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https://www.readbyqxmd.com/read/28078645/parp-inhibitors-in-reproductive-system-cancers-current-use-and-developments
#1
REVIEW
Geraldine O'Sullivan Coyne, Alice P Chen, Robert Meehan, James H Doroshow
The repair of DNA damage is a critical cellular process governed by multiple biochemical pathways that are often found to be defective in cancer cells. The poly(ADP-ribose) polymerase (PARP) family of proteins controls response to single-strand DNA breaks by detecting these damaged sites and recruiting the proper factors for repair. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage. While PARP inhibition may not, in itself, be sufficient to cause tumor cell death, inhibition of DNA repair with PARP inhibitors is an effective cytotoxic strategy when it is used in patients who carry other defective DNA-repair mechanisms, such as mutations in the genes BRCA 1 and 2...
January 11, 2017: Drugs
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#2
Xiaoqi Liu, Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff
Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28069724/synthetic-lethality-exploitation-by-an-anti-trop-2-sn-38-antibody-drug-conjugate-immu-132-plus-parp-inhibitors-in-brca1-2-wild-type-triple-negative-breast-cancer
#3
Thomas M Cardillo, Robert M Sharkey, Diane L Rossi, Roberto Arrojo, Ali Mostafa, David M Goldenberg
PURPOSE: Both Poly(ADP-ribose) polymerase inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC. EXPERIMENTAL DESIGN: In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest...
January 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28034904/rad51-mediates-resistance-of-cancer-stem-cells-to-parp-inhibition-in-triple-negative-breast-cancer
#4
Yajing Liu, Monika L Burness, Rachel Martin-Trevino, Joey Guy, Shoumin Bai, Ramdane Harouaka, Michael D Brooks, Li Shang, Alex Fox, Tahra K Luther, April Davis, Trenton L Baker, Justin Colacino, Shawn G Clouthier, Zhi-Ming Shao, Max S Wicha, Suling Liu
INTRODUCTION: PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence...
December 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28003870/new-perspective-on-maintenance-therapies-for-platinum-sensitive-recurrent-ovarian-cancer-in-women-with-germline-and-somatic-mutations-in-brca1-and-brca2-genes
#5
I Vergote, V Bours, B Blaumeiser, J-F Baurain
Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum-sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARPi)...
September 2016: Facts, Views & Vision in ObGyn
https://www.readbyqxmd.com/read/27993965/targeting-the-atr-chk1-axis-with-parp-inhibition-results-in-tumor-regression-in-brca-mutant-ovarian-cancer-models
#6
Hyoung Kim, Erin George, Ryan L Ragland, Stavros Rafail, Rugang Zhang, Clemens Krepler, Mark Morgan, Meenhard Herlyn, Eric J Brown, Fiona Simpkins
PURPOSE: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression. EXPERIMENTAL DESIGN: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776) or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell-cycle, genome instability and apoptosis were evaluated in BRCA1/2MUT HGSOC cells...
December 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27884198/use-of-poly-adp-ribose-polymerase-parp-inhibitors-in-cancer-cells-bearing-ddr-defects-the-rationale-for-their-inclusion-in-the-clinic
#7
REVIEW
Aniello Cerrato, Francesco Morra, Angela Celetti
BACKGROUND: DNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects...
November 24, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27866910/proteome-wide-profiling-of-clinical-parp-inhibitors-reveals-compound-specific-secondary-targets
#8
Claire E Knezevic, Gabriela Wright, Lily L Remsing Rix, Woosuk Kim, Brent M Kuenzi, Yunting Luo, January M Watters, John M Koomen, Eric B Haura, Alvaro N Monteiro, Caius Radu, Harshani R Lawrence, Uwe Rix
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we generated a comparative proteome-wide target map of the four clinical PARPi, olaparib, veliparib, niraparib, and rucaparib. PARPi as a class displayed high target selectivity. However, in addition to the canonical targets PARP1, PARP2, and several of their binding partners, we also identified hexose-6-phosphate dehydrogenase (H6PD) and deoxycytidine kinase (DCK) as previously unrecognized targets of rucaparib and niraparib, respectively...
December 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27821315/current-perspectives-on-recommendations-for-brca-genetic-testing-in-ovarian-cancer-patients
#9
Ignace Vergote, Susana Banerjee, Anne-Marie Gerdes, Christi van Asperen, Christian Marth, Fatima Vaz, Isabelle Ray-Coquard, Dominique Stoppa-Lyonnet, Antonio Gonzalez-Martin, Jalid Sehouli, Nicoletta Colombo
Traditionally, BRCA genetic testing has been undertaken to identify patients and family members at future risk of developing cancer and patients have been referred for testing based on family history. However, the now recognised risk of ovarian cancer (OC) patients, even those with no known family history, harbouring a mutation in BRCA1/2, together with the first poly adenosine diphosphate ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) being licenced for the treatment of BRCA-mutated OC, has led to reconsideration of referral criteria for OC patients...
November 4, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27742776/germline-missense-pathogenic-variants-in-the-brca1-brct-domain-p-gly1706glu-and-p-ala1708glu-increase-cellular-sensitivity-to-parp-inhibitor-olaparib-by-a-dominant-negative-effect
#10
Tereza Vaclová, Nicholas T Woods, Diego Megías, Sergio Gomez-Lopez, Fernando Setién, José María García Bueno, José Antonio Macías, Alicia Barroso, Miguel Urioste, Manel Esteller, Alvaro N A Monteiro, Javier Benítez, Ana Osorio
BRCA1-deficient cells show defects in DNA repair and rely on other members of the DNA repair machinery, which makes them sensitive to PARP inhibitors (PARPi). Although carrying a germline pathogenic variant in BRCA1/2 is the best determinant of response to PARPi, a significant percentage of the patients do not show sensitivity and/or display increased toxicity to the agent. Considering previously suggested mutation-specific BRCA1 haploinsufficiency, we aimed to investigate whether there are any differences in cellular response to PARPi olaparib depending on the BRCA1 mutation type...
October 13, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27728808/enhancing-the-cytotoxic-effects-of-parp-inhibitors-with-dna-demethylating-agents-a-potential-therapy-for-cancer
#11
Nidal E Muvarak, Khadiza Chowdhury, Limin Xia, Carine Robert, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Zeba N Singh, Vu H Duong, Tyler Rutherford, Pratik Nagaria, Søren M Bentzen, Michael M Seidman, Maria R Baer, Rena G Lapidus, Stephen B Baylin, Feyruz V Rassool
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites...
October 10, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27708213/resistance-to-parp-inhibitors-by-slfn11-inactivation-can-be-overcome-by-atr-inhibition
#12
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/27689533/iodinated-benzimidazole-parp-radiotracer-for-evaluating-parp1-2-expression-in-vitro-and-in-vivo
#13
Redmond-Craig Anderson, Mehran Makvandi, Kuiying Xu, Brian P Lieberman, Chenbo Zeng, Daniel A Pryma, Robert H Mach
BACKGROUND: PARP inhibitors (PARPi) have the potential to impact cancer therapy in a selective patient population; however, despite current patient selection methods clinical trials have shown mixed response rates. It is therefore clinically useful to determine which patients will respond prior to receiving PARPi therapy. One essential biomarker is to measure the level of PARP enzyme expression in tumors. Small molecule radiotracers have been developed to accurately quantify PARP-1 expression in vitro and in vivo...
December 2016: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/27663419/inhibiting-poly-adp-ribosylation-increases-fatty-acid-oxidation-and-protects-against-fatty-liver-disease
#14
Karim Gariani, Dongryeol Ryu, Keir J Menzies, Hyon-Seung Yi, Sokrates Stein, Hongbo Zhang, Alessia Perino, Vera Lemos, Elena Katsyuba, Pooja Jha, Sandrine Vijgen, Laura Rubbia-Brandt, Yong Kyung Kim, Jung Tae Kim, Koon Soon Kim, Minho Shong, Kristina Schoonjans, Johan Auwerx
BACKGROUND & AIMS: To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD. METHODS: As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD(+)), we hypothesized that overactivation of PARPs drives NAD(+) depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD(+) and activate NAD(+)-dependent sirtuins, hence improving hepatic fatty acid oxidation...
January 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/27559053/drug-driven-synthetic-lethality-bypassing-tumor-cell-genetics-with-a-combination-of-asidna-and-parp-inhibitors
#15
Wael Jdey, Sylvain Thierry, Christophe Russo, Flavien Devun, Muthana Al Abo, Patricia Noguiez-Hellin, Jian-Sheng Sun, Emmanuel Barillot, Andrei Zinovyev, Inna Kuperstein, Yves Pommier, Marie Dutreix
PURPOSE: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy. EXPERIMENTAL DESIGN: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage...
August 24, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27555886/cytotoxic-and-targeted-therapy-for-hereditary-cancers
#16
REVIEW
Aglaya G Iyevleva, Evgeny N Imyanitov
There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies...
2016: Hereditary Cancer in Clinical Practice
https://www.readbyqxmd.com/read/27498558/synthetic-viability-by-brca2-and-parp1-artd1-deficiencies
#17
Xia Ding, Arnab Ray Chaudhuri, Elsa Callen, Yan Pang, Kajal Biswas, Kimberly D Klarmann, Betty K Martin, Sandra Burkett, Linda Cleveland, Stacey Stauffer, Teresa Sullivan, Aashish Dewan, Hanna Marks, Anthony T Tubbs, Nancy Wong, Eugen Buehler, Keiko Akagi, Scott E Martin, Jonathan R Keller, André Nussenzweig, Shyam K Sharan
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2(cko/ko) mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2(ko/ko) cells...
August 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27473567/parp-inhibitor-induced-synthetic-lethality-for-acute-myeloid-leukemia-treatment
#18
REVIEW
Lu Zhao, Chi Wai Eric So
Genomic instability is one of the most common and critical characteristics of cancer cells. The combined effect of replication stress and DNA damage repair defects associated with various oncogenic events drives genomic instability and disease progression. However, these DNA repair defects found in cancer cells can also provide unique therapeutic opportunities and form the basis of synthetic lethal targeting of solid tumors carrying BRCA mutations. Although the idea of utilizing synthetic lethality as a therapy strategy has been gaining momentum in various solid tumors, its application in leukemia still largely lags behind...
October 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27456662/triple-negative-breast-cancer-a-tale-of-two-decades
#19
Arwa Mohammed Ali, Jawaher Ali Ansari, Nashwa Mohammed AbdelAziz, Waleed Aabozeed, Ahmed Warith, Khalid Alsaleh, Jean-Marc Nabholtz
Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% of breast cancer cases worldwide. TNBC is associated with poor prognosis and lack of sustained response to conventional chemotherapeutic agents. Tumoral heterogeneity and the presence of several subtypes of TNBC such as Basal like (BL)-1, BL-2, immune-modulatory, luminal androgen receptor, mesenchymal, and mesenchymal/stem like subtype and claudin low subtype, may explain some of the difficulties faced in managing this challenging disease subgroup...
July 25, 2016: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27454289/ring-domain-deficient-brca1-promotes-parp-inhibitor-and-platinum-resistance
#20
Yifan Wang, John J Krais, Andrea J Bernhardy, Emmanuelle Nicolas, Kathy Q Cai, Maria I Harrell, Hyoung H Kim, Erin George, Elizabeth M Swisher, Fiona Simpkins, Neil Johnson
Patients with cancers that harbor breast cancer 1 (BRCA1) mutations initially respond well to platinum and poly(ADP-ribose) polymerase inhibitor (PARPi) therapy; however, resistance invariably arises in these patients and is a major clinical problem. The BRCA1185delAG allele is a common inherited mutation located close to the protein translation start site that is thought to produce a shortened, nonfunctional peptide. In this study, we investigated the mechanisms that lead to PARPi and platinum resistance in the SUM1315MO2 breast cancer cell line, which harbors a hemizygous BRCA1185delAG mutation...
August 1, 2016: Journal of Clinical Investigation
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