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https://www.readbyqxmd.com/read/27902969/rac1-gtp-ase-signals-wnt-beta-catenin-pathway-mediated-integrin-directed-metastasis-associated-tumor-cell-phenotypes-in-triple-negative-breast-cancers
#1
Pradip De, Jennifer H Carlson, Tyler Jepperson, Scooter Willis, Brian Leyland-Jones, Nandini Dey
The acquisition of integrin-directed metastasis-associated (ID-MA) phenotypes by Triple-Negative Breast Cancer (TNBC) cells is caused by an upregulation of the Wnt-beta-catenin pathway (WP). We reported that WP is one of the salient genetic features of TNBC. RAC-GTPases, small G-proteins which transduce signals from cell surface proteins including integrins, have been implicated in tumorigenesis and metastasis by their role in essential cellular functions like motility. The collective percentage of alteration(s) in RAC1 in ER+ve BC was lower as compared to ER-ve BC (35% vs 57%) (brca/tcga/pub2015)...
November 25, 2016: Oncotarget
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
#2
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/27880910/cdk12-inhibition-reverses-de-novo-and-acquired-parp-inhibitor-resistance-in-brca-wild-type-and-mutated-models-of-triple-negative-breast-cancer
#3
Shawn F Johnson, Cristina Cruz, Ann Katrin Greifenberg, Sofia Dust, Daniel G Stover, David Chi, Benjamin Primack, Shiliang Cao, Andrea J Bernhardy, Rhiannon Coulson, Jean-Bernard Lazaro, Bose Kochupurakkal, Heather Sun, Christine Unitt, Lisa A Moreau, Kristopher A Sarosiek, Maurizio Scaltriti, Dejan Juric, José Baselga, Andrea L Richardson, Scott J Rodig, Alan D D'Andrea, Judith Balmaña, Neil Johnson, Matthias Geyer, Violeta Serra, Elgene Lim, Geoffrey I Shapiro
Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27811964/the-poly-adp-ribose-polymerase-inhibitor-veliparib-and-radiation-cause-significant-cell-line-dependent-metabolic-changes-in-breast-cancer-cells
#4
Vijesh J Bhute, Yan Ma, Xiaoping Bao, Sean P Palecek
Breast tumors are characterized into subtypes based on their surface marker expression, which affects their prognosis and treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in clinical trials, both as single agents and in combination with other chemotherapeutics, in several subtypes of breast cancer patients. Here, we used NMR-based metabolomics to probe cell line-specific effects of the PARP inhibitor Veliparib and radiation on metabolism in three breast cancer cell lines...
November 4, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27766838/3d-bioprinting-a-cell-laden-bone-matrix-for-breast-cancer-metastasis-study
#5
Xuan Zhou, Wei Zhu, Margaret Nowicki, Shida Miao, Haitao Cui, Benjamin Holmes, Robert I Glazer, Lijie Grace Zhang
Metastasis is one of the deadliest consequences of breast cancer, with bone being one of the primary sites of occurrence. Insufficient 3D biomimetic models currently exist to replicate this process in vitro. In this study, we developed a biomimetic bone matrix using 3D bioprinting technology to investigate the interaction between breast cancer (BrCa) cells and bone stromal cells (fetal osteoblasts and human bone marrow mesenchymal stem cells (MSCs)). A tabletop stereolithography 3D bioprinter was employed to fabricate a series of bone matrices consisting of osteoblasts or MSCs encapsulated in gelatin methacrylate (GelMA) hydrogel with nanocrystalline hydroxyapatite (nHA)...
October 28, 2016: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/27740936/reduced-pak1-activity-sensitizes-fa-brca-proficient-breast-cancer-cells-to-parp-inhibition
#6
Olga Villamar Cruz, Tatiana Y Prudnikova, Daniela Araiza-Olivera, Carlos Perez-Plasencia, Neil Johnson, Andrea J Bernhardy, Michael Slifker, Catherine Renner, Jonathan Chernoff, Luis E Arias-Romero
Cells that are deficient in homologous recombination, such as those that have mutations in any of the Fanconi Anemia (FA)/BRCA genes, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, FA/BRCA-deficient tumors represent a small fraction of breast cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. The gene encoding the serine-threonine protein kinase p21-activated kinase 1 (PAK1) is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors...
October 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27716873/the-current-status-of-parp-inhibitors-in-ovarian-cancer
#7
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
#8
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/27673289/the-status-of-poly-adenosine-diphosphate-ribose-polymerase-parp-inhibitors-in-ovarian-cancer-part-2-extending-the-scope-beyond-olaparib-and-brca1-2-mutations
#9
Rowan E Miller, Jonathan A Ledermann
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition...
September 2016: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/27634150/update-on-poly-adp-ribose-polymerase-inhibition-for-ovarian-cancer-treatment
#10
REVIEW
Anselmo Papa, Davide Caruso, Martina Strudel, Silverio Tomao, Federica Tomao
BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors...
2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27621574/perspectives-on-the-combination-of-radiotherapy-and-targeted-therapy-with-dna-repair-inhibitors-in-the-treatment-of-pancreatic-cancer
#11
REVIEW
Shih-Hung Yang, Ting-Chun Kuo, Hsu Wu, Jhe-Cyuan Guo, Chiun Hsu, Chih-Hung Hsu, Yu-Wen Tien, Kun-Huei Yeh, Ann-Lii Cheng, Sung-Hsin Kuo
Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways...
August 28, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27613028/review-and-literature-mining-on-proteostasis-factors-and-cancer
#12
Ana Sofia Carvalho, Manuel S Rodríguez, Rune Matthiesen
Automatic analysis of increasingly growing literature repositories including data integration to other databases is a powerful tool to propose hypothesis that can be used to plan experiments to validate or disprove the hypothesis. Furthermore, it provides means to evaluate the redundancy of research line in comparison to the published literature. This is potentially beneficial for those developing research in a specific disease which are interested in exploring a particular pathway or set of genes/proteins...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27487106/the-status-of-poly-adenosine-diphosphate-ribose-polymerase-parp-inhibitors-in-ovarian-cancer-part-1-olaparib
#13
Rowan E Miller, Jonathan A Ledermann
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown promising clinical activity in epithelial ovarian cancer. Following the observation in vitro that PARP inhibition is synthetically lethal in tumors with BRCA mutations, PARP inhibition has become the first genotype-directed therapy for BRCA1- and BRCA2-associated ovarian cancer. However, it is becoming clear that PARP inhibition also may have clinical utility in cancers associated with defects or aberrations in DNA repair that are unrelated to BRCA mutations...
August 2016: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/27465688/mk-2206-sensitizes-brca-deficient-epithelial-ovarian-adenocarcinoma-to-cisplatin-and-olaparib
#14
Margaret E Whicker, Z Ping Lin, Ruth Hanna, Alan C Sartorelli, Elena S Ratner
BACKGROUND: Platinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation of the AKT pathway promotes platinum resistance while inhibition of AKT sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus a defect in the homologous recombination (HR) repair pathway, demonstrate greater clinical response to platinum and olaparib therapy than patients with BRCA wild-type EOC. MK-2206, an allosteric inhibitor of AKT phosphorylation, sensitizes a variety of cell types to various anticancer agents and is currently undergoing phase II trials as monotherapy for platinum-resistant ovarian, fallopian tube, and peritoneal cancer...
July 27, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27461625/combinatorial-effect-of-zoledronic-acid-and-irradiation-on-the-prevention-of-dmba-induced-precancerogenic-changes-in-the-mammary-tissues-of-rats
#15
Simay G Rocak, Aysun Bay Karabulut, Mehmet Tuzcu, Nurhan Şahin, Öztun Temelli, Volkan İnce, Kazim Şahin
BACKGROUND: At present, the rates of breast cancer are continuously increasing, with over a million new cases being diagnosed worldwide each year. Hence, the development of new breast cancer chemopreventive drugs with acceptable efficacy and toxicity that are suitable for use for a protracted period of time is urgently needed. The present study investigated the potential preventive effects of zoledronic acid [ZOL] and radiotherapy [RT], both alone and in combination, on precancerogenic changes on the breast tissues of females...
April 2016: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/27455135/dna-damage-response-as-a-therapeutic-target-in-gynecological-cancers
#16
Alexandra Leary, Aurelie Auguste, Soizick Mesnage
PURPOSE OF REVIEW: The proven activity of poly ADP ribose polymerase (PARP) inhibitors in BRCA-mutated homologous recombination deficient (HRD) ovarian cancer has led to the availability to patients with ovarian cancer of the first targeted therapy with an associated predictive biomarker. Our focus has recently turned towards expanding the clinical utility of PARP inhibitors beyond BRCA mutated ovarian cancer, and to a search for novel targets within DNA damage response (DDR). RECENT FINDINGS: Early trials in unselected patients with ovarian cancer showed responses to PARP inhibition in BRCA-wildtype ovarian cancer, and recent genomic studies have demonstrated that germline or somatic aberrations in other homologous recombination genes are present in a significant proportion of ovarian cancers...
September 2016: Current Opinion in Oncology
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
#17
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/27443740/replication-fork-stability-confers-chemoresistance-in-brca-deficient-cells
#18
Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A Calvo, Nicholas J Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M Starnes, Julian R de Ruiter, Jeremy A Daniel, Panagiotis A Konstantinopoulos, David Cortez, Sharon B Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K Sharan, André Nussenzweig
Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks...
July 20, 2016: Nature
https://www.readbyqxmd.com/read/27434671/small-molecule-inhibitors-identify-the-rad52-ssdna-interaction-as-critical-for-recovery-from-replication-stress-and-for-survival-of-brca2-deficient-cells
#19
Sarah R Hengel, Eva Malacaria, Laura Folly da Silva Constantino, Fletcher E Bain, Andrea Diaz, Brandon G Koch, Liping Yu, Meng Wu, Pietro Pichierri, M Ashley Spies, Maria Spies
The DNA repair protein RAD52 is an emerging therapeutic target of high importance for BRCA-deficient tumors. Depletion of RAD52 is synthetically lethal with defects in tumor suppressors BRCA1, BRCA2 and PALB2. RAD52 also participates in the recovery of the stalled replication forks. Anticipating that ssDNA binding activity underlies the RAD52 cellular functions, we carried out a high throughput screening campaign to identify compounds that disrupt the RAD52-ssDNA interaction. Lead compounds were confirmed as RAD52 inhibitors in biochemical assays...
2016: ELife
https://www.readbyqxmd.com/read/27428646/parp-inhibitors-in-clinical-use-induce-genomic-instability-in-normal-human-cells
#20
Shuhei Ito, Conleth G Murphy, Ekaterina Doubrovina, Maria Jasin, Mary Ellen Moynahan
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer...
2016: PloS One
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