2016: PloS One
https://www.readbyqxmd.com/read/26837770/effects-of-anticancer-drugs-on-chromosome-instability-and-new-clinical-implications-for-tumor-suppressing-therapies
#9
Hee-Sheung Lee, Nicholas C O Lee, Natalay Kouprina, Jung-Hyun Kim, Alex Kagansky, Susan Bates, Jane B Trepel, Yves Pommier, Dan Sackett, Vladimir Larionov
Whole chromosomal instability (CIN), manifested as unequal chromosome distribution during cell division, is a distinguishing feature of most cancer types. CIN is generally considered to drive tumorigenesis, but a threshold level exists whereby further increases in CIN frequency in fact hinder tumor growth. While this attribute is appealing for therapeutic exploitation, drugs that increase CIN beyond this therapeutic threshold are currently limited. In our previous work, we developed a quantitative assay for measuring CIN based on the use of a nonessential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene...
February 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/26652717/discovery-and-characterization-of-8s-9r-5-fluoro-8-4-fluorophenyl-9-1-methyl-1h-1-2-4-triazol-5-yl-2-7-8-9-tetrahydro-3h-pyrido-4-3-2-de-phthalazin-3-one-bmn-673-talazoparib-a-novel-highly-potent-and-orally-efficacious-poly-adp-ribose-polymerase-1-2-inhibitor
#10
Bing Wang, Daniel Chu, Ying Feng, Yuqiao Shen, Mika Aoyagi-Scharber, Leonard E Post
We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1...
January 14, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26546619/mtor-inhibitors-suppress-homologous-recombination-repair-and-synergize-with-parp-inhibitors-via-regulating-suv39h1-in-brca-proficient-triple-negative-breast-cancer
#11
Wei Mo, Qingxin Liu, Curtis Chun-Jen Lin, Hui Dai, Yang Peng, Yulong Liang, Guang Peng, Funda Meric-Bernstam, Gordon B Mills, Kaiyi Li, Shiaw-Yih Lin
PURPOSE: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can extend the use of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/BRCA2 Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC...
April 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26539646/parp1-expression-activity-and-ex-vivo-sensitivity-to-the-parp-inhibitor-talazoparib-bmn-673-in-chronic-lymphocytic-leukaemia
#12
Ashleigh Herriott, Susan J Tudhope, Gesa Junge, Natalie Rodrigues, Miranda J Patterson, Laura Woodhouse, John Lunec, Jill E Hunter, Evan A Mulligan, Michael Cole, Lisa M Allinson, Jonathan P Wallis, Scott Marshall, Evelyn Wang, Nicola J Curtin, Elaine Willmore
In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors.We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 - 190052 pmol PAR/10⁶ cells) compared to that seen in healthy volunteer lymphocytes (2451 - 7519 pmol PAR/10⁶ cells)...
December 22, 2015: Oncotarget
https://www.readbyqxmd.com/read/26438158/parp-inhibitors-sensitize-ewing-sarcoma-cells-to-temozolomide-induced-apoptosis-via-the-mitochondrial-pathway
#13
Florian Engert, Cornelius Schneider, Lilly Magdalena Weiβ, Marie Probst, Simone Fulda
Ewing sarcoma has recently been reported to be sensitive to poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for synergistic drug combinations, we tested several PARP inhibitors (talazoparib, niraparib, olaparib, veliparib) together with chemotherapeutics. Here, we report that PARP inhibitors synergize with temozolomide (TMZ) or SN-38 to induce apoptosis and also somewhat enhance the cytotoxicity of doxorubicin, etoposide, or ifosfamide, whereas actinomycin D and vincristine show little synergism. Furthermore, triple therapy of olaparib, TMZ, and SN-38 is significantly more effective compared with double or monotherapy...
December 2015: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26217019/mechanistic-dissection-of-parp1-trapping-and-the-impact-on-in-vivo-tolerability-and-efficacy-of-parp-inhibitors
#14
Todd A Hopkins, Yan Shi, Luis E Rodriguez, Larry R Solomon, Cherrie K Donawho, Enrico L DiGiammarino, Sanjay C Panchal, Julie L Wilsbacher, Wenqing Gao, Amanda M Olson, DeAnne F Stolarik, Donald J Osterling, Eric F Johnson, David Maag
UNLABELLED: Poly(ADP-ribose) polymerases (PARP1, -2, and -3) play important roles in DNA damage repair. As such, a number of PARP inhibitors are undergoing clinical development as anticancer therapies, particularly in tumors with DNA repair deficits and in combination with DNA-damaging agents. Preclinical evidence indicates that PARP inhibitors potentiate the cytotoxicity of DNA alkylating agents. It has been proposed that a major mechanism underlying this activity is the allosteric trapping of PARP1 at DNA single-strand breaks during base excision repair; however, direct evidence of allostery has not been reported...
November 2015: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/25758918/trapping-poly-adp-ribose-polymerase
#15
Yuqiao Shen, Mika Aoyagi-Scharber, Bing Wang
Recent findings indicate that a major mechanism by which poly(ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells...
June 2015: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/25500058/synergistic-activity-of-parp-inhibition-by-talazoparib-bmn-673-with-temozolomide-in-pediatric-cancer-models-in-the-pediatric-preclinical-testing-program
#16
Malcolm A Smith, C Patrick Reynolds, Min H Kang, E Anders Kolb, Richard Gorlick, Hernan Carol, Richard B Lock, Stephen T Keir, John M Maris, Catherine A Billups, Dmitry Lyalin, Raushan T Kurmasheva, Peter J Houghton
PURPOSE: Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. EXPERIMENTAL DESIGN: Talazoparib was tested in vitro in combination with temozolomide (0...
February 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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