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Aurora A kinase clinical trials

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https://www.readbyqxmd.com/read/27905678/a-phase-i-ii-trial-of-at9283-a-selective-inhibitor-of-aurora-kinase-in-children-with-relapsed-or-refractory-acute-leukemia-challenges-to-run-early-phase-clinical-trials-for-children-with-leukemia
#1
B Vormoor, G J Veal, M J Griffin, A V Boddy, J Irving, L Minto, M Case, U Banerji, K E Swales, J R Tall, A S Moore, M Toguchi, G Acton, K Dyer, C Schwab, C J Harrison, J D Grainger, D Lancaster, P Kearns, D Hargrave, J Vormoor
Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies...
December 1, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27502708/phase-ii-study-of-mln8237-alisertib-in-advanced-metastatic-sarcoma
#2
M A Dickson, M R Mahoney, W D Tap, S P D'Angelo, M L Keohan, B A Van Tine, M Agulnik, L E Horvath, J S Nair, G K Schwartz
BACKGROUND: Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor. PATIENTS AND METHODS: This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other...
October 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27496137/pharmacological-profile-of-bi-847325-an-orally-bioavailable-atp-competitive-inhibitor-of-mek-and-aurora-kinases
#3
Patrizia Sini, Ulrich Gürtler, Stephan K Zahn, Christoph Baumann, Dorothea Rudolph, Rosa Baumgartinger, Eva Strauss, Christian Haslinger, Ulrike Tontsch-Grunt, Irene C Waizenegger, Flavio Solca, Gerd Bader, Andreas Zoephel, Matthias Treu, Ulrich Reiser, Pilar Garin-Chesa, Guido Boehmelt, Norbert Kraut, Jens Quant, Günther R Adolf
Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays...
October 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27496133/barasertib-azd1152-a-small-molecule-aurora-b-inhibitor-inhibits-the-growth-of-sclc-cell-lines-in-vitro-and-in-vivo
#4
Barbara A Helfrich, Jihye Kim, Dexiang Gao, Daniel C Chan, Zhiyong Zhang, Aik-Choon Tan, Paul A Bunn
Small-cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation, and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan-Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor, but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib...
October 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27235164/combination-of-eribulin-and-aurora-a-inhibitor-mln8237-prevents-metastatic-colonization-and-induces-cytotoxic-autophagy-in-breast-cancer
#5
Varvara K Kozyreva, Anna A Kiseleva, Ryan J Ice, Brandon C Jones, Yuriy V Loskutov, Fatimah Matalkah, Matthew B Smolkin, Kristina Marinak, Ryan H Livengood, Mohamad A Salkeni, Sijin Wen, Hannah W Hazard, Ginger P Layne, Callee M Walsh, Pamela S Cantrell, Greg W Kilby, Sricharan Mahavadi, Neal Shah, Elena N Pugacheva
Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule-targeting drug eribulin on different stages of metastasis in triple-negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer...
August 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27213815/a-myc-aurora-kinase-a-protein-complex-represents-an-actionable-drug-target-in-p53-altered-liver-cancer
#6
Daniel Dauch, Ramona Rudalska, Giacomo Cossa, Jean-Charles Nault, Tae-Won Kang, Torsten Wuestefeld, Anja Hohmeyer, Sandrine Imbeaud, Tetyana Yevsa, Lisa Hoenicke, Tatu Pantsar, Przemyslaw Bozko, Nisar P Malek, Thomas Longerich, Stefan Laufer, Antti Poso, Jessica Zucman-Rossi, Martin Eilers, Lars Zender
MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19(ARF)...
July 2016: Nature Medicine
https://www.readbyqxmd.com/read/27209210/aurora-kinase-a-expression-predicts-platinum-resistance-and-adverse-outcome-in-high-grade-serous-ovarian-carcinoma-patients
#7
Chiara Mignogna, Nicoletta Staropoli, Cirino Botta, Carmela De Marco, Antonia Rizzuto, Michele Morelli, Annalisa Di Cello, Renato Franco, Caterina Camastra, Ivan Presta, Natalia Malara, Angela Salvino, Pierfrancesco Tassone, Pierosandro Tagliaferri, Tullio Barni, Giuseppe Donato, Anna Di Vito
High-Grade Serous Ovarian Carcinoma (HGSOC) is the predominant histotype of epithelial ovarian cancer (EOC), characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based-chemotherapy. To date, standard first-line-chemotherapy in advanced EOC includes platinum salts and paclitaxel with or without bevacizumab. The major prognostic factor is the response duration from the end of the platinum-based treatment (platinum-free interval) and about 10-0 % of EOC patients bear a platinum-refractory disease or develop early resistance (platinum-free interval shorter than 6 months)...
2016: Journal of Ovarian Research
https://www.readbyqxmd.com/read/27147567/continuous-anti-angiogenic-therapy-after-tumor-progression-in-patients-with-recurrent-high-grade-epithelial-ovarian-cancer-phase-i-trial-experience
#8
Ming-Mo Hou, Zhijie Wang, Filip Janku, Sarina Piha-Paul, Aung Naing, David Hong, Shannon Westin, Robert L Coleman, Anil K Sood, Apostolia M Tsimberidou, Vivek Subbiah, Jennifer Wheler, Ralph Zinner, Karen Lu, Funda Meric-Bernstam, Siqing Fu
High-grade epithelial ovarian cancer (HG-EOC) is the most lethal gynecologic malignancy worldwide Once patients develop chemoresistance, effective novel strategies are required to improve prognosis We analyzed characteristics and outcomes of 242 consecutive patients with HG-EOC participating in 94 phase I clinical trials at The University of Texas MD Anderson Cancer Center. Baseline lactate dehydrogenase levels, albumin levels, and number of metastatic sites were independent predictors of overall survival (OS)...
June 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27101098/clinical-outcome-of-treatment-with-serine-threonine-kinase-inhibitors-in-recurrent-epithelial-ovarian-cancer-a-systematic-review-of-literature
#9
Marcia A Ciccone, Asaf Maoz, Jennifer K Casabar, Hiroko Machida, Seiji Mabuchi, Koji Matsuo
INTRODUCTION: While serine-threonine kinases (STK) are attractive therapeutic targets in epithelial ovarian cancer, clinical outcomes of STK inhibitors in the management of recurrent disease have not been completely described. AREAS COVERED: A systematic literature review of published clinical studies on STK inhibitors targeting mTOR, MAPK, and aurora kinase pathways in recurrent epithelial ovarian cancer was conducted, revealing 18 clinical trials (497 patients)...
July 2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27082996/otssp167-abrogates-mitotic-checkpoint-through-inhibiting-multiple-mitotic-kinases
#10
Wenbin Ji, Christopher Arnst, Aaron R Tipton, Michael E Bekier, William R Taylor, Tim J Yen, Song-Tao Liu
OTSSP167 was recently characterized as a potent inhibitor for maternal embryonic leucine zipper kinase (MELK) and is currently tested in Phase I clinical trials for solid tumors that have not responded to other treatment. Here we report that OTSSP167 abrogates the mitotic checkpoint at concentrations used to inhibit MELK. The abrogation is not recapitulated by RNAi mediated silencing of MELK in cells. Although OTSSP167 indeed inhibits MELK, it exhibits off-target activity against Aurora B kinase in vitro and in cells...
2016: PloS One
https://www.readbyqxmd.com/read/26999067/an-update-on-the-pharmacokinetics-and-pharmacodynamics-of-alisertib-a-selective-aurora-kinase-a-inhibitor
#11
REVIEW
Cameron T Durlacher, Zhi-Ling Li, Xiao-Wu Chen, Zhi-Xu He, Shu-Feng Zhou
Human Aurora kinases, including Aurora kinase A (AURKA), B (AURKB), and C (AURKC), play an essential role in mitotic events such as monitoring of the mitotic checkpoint, creation of bipolar mitotic spindle and alignment of centrosomes on it, also regulating centrosome separation, bio-orientation of chromosomes and cytokinesis. AURKA and AURKB are key regulators of mitosis and centrosome via polymerizing microfilaments and controlling chromatid segregation. In particular, AURKA plays critical roles in the regulation of mitotic entry, centrosome function, bipolar spindle assembly, and chromosome segregation...
June 2016: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/26967327/overview-of-current-treatment-options-and-investigational-targeted-therapies-for-locally-advanced-squamous-cell-carcinoma-of-the-head-and-neck
#12
Matthew Zibelman, Ranee Mehra
Patients with squamous cell carcinoma of the head and neck (SCCHN) typically present with locally advanced (LA) stage III or IV disease and are treated with combined-modality therapy with chemotherapy, radiotherapy, and surgery (if resectable). These aggressive, upfront treatment measures are often associated with substantial morbidity, and about half the patients develop locoregional or distant recurrences. Thus, new therapeutic strategies are needed that offer similar efficacy benefits with less toxicity...
August 2016: American Journal of Clinical Oncology
https://www.readbyqxmd.com/read/26962685/overcoming-mitf-conferred-drug-resistance-through-dual-aurka-mapk-targeting-in-human-melanoma-cells
#13
G Pathria, B Garg, V Borgdorff, K Garg, C Wagner, G Superti-Furga, S N Wagner
MITF (microphthalmia-associated transcription factor) is a frequently amplified lineage-specific oncogene in human melanoma, whose role in intrinsic drug resistance has not been systematically investigated. Utilizing chemical inhibitors for major signaling pathways/cellular processes, we witness MITF as an elicitor of intrinsic drug resistance. To search kinase(s) targets able to bypass MITF-conferred drug resistance, we employed a multi-kinase inhibitor-directed chemical proteomics-based differential affinity screen in human melanocytes carrying ectopic MITF overexpression...
March 10, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/26755072/atypical-teratoid-rhabdoid-tumors-current-concepts-advances-in-biology-and-potential-future-therapies
#14
REVIEW
Michael C Frühwald, Jaclyn A Biegel, Franck Bourdeaut, Charles W M Roberts, Susan N Chi
Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood...
June 2016: Neuro-oncology
https://www.readbyqxmd.com/read/26622997/recent-advances-in-the-development-of-aurora-kinases-inhibitors-in-hematological-malignancies
#15
REVIEW
Iqra Choudary, Paul M Barr, Jonathan Friedberg
Over the last two decades, since the discovery of Drosophila mutants in 1995, much effort has been made to understand Aurora kinase biology. Three mammalian subtypes have been identified thus far which include the Aurora A, B and C kinases. These regulatory proteins specifically work at the cytoskeleton and chromosomal structures between the kinetochores and have vital functions in the early phases of the mitotic cell cycle. Today, there are multiple phase I and phase II clinical trials as well as numerous preclinical studies taking place looking at Aurora kinase inhibitors in both hematologic and solid malignancies...
December 2015: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/26615129/aurora-kinase-inhibitors-in-oncology-clinical-trials-current-state-of-the-progress
#16
REVIEW
Gerald S Falchook, Christel C Bastida, Razelle Kurzrock
The Aurora kinase family of kinases (Aurora A, B, and C) are involved in multiple mitotic events, and aberrant expression of these kinases is associated with tumorigenesis. Aurora A and Aurora B are validated anticancer targets, and the development of Aurora kinase inhibitors has progressed from preclinical to clinical studies. A variety of Aurora A, B and pan-Aurora kinase inhibitors have entered the clinic. The main side effects include febrile neutropenia, stomatitis, gastrointestinal toxicity, hypertension, and fatigue...
December 2015: Seminars in Oncology
https://www.readbyqxmd.com/read/26590712/targeting-mitosis-in-cancer-emerging-strategies
#17
REVIEW
Carmen Dominguez-Brauer, Kelsie L Thu, Jacqueline M Mason, Heiko Blaser, Mark R Bray, Tak W Mak
The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic. This review briefly examines past cell-cycle-targeted therapeutics and outlines how experience with these agents has provided valuable insight to refine and improve anti-mitotic strategies...
November 19, 2015: Molecular Cell
https://www.readbyqxmd.com/read/26528438/opposing-effects-of-inhibitors-of-aurora-a-and-egfr-in-autosomal-dominant-polycystic-kidney-disease
#18
Anna S Nikonova, Alexander Y Deneka, Louisa Eckman, Meghan C Kopp, Harvey H Hensley, Brian L Egleston, Erica A Golemis
Aurora-A kinase (AURKA) overexpression in numerous tumors induces aneuploidy, in part because of cytokinetic defects. Alisertib and other small-molecule inhibitors targeting AURKA are effective in some patients as monotherapies or combination therapies. Epidermal growth factor receptor (EGFR) pro-proliferative signaling activity is commonly elevated in cancer, and the EGFR inhibitor erlotinib is commonly used as a standard of care agent for cancer. An erlotinib/alisertib combination therapy is currently under assessment in clinical trials, following pre-clinical studies that indicated synergy of these drugs in cancer...
2015: Frontiers in Oncology
https://www.readbyqxmd.com/read/26497213/aurora-b-kinase-is-a-potent-and-selective-target-in-mycn-driven-neuroblastoma
#19
Dominik Bogen, Jun S Wei, David O Azorsa, Pinar Ormanoglu, Eugen Buehler, Rajarshi Guha, Jonathan M Keller, Lesley A Mathews Griner, Marc Ferrer, Young K Song, Hongling Liao, Arnulfo Mendoza, Berkley E Gryder, Sivasish Sindri, Jianbin He, Xinyu Wen, Shile Zhang, John F Shern, Marielle E Yohe, Sabine Taschner-Mandl, Jason M Shohet, Craig J Thomas, Scott E Martin, Peter F Ambros, Javed Khan
Despite advances in multimodal treatment, neuroblastoma (NB) is often fatal for children with high-risk disease and many survivors need to cope with long-term side effects from high-dose chemotherapy and radiation. To identify new therapeutic targets, we performed an siRNA screen of the druggable genome combined with a small molecule screen of 465 compounds targeting 39 different mechanisms of actions in four NB cell lines. We identified 58 genes as targets, including AURKB, in at least one cell line. In the drug screen, aurora kinase inhibitors (nine molecules) and in particular the AURKB-selective compound, barasertib, were the most discriminatory with regard to sensitivity for MYCN-amplified cell lines...
November 3, 2015: Oncotarget
https://www.readbyqxmd.com/read/26486823/development-of-cell-cycle-checkpoint-therapy-for-solid-tumors
#20
REVIEW
Kenji Tamura
Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available...
December 2015: Japanese Journal of Clinical Oncology
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