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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...
January 3, 2017: Oncotarget
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
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
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...
October 8, 2016: Blood Reviews
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
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
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
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
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]
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
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
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
Renata Ferrarotto, Ruchitha Goonatilake, Suk Young Yoo, Pan Tong, Uma Giri, Shaohua Peng, John Minna, Luc Girard, Yuehong Wang, Liguang Wang, Lerong Li, Lixia Diao, David H Peng, Don L Gibbons, Bonnie S Glisson, John V Heymach, Jing Wang, Lauren A Byers, Faye M Johnson
PURPOSE: To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development. EXPERIMENTAL DESIGN: To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines...
April 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Chetasi Talati, Elizabeth A Griffiths, Meir Wetzler, Eunice S Wang
Polo-like kinases (Plk) are key regulators of the cell cycle and multiple aspects of mitosis. Two agents that inhibit the Plk signaling pathway have shown promising activity in patients with hematologic malignancies and are currently in phase III trials. Volasertib is a Plk inhibitor under evaluation combined with low-dose cytarabine in older patients with acute myeloid leukemia (AML) ineligible for intensive induction therapy. Rigosertib, a dual inhibitor of the Plk and phosphatidylinositol 3-kinase pathways, is under investigation in patients with myelodysplastic syndrome (MDS) who have failed azacitidine or decitabine treatment...
February 2016: Critical Reviews in Oncology/hematology
Yukio Kobayashi, Takahiro Yamauchi, Hitoshi Kiyoi, Toru Sakura, Tomoko Hata, Kiyoshi Ando, Aiko Watabe, Akiko Harada, Tillmann Taube, Yasushi Miyazaki, Tomoki Naoe
This phase I trial conducted in Japanese patients with acute myeloid leukemia evaluated the safety, maximum tolerated dose and pharmacokinetics of volasertib (BI 6727), a selective Polo-like kinase inhibitor. The primary endpoints were the maximum tolerated dose of volasertib and the incidence of dose-limiting toxicities. Secondary endpoints were best response and remission duration. Other endpoints included safety and pharmacokinetics. Patients who were ineligible for standard induction therapy or with relapsed or refractory disease received volasertib monotherapy as a 2-h infusion on days 1 and 15 of a 28-day cycle, with dose escalation following a 3 + 3 design...
November 2015: Cancer Science
F de Braud, S Cascinu, G Spitaleri, K Pilz, L Clementi, D Liu, P Sikken, T De Pas
BACKGROUND: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230...
November 2015: Annals of Oncology: Official Journal of the European Society for Medical Oncology
I Procházková, B Vojtěšek
Individual proteins from polo-like kinase (Plk) family fulfil different but critical functions in regulating cell cycle and coordinate cell response to DNA  damage. The most studied one from this five  member family is Plk1. It is a serine/ threonine kinase that plays a pivotal role in many aspects of mitosis and its deregulation is common in various tumor types where the elevated level is mostly associated with worse prognosis. From the therapeutical point of view, intertwined relationship between Plk1 and p53 protein is very interesting and will be discussed...
2015: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
Jean-Pascal Machiels, Marc Peeters, Catherine Herremans, Veerle Surmont, Pol Specenier, Marina De Smet, Korinna Pilz, Natalja Strelkowa, Dan Liu, Sylvie Rottey
PURPOSE: To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230.20). METHODS: Patients with advanced non-resectable and/or metastatic disease following failure of conventional treatment received intravenous volasertib 150-300 mg on day 1 every 21 days, combined with oral afatinib 30-40 mg on days 2-21 of a 3-week cycle (Schedule A), or 50-90 mg on days 2-6 of a 3-week cycle (Schedule B)...
October 2015: Cancer Chemotherapy and Pharmacology
Zhonglin Hao, Vamsi Kota
Acute myeloid leukemia (AML) is a disease diagnosed mostly in patients >65 years of age. Despite its heterogeneous nature, the different types of AMLs are still managed by standard induction chemotherapy for those who can tolerate it in the beginning. For the elderly and infirm patients, however, this approach leads to unacceptably high induction mortality rate. This article reviews past and current efforts searching for low-intensiveness treatments for the elderly and infirm patients who cannot tolerate the standard induction regimen...
2015: OncoTargets and Therapy
Peter M Ellis, Natasha B Leighl, Vera Hirsh, M Neil Reaume, Normand Blais, Rafal Wierzbicki, Behbood Sadrolhefazi, Yu Gu, Dan Liu, Korinna Pilz, Quincy Chu
UNLABELLED: Second-line therapy options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n [ 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy...
November 2015: Clinical Lung Cancer
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