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Volasertib

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https://www.readbyqxmd.com/read/28778089/identification-of-volasertib-resistant-mechanism-and-evaluation-of-combination-effects-with-volasertib-and-other-agents-on-acute-myeloid-leukemia
#1
Yoshiya Adachi, Yuichi Ishikawa, Hitoshi Kiyoi
Volasertib, a selective PLK1 inhibitor, was effective for acute myeloid leukemia (AML) patients in clinical trials. However, its efficacy was limited in mono-therapy, and a higher incidence of fatal events was revealed in the combination with low-dose cytarabine. Thus, optimization of combination therapy with volasertib and other agents is necessary for its clinical development, and the predictive factors for response or resistance to volasertib remain largely unknown. In this study, we investigated the resistance mechanism in volasertib-resistant cell lines and the combination effects with other agents, such as azacitidine (AZA), on AML cells...
July 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28652654/bcl-2-degradation-is-an-additional-pro-apoptotic-effect-of-polo-like-kinase-inhibition-in-cholangiocarcinoma-cells
#2
Svenja Sydor, Sami Jafoui, Lena Wingerter, Sandra Swoboda, Joachim C Mertens, Guido Gerken, Ali Canbay, Andreas Paul, Christian D Fingas
AIM: To examine the influence on apoptotic mechanisms following inhibition of polo-like kinases as therapeutically approach for cholangiocellular cancer treatment. METHODS: As most cholangiocarcinomas are chemotherapy-resistant due to mechanisms preventing tumor cell death, we investigated the effect of Cisplatin on cholangiocellular carcinoma (CCA) cell lines KMCH-1 and Mz-Ch-1. Polo-like kinases (PLK) are important regulators of the cell cycle and their inhibition is discussed as a potential therapy while PLK inhibition can regulate apoptotic mediators...
June 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28631179/population-pharmacokinetics-of-volasertib-administered-in-patients-with-acute-myeloid-leukaemia-as-a-single-agent-or-in-combination-with-cytarabine
#3
Belén P Solans, Angèle Fleury, Matthias Freiwald, Holger Fritsch, Karin Haug, Iñaki F Trocóniz
BACKGROUND: Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in combination with cytarabine in patients with acute myeloid leukaemia. OBJECTIVES: The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination. METHODS: Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7...
June 19, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28556483/drug-sensitivity-and-resistance-testing-identifies-plk1-inhibitors-and-gemcitabine-as-potent-drugs-for-malignant-peripheral-nerve-sheath-tumors-mpnst
#4
Matthias Kolberg, Jarle Bruun, Astrid Murumägi, John P Mpindi, Christian H Bergsland, Maren Høland, Ina A Eilertsen, Stine A Danielsen, Olli Kallioniemi, Ragnhild A Lothe
Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity and apoptosis...
May 29, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28482026/pre-clinical-drug-screen-reveals-topotecan-actinomycin-d-and-volasertib-as-potential-new-therapeutic-candidates-for-etmr-brain-tumor-patients
#5
Christin Schmidt, Nil A Schubert, Sebastian Brabetz, Norman Mack, Benjamin Schwalm, Jennifer A Chan, Florian Selt, Christel Herold-Mende, Olaf Witt, Till Milde, Stefan M Pfister, Andrey Korshunov, Marcel Kool
Background: Embryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the WHO classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a pre-clinical drug screen in order to inform potentially more active clinical trial protocols...
May 8, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28420416/emerging-therapies-for-acute-myeloid-leukemia
#6
REVIEW
Caner Saygin, Hetty E Carraway
Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28416758/synergistic-interactions-between-plk1-and-hdac-inhibitors-in-non-hodgkin-s-lymphoma-cells-occur-in-vitro-and-in-vivo-and-proceed-through-multiple-mechanisms
#7
Tri Nguyen, Rebecca Parker, Elisa Hawkins, Beata Holkova, Victor Yazbeck, Akhil Kolluri, Maciej Kmieciak, Mohamed Rahmani, Steven Grant
Interactions between the polo-like kinase 1 (PLK1) inhibitor volasertib and the histone deacetylase inhibitor (HDACI) belinostat were examined in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells in vitro and in vivo. Exposure of DLBCL cells to very low concentrations of volasertib in combination with belinostat synergistically increased cell death (apoptosis). Similar interactions occurred in GC-, ABC-, double-hit DLBCL cells, MCL cells, bortezomib-resistant cells and primary lymphoma cells...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416751/proteasome-inhibition-enhances-the-efficacy-of-volasertib-induced-mitotic-arrest-in-aml-in-vitro-and-prolongs-survival-in-vivo
#8
Dominik Schnerch, Julia Schüler, Marie Follo, Julia Felthaus, Dagmar Wider, Kathrin Klingner, Christine Greil, Justus Duyster, Monika Engelhardt, Ralph Wäsch
Elderly and frail patients, diagnosed with acute myeloid leukemia (AML) and ineligible to undergo intensive treatment, have a dismal prognosis. The small molecule inhibitor volasertib induces a mitotic block via inhibition of polo-like kinase 1 and has shown remarkable anti-leukemic activity when combined with low-dose cytarabine. We have demonstrated that AML cells are highly vulnerable to cell death in mitosis yet manage to escape a mitotic block through mitotic slippage by sustained proteasome-dependent slow degradation of cyclin B...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28061448/targeting-basal-like-breast-tumors-with-bromodomain-and-extraterminal-domain-bet-and-polo-like-kinase-inhibitors
#9
Cristina Nieto-Jiménez, Ana Alcaraz-Sanabria, Javier Pérez-Peña, Verónica Corrales-Sánchez, Gemma Serrano-Heras, Eva M Galán-Moya, Leticia Serrano-Oviedo, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Atanasio Pandiella, Alberto Ocaña
Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/27904765/volasertib-suppresses-the-growth-of-human-hepatocellular-carcinoma-in-vitro-and-in-vivo
#10
Di-Wei Zheng, You-Qiu Xue, Yong Li, Jin-Ming Di, Jian-Ge Qiu, Wen-Ji Zhang, Qi-Wei Jiang, Yang Yang, Yao Chen, Meng-Ning Wei, Jia-Rong Huang, Kun Wang, Xing Wei, Zhi Shi
Hepatocellular carcinoma (HCC) is the sixth most frequent malignant tumor with poor prognosis, and its clinical therapeutic outcome is poor. Volasertib, a potent small molecular inhibitor of polo-like kinase 1 (PLK1), is currently tested for treatment of multiple cancers in the clinical trials. However, the antitumor effect of volasertib on HCC is still unknown. In this study, our data show that volasertib is able to induce cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the spindle abnormalities in human HCC cells...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27793694/small-molecule-inhibition-of-polo-like-kinase-1-by-volasertib-bi-6727-causes-significant-melanoma-growth-delay-and-regression-in%C3%A2-vivo
#11
Brian D Cholewa, Mary A Ndiaye, Wei Huang, Xiaoqi Liu, Nihal Ahmad
The objective of this study was to determine the therapeutic potential of polo-like kinase 1 (Plk1) inhibition in melanoma, in vivo. Employing Vectra technology, we assessed the Plk1 expression profile in benign nevi, malignant (stages I-IV) and metastatic melanomas. We found a significant elevation of Plk1 immunostaining in melanoma tissues. Further, a second generation small molecule Plk1 inhibitor, BI 6727, resulted in reductions in growth, viability and clonogenic survival, as well as an increase in apoptosis of A375 and Hs 294T melanoma cells...
January 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27745715/selecting-initial-treatment-of-acute-myeloid-leukaemia-in-older-adults
#12
REVIEW
Nikolai A Podoltsev, Maximilian Stahl, Amer M Zeidan, Steven D Gore
More than half of the patients with acute myeloid leukaemia (AML) are older than 60years. The treatment outcomes in this group remain poor with a median overall survival of <1year. Selecting initial treatment for these patients involves an assessment of 'fitness' for induction chemotherapy. This is done based on patient and disease-related characteristics which help to estimate treatment-related mortality and chance of complete remission with induction chemotherapy. If the risk of treatment-related mortality is high and/or the likelihood of a patient achieving a complete remission is low, lower-intensity treatment (low-dose cytarabine, decitabine and azacitidine) should be discussed...
March 2017: Blood Reviews
https://www.readbyqxmd.com/read/27594913/negative-trials-in-ovarian-cancer-is-there-such-a-thing-as-too-much-optimism
#13
EDITORIAL
Bishal Gyawali, Vinay Prasad
Recently, two clinical trials of novel agents in metastatic ovarian cancer were published: a phase 3 study of nintedanib and a phase 2 study of volasertib. There seemed to be discordance between the results and conclusions in the publication of both these trials. Despite not very optimistic results, the studies concluded optimistically in favor of the new agents under study. Using these examples, we point out the discrepancies and the risks of concluding optimistically based on statistical significance when the actual benefit is minimal...
2016: Ecancermedicalscience
https://www.readbyqxmd.com/read/27384992/polo-like-kinase-1-inhibition-diminishes-acquired-resistance-to-epidermal-growth-factor-receptor-inhibition-in-non-small-cell-lung-cancer-with-t790m-mutations
#14
Yuehong Wang, Ratnakar Singh, Liguang Wang, Monique Nilsson, Ruchitha Goonatilake, Pan Tong, Lerong Li, Uma Giri, Pamela Villalobos, Barbara Mino, Jaime Rodriguez-Canales, Ignacio Wistuba, Jing Wang, John V Heymach, Faye M Johnson
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial-mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines...
July 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27330107/plk1-inhibitors-in-cancer-therapy-from-laboratory-to-clinics
#15
REVIEW
Rosie Elizabeth Ann Gutteridge, Mary Ann Ndiaye, Xiaoqi Liu, Nihal Ahmad
Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved...
July 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27140825/spotlight-on-volasertib-preclinical-and-clinical-evaluation-of-a-promising-plk1-inhibitor
#16
REVIEW
J Van den Bossche, F Lardon, V Deschoolmeester, I De Pauw, J B Vermorken, P Specenier, P Pauwels, M Peeters, A Wouters
Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment...
July 2016: Medicinal Research Reviews
https://www.readbyqxmd.com/read/26952039/radiosensitization-in-esophageal-squamous-cell-carcinoma-effect-of-polo-like-kinase-1-inhibition
#17
Jenny Ling-Yu Chen, Jo-Pai Chen, Yu-Sen Huang, Yuan-Chun Tsai, Ming-Hsien Tsai, Fu-Shan Jaw, Jason Chia-Hsien Cheng, Sung-Hsin Kuo, Ming-Jium Shieh
PURPOSE: This study examined the efficacy of polo-like kinase 1 (PLK1) inhibition on radiosensitivity in vitro and in vivo by a pharmacologic approach using the highly potent PLK1 inhibitor volasertib. METHODS AND MATERIALS: Human esophageal squamous cell carcinoma (ESCC) cell lines KYSE 70 and KYSE 150 were used to evaluate the synergistic effect of volasertib and irradiation in vitro using cell viability assay, colony formation assay, cell cycle phase analysis, and western blot, and in vivo using ectopic tumor models...
April 2016: Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft ... [et Al]
https://www.readbyqxmd.com/read/26877780/bet-bromodomain-inhibition-as-a-therapeutic-strategy-in-ovarian-cancer-by-downregulating-foxm1
#18
Zhenfeng Zhang, Pengfei Ma, Ying Jing, Ying Yan, Mei-Chun Cai, Meiying Zhang, Shengzhe Zhang, Huixin Peng, Zhi-Liang Ji, Wen Di, Zhenyu Gu, Wei-Qiang Gao, Guanglei Zhuang
Ovarian cancer is responsible for the highest mortality among all gynecologic malignancies, and novel therapies are urgently needed to improve patient outcome. Here we performed an integrative genomic analysis and identified the bromodomain and extraterminal domain (BET) protein BRD4 as a potential therapeutic target in ovarian cancer. Suppression of BRD4 using small-molecule BET inhibitors JQ1 and I-BET151, or dual kinase-bromodomain inhibitor volasertib, led to robust and broad antitumor effects across all subclasses of ovarian cancer...
2016: Theranostics
https://www.readbyqxmd.com/read/26851014/polo-like-kinase-inhibitor-volasertib-exhibits-antitumor-activity-and-synergy-with-vincristine-in-pediatric-malignancies
#19
Samuel Abbou, Claudia Lanvers-Kaminsky, Estelle Daudigeos-Dubus, Ludivine LE Dret, Corinne Laplace-Builhe, Jan Molenaar, Gilles Vassal, Birgit Geoerger
BACKGROUND: Polo-like kinase 1 (PLK1) controls the main cell-cycle checkpoints, suggesting utility of its inhibition for cancer treatment, including of highly proliferative pediatric cancer. This preclinical study explored the selective PLK1 inhibitor volasertib (BI 6727) alone and combined with chemotherapy in pediatric malignancies. MATERIALS AND METHODS: Inhibition of proliferation was explored in vitro using dimethylthiazol carboxymethoxyphenyl sulfophenyl tetrazolium (MTS) assay...
February 2016: Anticancer Research
https://www.readbyqxmd.com/read/26627079/phase-i-trial-of-volasertib-a-polo-like-kinase-inhibitor-in-japanese-patients-with-advanced-solid-tumors
#20
COMPARATIVE STUDY
Hiroshi Nokihara, Yasuhide Yamada, Yutaka Fujiwara, Noboru Yamamoto, Hiroshi Wakui, Shinji Nakamichi, Satoru Kitazono, Kohei Inoue, Akiko Harada, Tillmann Taube, Yoshito Takeuchi, Tomohide Tamura
PURPOSE: This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15). METHODS: In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) received volasertib (200-350 mg) as a single dose by intravenous infusion over 2 h on day 1 every 21 days until disease progression or unacceptable toxicity...
February 2016: Investigational New Drugs
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