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Carboplatin resistant ovarian cancer

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https://www.readbyqxmd.com/read/28087643/tumor-brca1-reversion-mutation-arising-during-neoadjuvant-platinum-based-chemotherapy-in-triple-negative-breast-cancer-is-associated-with-therapy-resistance
#1
Anosheh Afghahi, Kirsten M Timms, Shaveta Vinayak, Kristin C Jensen, Allison W Kurian, Robert W Carlson, Pei-Jen Chang, Elizabeth A Schackmann, Anne-Renee Hartman, James M Ford, Melinda L Telli
BACKGROUND: In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed BRCA1/2-mutant breast cancer patients with poor response to neoadjuvant platinum-based therapy. METHODS: PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin and iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n=80)...
January 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28060758/exosomes-as-mediators-of-platinum-resistance-in-ovarian-cancer
#2
Jennifer Crow, Safinur Atay, Samagya Banskota, Brittany Artale, Sarah Schmitt, Andrew K Godwin
Exosomes have been implicated in the cell-cell transfer of oncogenic proteins and genetic material. We speculated this may be one mechanism by which an intrinsically platinum-resistant population of epithelial ovarian cancer (EOC) cells imparts its influence on surrounding tumor cells. To explore this possibility we utilized a platinum-sensitive cell line, A2780 and exosomes derived from its resistant subclones, and an unselected, platinum-resistant EOC line, OVCAR10. A2780 cells demonstrate a ~2-fold increase in viability upon treatment with carboplatin when pre-exposed to exosomes from platinum-resistant cells as compared to controls...
January 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28031411/a-systematic-analysis-of-negative-growth-control-implicates-the-dream-complex-in-cancer-cell-dormancy
#3
James MacDonald, Yudith Ramos-Valdes, Piru Perampalam, Larisa Litovchick, Gabriel E DiMattia, Frederick A Dick
: Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some Cyclin Dependent Kinase Inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested...
December 28, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28031236/proteomics-analysis-of-ovarian-cancer-cell-lines-and-tissues-reveals-drug-resistance-associated-proteins
#4
Isa N Cruz, Helen M Coley, Holger B Kramer, Thumuluru Kavitah Madhuri, Nur A M Safuwan, Ana Rita Angelino, Min Yang
BACKGROUND: Carboplatin and paclitaxel form the cornerstone of chemotherapy for epithelial ovarian cancer, however, drug resistance to these agents continues to present challenges. Despite extensive research, the mechanisms underlying this resistance remain unclear. MATERIALS AND METHODS: A 2D-gel proteomics method was used to analyze protein expression levels of three human ovarian cancer cell lines and five biopsy samples. Representative proteins identified were validated via western immunoblotting...
January 2017: Cancer Genomics & Proteomics
https://www.readbyqxmd.com/read/28013349/pharmacology-and-toxicology-of-the-novel-investigational-agent-cantrixil-trx-e-002-1
#5
REVIEW
Muhammad Wasif Saif, Andrew Heaton, Kimberley Lilischkis, James Garner, David M Brown
PURPOSE: Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity for tumour repair. Cantrixil targets this sub-population of cells and is being developed as an intraperitoneal therapy to be used as first-line therapy in combination with carboplatin for epithelial ovarian cancer. The studies presented here justify further development. METHODS: A GLP dog CV study using a 4 × 4 Latin Square Crossover study was conducted using telemetric ECG recordings from dogs post IP administration to assess for cardiac abnormalities...
December 24, 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27998224/phase-ii-study-of-wee1-inhibitor-azd1775-plus-carboplatin-in-patients-with-tp53-mutated-ovarian-cancer-refractory-or-resistant-to-first-line-therapy-within-3-months
#6
Suzanne Leijen, Robin M J M van Geel, Gabe S Sonke, Daphne de Jong, Efraim H Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Shelonitda Rose, Mark A Lee, Tomoko Freshwater, Jos H Beijnen, Jan H M Schellens
Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies...
December 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27980217/the-association-between-copper-transporters-and-the-prognosis-of-cancer-patients-undergoing-chemotherapy-a-meta-analysis-of-literatures-and-datasets
#7
REVIEW
Si Sun, Jing Cai, Qiang Yang, Simei Zhao, Zehua Wang
Copper transporter 1 (CTR1), copper transporter 2 (CTR2), copper-transporting p-type adenosine triphosphatase 1 and 2 (ATP7A and ATP7B) are key mediators of cellular cisplatin, carboplatin and oxaliplatin accumulation. In this meta-analysis, we aimed to evaluate the relation of CTR1, CTR2, ATP7A and ATP7B to overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) and treatment response (TR) of cancer patients who received chemotherapy based on published literatures, the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) datasets...
December 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27889646/mirvetuximab-soravtansine-imgn853-a-folate-receptor-alpha-targeting-antibody-drug-conjugate-potentiates-the-activity-of-standard-of-care-therapeutics-in-ovarian-cancer-models
#8
Jose F Ponte, Olga Ab, Leanne Lanieri, Jenny Lee, Jennifer Coccia, Laura M Bartle, Marian Themeles, Yinghui Zhou, Jan Pinkas, Rodrigo Ruiz-Soto
Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC...
December 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27779244/predictive-value-of-atp7b-brca1-brca2-parp1-uimc1-rap80-hoxa9-daxx-txn-trx1-thbs1-tsp1-and-prr13-txr1-genes-in-patients-with-epithelial-ovarian-cancer-who-received-platinum-taxane-first-line-therapy
#9
S Pontikakis, C Papadaki, M Tzardi, M Trypaki, M Sfakianaki, F Koinis, E Lagoudaki, L Giannikaki, A Kalykaki, E Kontopodis, Z Saridaki, N Malamos, V Georgoulias, J Souglakos
To evaluate the predictive value of genes involved in resistance to platinum-taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR...
October 25, 2016: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27764790/is-ovarian-cancer-a-targetable-disease-a-systematic-review-and-meta-analysis-and-genomic-data-investigation
#10
Nicoletta Staropoli, Domenico Ciliberto, Silvia Chiellino, Francesca Caglioti, Teresa Del Giudice, Simona Gualtieri, Angela Salvino, Alessandra Strangio, Cirino Botta, Sandro Pignata, Pierfrancesco Tassone, Pierosandro Tagliaferri
OBJECTIVES: The current gold-standard for the first-line treatment in IIIb/IV stages of epithelial ovarian cancer (EOC) is the combination of carboplatin and paclitaxel plus bevacizumab in some countries. In the era of personalized medicine, there is still uncertainty on the impact of several molecularly targeted agents, which have been investigated for the management of this disease. To shed light on the actual role of targeted therapy in EOC, a systematic review and meta-analysis was performed...
October 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27712076/nanoscale-coordination-polymers-codeliver-carboplatin-and-gemcitabine-for-highly-effective-treatment-of-platinum-resistant-ovarian-cancer
#11
Christopher Poon, Xiaopin Duan, Christina Chan, Wenbo Han, Wenbin Lin
Due to the ability of ovarian cancer (OCa) to acquire drug resistance, it has been difficult to develop efficient and safe chemotherapy for OCa. Here, we examined the therapeutic use of a new self-assembled core-shell nanoscale coordination polymer nanoparticle (NCP-Carbo/GMP) that delivers high loadings of carboplatin (28.0 ± 2.6 wt %) and gemcitabine monophosphate (8.6 ± 1.5 wt %). A strong synergistic effect was observed between carboplatin and gemcitabine against platinum-resistant OCa cells, SKOV-3 and A2780/CDPP, in vitro...
November 7, 2016: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27668267/doxil-when-combined-with-withaferin-a-wfa-targets-aldh1-positive-cancer-stem-cells-in-ovarian-cancer
#12
Sham S Kakar, Christopher A Worth, Zhenglong Wang, Kelsey Carter, Mariusz Ratajczak, Pranesh Gunjal
Ovarian cancer is a highly aggressive and deadly disease. Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly cisplatin or carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately, after few months of initial treatment, tumor relapse occurs due to platinum-resistance. DOXIL (liposomal preparation of doxorubicin) is a choice of drug for recurrent ovarian cancer. However, its response rate is very low and is accompanied by myocardial toxicity...
2016: Journal of Cancer Stem Cell Research
https://www.readbyqxmd.com/read/27633667/influence-of-a-novel-histone-deacetylase-inhibitor-panobinostat-lbh589-on-the-growth-of-ovarian-cancer
#13
Leslie A Garrett, Whitfield B Growdon, Bo R Rueda, Rosemary Foster
BACKGROUND: Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors. METHODS: The ovarian cancer cell lines OVCAR8, SKOV3 and their paclitaxel-resistant derivatives OVCAR8-TR and SKOV3-TR were treated with increasing doses of LBH589...
September 15, 2016: Journal of Ovarian Research
https://www.readbyqxmd.com/read/27614696/in-vivo-anti-tumor-activity-of-the-parp-inhibitor-niraparib-in-homologous-recombination-deficient-and-proficient-ovarian-carcinoma
#14
Mariam M AlHilli, Marc A Becker, S John Weroha, Karen S Flatten, Rachel M Hurley, Maria I Harrell, Ann L Oberg, Matt J Maurer, Kieran M Hawthorne, Xiaonan Hou, Sean C Harrington, Sarah McKinstry, X Wei Meng, Keith M Wilcoxen, Kimberly R Kalli, Elizabeth M Swisher, Scott H Kaufmann, Paul Haluska
OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo...
November 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/27591123/insights-into-the-anti-angiogenic-properties-of-phosphaplatins
#15
Lu Yang, Shadi Moghaddas, Homa Dezvareh, Louiza Belkacemi, Steven J Bark, Rathindra N Bose, Loi H Do
Phosphaplatins are platinum-based antitumor compounds that, unlike other clinically utilized platinum drugs (i.e. cisplatin, carboplatin, and oxaliplatin), appear to target proteins rather than DNA. Because of their unique mode of action, phosphaplatins are promising drug candidates for cisplatin-resistant cancers. In this study, we discovered that Pt(II) and Pt(IV) phosphaplatins possess diverse antitumor properties. In addition to targeting apoptosis antigen (FAS) and proapoptotic gene products as described previously, phosphaplatins also target angiogenesis...
November 2016: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/27590741/ovarian-cancer-chemoresistance-relies-on-the-the-stem-cell-reprogramming-factor-pbx1
#16
Jin-Gyoung Jung, Ie-Ming Shih, Joon Tae Park, Emily Gerry, Tae Hoen Kim, Ayse Ayhan, Karen Handschuh, Ben Davidson, Amanda Nickles Fader, Licia Selleri, Tian-Li Wang
The evolution of chemoresistance is a fundamental characteristic of cancer that ultimately defeats its clinical management. However, it may be possible improve patient outcomes significantly by defeating nodal resistance mechanisms which cancers rely upon during the evolution to an untreatable state. Here we report an essential role for upregulation of the stem cell reprogramming factor PBX1 in mediating chemoresistance in recurrent ovarian carcinomas. In clinical specimens, high levels of PBX1 expression correlated with shorter survival in post-chemotherapy ovarian cancer patients...
September 2, 2016: Cancer Research
https://www.readbyqxmd.com/read/27569743/a-novel-ief-peptide-fractionation-method-reveals-a-detailed-profile-of-n-terminal-acetylation-in-chemotherapy-responsive-and-resistant-ovarian-cancer-cells
#17
Florian Weiland, Georgia Arentz, Manuela Klingler-Hoffmann, Peter McCarthy, Noor A Lokman, Gurjeet Kaur, Martin K Oehler, Peter Hoffmann
Although acetylation is regarded as a common protein modification, a detailed proteome wide profile of this posttranslational modification may reveal important biological insight regarding differential acetylation of individual proteins. Here we optimised a novel peptide IEF fractionation method for use prior to LC-MS/MS analysis in order to obtain a more in depth coverage of N-terminally acetylated proteins from complex samples. Application of the method to the analysis of the serous ovarian cancer cell line OVCAR-5 identified 341 N-terminally acetylated proteins, 23 of which are previously un-reported...
August 29, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27566066/changes-in-the-in-vitro-activity-of-platinum-drugs-when-administered-in-two-aliquots
#18
Zaynab Al-Eisawi, Philip Beale, Charles Chan, Jun Qing Yu, Nicholas Proschogo, Mark Molloy, Fazlul Huq
BACKGROUND: The management of ovarian cancer remains a challenge. Because of the lack of early symptoms, it is often diagnosed at a late stage when it is likely to have metastasized beyond ovaries. Currently, platinum based chemotherapy is the primary treatment for the disease. However acquired drug resistance remains an on-going problem. As cisplatin brings about apoptosis by intrinsic and extrinsic pathways, this study aimed to determine changes in activity of platinum drugs when administered in two aliquots as against a bolus and sought to determine association with changes in GSH, speciation of platinum drugs and changes in protein expression...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27446402/effect-of-stk17a-on-the-sensitivity-of-ovarian-cancer-cells-to-paclitaxel-and-carboplatin
#19
Jianhua Gao, Dan Liu, Jie Li, Qianlin Song, Qi Wang
Ovarian cancer is the main cause of cancer mortality in gynecological tumors around the world. Drug resistance to a variety of chemotherapeutics continue to be one of the main causes of treatment failure. In a previous study, it was demonstrated that STK17A, a proapoptotic gene, was significantly downregulated in acquired resistance phenotypes of colon cancer cells that are resistant to oxaliplatin and 5-fluorouracil. Therefore in the present study, the association between STK17A expression and ovarian cancer with initial drug resistance was investigated and the influence of STK17 on ovarian cancer cell proliferation and doubling time...
August 2016: Oncology Letters
https://www.readbyqxmd.com/read/27415012/abcb1-mdr1-induction-defines-a-common-resistance-mechanism-in-paclitaxel-and-olaparib-resistant-ovarian-cancer-cells
#20
Aparajitha Vaidyanathan, Lynne Sawers, Anne-Louise Gannon, Probir Chakravarty, Alison L Scott, Susan E Bray, Michelle J Ferguson, Gillian Smith
BACKGROUND: Clinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of routinely prescribed chemotherapy drugs are poorly understood. METHODS: We created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil and elacridar and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461...
August 9, 2016: British Journal of Cancer
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