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Aurora A kinase clinical trials

Michael L Maitland, Sarina Piha-Paul, Gerald Falchook, Razelle Kurzrock, Ly Nguyen, Linda Janisch, Sanja Karovic, Mark McKee, Elizabeth Hoening, Shekman Wong, Wijith Munasinghe, Joann Palma, Cherrie Donawho, Guinan K Lian, Peter Ansell, Mark J Ratain, David Hong
BACKGROUND: Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib. METHODS: Ilorasertib monotherapy was administered at 10-180 mg orally once daily (Arm I, n = 23), 40-340 mg orally twice daily (Arm II, n = 28), or 8-32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle...
March 19, 2018: British Journal of Cancer
Minle Li, Keyu Gao, Laili Chu, Junnian Zheng, Jing Yang
Aurora kinase A (Aurora-A), a member of the Aurora family of serine/threonine kinases, plays a critical role in multiple steps of mitotic progression, including microtubule stability during the G1 phase of the cell cycle, chromosome alignment and segregation, and cytokinesis and is aberrantly expressed in various types of human cancers. In addition to its classic functions, recent studies have indicated that Aurora-A is critical for controlling self-renewal of embryonic stem cells through negative regulation of p53...
March 12, 2018: International Journal of Biochemistry & Cell Biology
Sofie Martens, Vera Goossens, Lars Devisscher, Sam Hofmans, Polien Claeys, Marnik Vuylsteke, Nozomi Takahashi, Koen Augustyns, Peter Vandenabeele
The Aurora kinase family (Aurora A, B and C) are crucial regulators of several mitotic events, including cytokinesis. Increased expression of these kinases is associated with tumorigenesis and several compounds targeting Aurora kinase are under evaluation in clinical trials (a.o. AT9283, AZD1152, Danusertib, MLN8054). Here, we demonstrate that the pan-Aurora kinase inhibitor Tozasertib (VX-680 and MK-0457) not only causes cytokinesis defects through Aurora kinase inhibition, but is also a potent inhibitor of necroptosis, a cell death process regulated and executed by the RIPK1, RIPK3 and MLKL signalling axis...
February 12, 2018: Cell Death & Disease
Tufia C Haddad, Antonino D'Assoro, Vera Suman, Mateusz Opyrchal, Prema Peethambaram, Minetta C Liu, Matthew P Goetz, James N Ingle
PURPOSE: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). METHODS: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant...
December 30, 2017: Breast Cancer Research and Treatment
Susanne Liewer, Ashley Huddleston
Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib...
December 20, 2017: Expert Opinion on Investigational Drugs
Anne E Lykkesfeldt, Benedikte R Iversen, Maj-Britt Jensen, Bent Ejlertsen, Anita Giobbie-Hurder, Birgit E Reiter, Tove Kirkegaard, Birgitte B Rasmussen
BACKGROUND: Cell culture studies have disclosed that the mitotic Aurora kinase A is causally involved in both tamoxifen and aromatase inhibitor resistant cell growth and thus may be a potential new marker for endocrine resistance in the clinical setting. MATERIAL AND METHODS: Archival tumor tissue was available from 1323 Danish patients with estrogen receptor (ER) positive primary breast cancer, who participated in the Breast International Group (BIG) 1-98 trial, comparing treatment with tamoxifen and letrozole and both in a sequence...
January 2018: Acta Oncologica
Yaman Tayyar, Luqman Jubair, Sora Fallaha, Nigel A J McMillan
BACKGROUND: Many current anticancer chemotherapeutics suffer from significant side effects, which have led to the exploration of more targeted therapies. This resulted in the exploration of inhibitors of Aurora A kinase as a potential anti-cancer treatment. Alisertib (MLN8237) has proven to be a potent Aurora A kinase inhibitor that had the highest safety profile among its therapeutic family. Phase I/II/III clinical trials with Alisertib have been carried out and reported promising efficacy, yet serious side effects...
November 2017: Critical Reviews in Oncology/hematology
Anna E Vilgelm, Priscilla Cobb, Kiran Malikayil, David Flaherty, C Andrew Johnson, Dayanidhi Raman, Nabil Saleh, Brian Higgins, Brandon A Vara, Jeffrey N Johnston, Douglas B Johnson, Mark C Kelley, Sheau-Chiann Chen, Gregory D Ayers, Ann Richmond
Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage...
October 2017: EBioMedicine
Ankit C Borisa, Hardik G Bhatt
Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc...
November 10, 2017: European Journal of Medicinal Chemistry
Jia-Nian Chen, De-Wen Wu, Ting Li, Kang-Jian Yang, Li Cheng, Zu-Ping Zhou, Shi-Ming Pu, Wan-Hua Lin
Arylurea derivatives, an important class of small molecules, have received considerable attention in recent years due to their wide range of biological applications. Various molecular targeted agents with arylurea scaffold as potential enzyme/receptor inhibitors were constructed with the successful development of sorafenib and regorafenib. This review focuses on those arylureas possessing anti-cancer activities from 2010 to date. According to their different mechanisms of action, these arylureas are divided into the following six categories: (1) Ras/Raf/MEK/ERK signaling pathway inhibitors; (2) tumor angiogenesis inhibitors, their targets include Vascular Endothelial Growth Factor Receptors (VEGFRs), Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), Epidermal Growth Factor Receptors (EGFRs), Insulin-Like Growth Factor 1 Receptor (IGF-1R), Fmslike Tyrosine Kinase 3 (FLT3), c-Kit, MET, and Smoothened (Smo); (3) PI3K/AKT/mTOR signaling pathway inhibitors; (4) cell cycle inhibitors, their targets include Checkpoint Kinases (Chks), Cyclin- Dependent Kinases (CDKs), Aurora, SUMO activating enzyme 1 (SUMO E1), tubulin, and DNA; (5) tumor differentiation, migration, and invasion inhibitors, their targets include Matrix Metalloproteinases (MMPs), LIM kinase (Limk), Nicotinamide Phosphoribosyltransferase (Nampt), and Histone Deacetylase (HDAC); (6) arylureas from the rational modification of natural products...
November 20, 2017: Current Topics in Medicinal Chemistry
Andreas Seeber, Christoph Leitner, Kathrin Philipp-Abbrederis, Gilbert Spizzo, Florian Kocher
Systemic therapy options for small cell lung cancer patients with extensive disease remain poor. After an initial response on first-line therapy, virtually all patients develop disease progression. For those who showed an initial response only few therapy options with low response rates are currently available. Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapy options are clearly warranted for these patients. In this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials...
July 2017: Future Oncology
Lucas Moreno, Hubert Caron, Birgit Geoerger, Angelika Eggert, Gudrun Schleiermacher, Penelope Brock, Dominique Valteau-Couanet, Louis Chesler, Johannes H Schulte, Katleen De Preter, Jan Molenaar, Alexander Schramm, Martin Eilers, Tom Van Maerken, John Inge Johnsen, Michelle Garrett, Sally L George, Deborah A Tweddle, Per Kogner, Frank Berthold, Jan Koster, Giuseppe Barone, Elizabeth R Tucker, Lynley Marshall, Ralf Herold, Jaroslav Sterba, Koen Norga, Gilles Vassal, Andrew Dj Pearson
Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma...
August 2017: Expert Opinion on Drug Discovery
Arun Prasath Damodaran, Lucie Vaufrey, Olivia Gavard, Claude Prigent
Aurora kinases control multiple events during cell cycle progression and are essential for mitotic and meiotic bipolar spindle assembly and function. There are three Aurora kinases in mammals, some of which have oncogenic properties and all of which are overexpressed in multiple cancers. Pharmaceutical companies quickly made these kinases priority targets for the development of inhibitors to be used as cancer treatments. In this review, we focus on Aurora A, against which several inhibiting compounds have been discovered and made available; however, even though some of these compounds underwent clinical trials, none have yet gone beyond Phase III trials...
August 2017: Trends in Pharmacological Sciences
Dong-Yao Wang, Yan Cao, Le-Yi Zheng, Lang-Dong Chen, Xiao-Fei Chen, Zhan-Ying Hong, Zhen-Yu Zhu, Xiaoyu Li, Yi-Feng Chai
Accurate identification of the molecular targets of bioactive small molecules is a highly important yet challenging task in biomedical research. Previously, a method named DPAL (DNA-programmed affinity labeling) for labeling and identifying the cellular targets of small molecules and nucleic acids was developed. Herein, DPAL is applied for the target identification of Alisertib (MLN8237), which is a highly specific aurora kinase A (AKA) inhibitor and a drug candidate being tested in clinical trials for cancer treatment...
June 8, 2017: Chemistry: a European Journal
Anastasia A Ionkina, John J Tentler, Jihye Kim, Anna Capasso, Todd M Pitts, Karen A Ryall, Rebekah R Howison, Peter Kabos, Carol A Sartorius, Aik Choon Tan, S Gail Eckhardt, Jennifer R Diamond
PURPOSE: Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX) models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076. EXPERIMENTAL DESIGN: p53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment...
2017: Frontiers in Oncology
David Martin, Sora Fallaha, Martina Proctor, Alexander Stevenson, Lewis Perrin, Nigel McMillan, Brian Gabrielli
The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types. The most prominent Aurora inhibitor is alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials. Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor in vivo Here, we show that alisertib inhibits both Aurora A and B in vivo in preclinical models of HPV-driven cervical cancer, and that it is the inhibition of Aurora A and B that provides the selectivity and efficacy of this drug in vivo in this disease setting...
May 18, 2017: Molecular Cancer Therapeutics
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 World Health Organization 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 preclinical drug screen in order to inform potentially more active clinical trial protocols...
November 29, 2017: Neuro-oncology
Italia Anna Asteriti, Frederick Daidone, Gianni Colotti, Serena Rinaldo, Patrizia Lavia, Giulia Guarguaglini, Alessandro Paiardini
Aurora kinases are a family of cell division regulators that govern the correct assembly of a bipolar mitotic spindle and the fidelity of chromosome segregation. Their overexpression is associated with genomic instability and aneuploidy, and is frequently observed in cancer. Accordingly, competitive inhibitors targeting Aurora kinase activity at the ATP-binding site are being investigated for therapeutic purposes. Despite promising pre-clinical data, these molecules display moderate effects in clinical trials and incomplete selectivity, either against distinct family members, or other kinases...
May 9, 2017: Oncotarget
Shu-Fu Lin, Jen-Der Lin, Chuen Hsueh, Ting-Chao Chou, Richard J Wong
BACKGROUND: We explored the therapeutic effects of dinaciclib, a cyclin-dependent kinase (CDK) inhibitor, in the treatment of thyroid cancer. MATERIALS AND METHODS: Seven cell lines originating from three pathologic types of thyroid cancer (papillary, follicular and anaplastic) were studied. The cytotoxicity of dinaciclib was measured using a lactate dehydrogenase assay. The expression of proteins associated with cell cycle and apoptosis was assessed using Western blot analysis and immunofluorescence microscopy...
2017: PloS One
Mark A Currier, Les Sprague, Tilat A Rizvi, Brooke Nartker, Chun-Yu Chen, Pin-Yi Wang, Brian J Hutzen, Meghan R Franczek, Ami V Patel, Katherine E Chaney, Keri A Streby, Jeffrey A Ecsedy, Joe Conner, Nancy Ratner, Timothy P Cripe
Malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma models respond to the investigational small molecule Aurora A kinase inhibitor, alisertib. We previously reported that MPNST and neuroblastomas are also susceptible to oncolytic herpes virus (oHSV) therapy. Herein, we show that combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibits significantly increased antitumor efficacy compared to either monotherapy. Alisertib and HSV1716 reduced tumor growth and increased survival in two xenograft models of MPNST and neuroblastoma...
March 14, 2017: Oncotarget
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