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Aurora A Kinase inhibitors in prostate cancer

Richard Ottman, Jenna Levy, Grizzle E Williams, Ratna Chakrabarti
miR-17-92a cluster miRNAs are transcribed from a polycistronic transcription unit C13orf25 that generates six mature miRNAs, miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a that are overexpressed in lung and colon cancers. Here we show that the expression of miR-17-92a miRNAs are reduced in cancerous prostate tissues compared to uninvolved areas and also in aggressive prostate cancer cells. Restoration of expression of all members of miR-17-92a cluster showed, decreased expression of cell cycle regulatory proteins cyclin D1 and SSH1; and LIMK1 and FGD4 of RhoGTPase signaling pathway...
September 16, 2016: Oncotarget
Ying An, Eun Lee, Yeongji Yu, Jieun Yun, Myeong Youl Lee, Jong Soon Kang, Woo-Young Kim, Raok Jeon
A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a promising activity with respect to the inhibition of Aurora B kinase. A structure-activity relationship study indicated that linker length, regiochemistry, and halogen substitution play important roles in kinase inhibitory potency. The binding modes between representative compounds and Aurora kinases were interpreted through a molecular docking study to explain the inhibitory activity and selectivity for Aurora A and B kinases...
July 1, 2016: Bioorganic & Medicinal Chemistry Letters
M Luz Flores, Carolina Castilla, Jessica Gasca, Rafael Medina, Begoña Pérez-Valderrama, Francisco Romero, Miguel A Japón, Carmen Sáez
Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCδ silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis...
July 2016: Molecular Cancer Therapeutics
Julie N Graff, Celestia S Higano, Noah M Hahn, Matthew H Taylor, Bin Zhang, Xiaofei Zhou, Karthik Venkatakrishnan, E Jane Leonard, John Sarantopoulos
BACKGROUND: This study was designed to determine the safety, tolerability, and pharmacokinetics (PK) of alisertib (MLN8237) in combination with docetaxel and to identify a recommended dose for the combination. METHODS: Adults with metastatic cancer were treated on 21-day cycles with alisertib (10, 20, 30, or 40 mg) twice daily on days 1 to 7 or days 1 to 5 and with docetaxel (75 or 60 mg/m(2) ) on day 1. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) for future studies...
August 15, 2016: Cancer
Brett S Carver
In this issue of Cancer Cell, Lee and colleagues (2016) define the biologic role of MYCN in promoting prostate tumorigenesis and development of a neuroendocrine phenotype. This has important implications for the clinical management of neuroendocrine prostate cancer as Aurora A kinase inhibitors promoting N-Myc destabilization progress in the clinic.
April 11, 2016: Cancer Cell
Sudeshna Goswami, Neelam Sharma-Walia
BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that has multifaceted role and is associated with several cancer malignancies like that of bladder carcinoma, gastric carcinoma, prostate cancer, multiple myeloma and breast cancer. Also OPG has been associated with several organ pathologies. The widespread expression of OPG suggests that OPG may have multiple biological activities that are yet to be explored. METHODS: The anchorage-independent sphere cultures of the adherent cells were instrumental in our study as it provided a deeper insight into the complexity of a 3D tumor...
2015: BMC Cancer
Huifeng Niu, Mark Manfredi, Jeffrey A Ecsedy
Alisertib (MLN8237) is a selective small molecule inhibitor of Aurora A kinase that is being developed in multiple cancer indications as a single agent and in combination with other therapies. A significant amount of research has elucidated a role for Aurora A in orchestrating numerous activities of cells transiting through mitosis and has begun to shed light on potential non-mitotic roles for Aurora A as well. These biological insights laid the foundation for multiple clinical trials evaluating the antitumor activity of alisertib in both solid cancers and heme-lymphatic malignancies...
2015: Frontiers in Oncology
Panagiotis J Vlachostergios, Christos N Papandreou
Neuroendocrine prostate carcinoma, either co-present with the local adenocarcinoma disease or as a result of transdifferentiation later in time, was described as one major process of emerging resistance to androgen deprivation therapies, and at the clinical level it is consistent with the development of rapidly progressive visceral disease, often in the absence of elevated serum prostate-specific antigen level. Until present, platinum-based chemotherapy has been the only treatment modality, able to produce a fair amount of responses but of short duration...
2015: Frontiers in Oncology
Mannan Nouri, Ellca Ratther, Nataly Stylianou, Colleen C Nelson, Brett G Hollier, Elizabeth D Williams
Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow...
2014: Frontiers in Oncology
Kurt W Fisher, Rodolfo Montironi, Antonio Lopez Beltran, Holger Moch, Lisha Wang, Marina Scarpelli, Sean R Williamson, Michael O Koch, Liang Cheng
Prostate cancer is the most common and second most lethal cancer in men. The majority of prostate cancers are histologically similar to acinar adenocarcinomas and rely on androgen-dependent signaling for their development and progression. Androgen deprivation therapy is a mainstay of treatment regimens and we discuss the recent advancements in androgen-deprivation therapy. Recent advances in defining the genetic landscape of prostate cancer have shown that the depth of genetic heterogeneity surpasses what can be seen histologically and has the ability to redefine treatments...
2015: Current Drug Targets
Ali Zekri, Seyed H Ghaffari, Samad Ghanizadeh-Vesali, Marjan Yaghmaie, Arash Salmaninejad, Kamran Alimoghaddam, Mohammad H Modarressi, Ardeshir Ghavamzadeh
Prostate cancer is the frequent non-cutaneous tumor with high mortality in men. Prostate tumors contain cells with different status of androgen receptor. Androgen receptor plays important roles in progression and treatment of prostate cancer. Aurora B kinase, with oncogenic potential, is involved in chromosome segregation and cytokinesis, and its inhibition is a promising anti-cancer therapy. In the present study, we aimed to investigate the effects of Aurora B inhibitor, AZD1152-HQPA, on survival and proliferation of androgen receptor (AR)-positive prostate cancer cells...
February 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kyung Park, Zhengming Chen, Theresa Y MacDonald, Javed Siddiqui, Huihui Ye, Andreas Erbersdobler, Maria M Shevchuk, Brian D Robinson, Martin G Sanda, Arul M Chinnaiyan, Himisha Beltran, Mark A Rubin, Juan Miguel Mosquera
Aurora kinase A (AURKA) gene amplification has been documented in 67% of hormone-naive prostate cancer cases that progress to a highly aggressive variant of castrate-resistant disease, clinically referred to as "neuroendocrine" prostate cancer, "small cell" prostate carcinoma, or "anaplastic" prostate cancer. Therefore, AURKA amplification is a potential prognostic biomarker that may help to identify patients with prostate cancer who are at high risk for developing castrate-resistant disease with clinical features of small cell carcinoma...
October 2014: Human Pathology
Channing J Paller, Michel D Wissing, Janet Mendonca, Anup Sharma, Eugene Kim, Hea-Soo Kim, Madeleine S Q Kortenhorst, Stephanie Gerber, Marc Rosen, Faraz Shaikh, Marianna L Zahurak, Michelle A Rudek, Hans Hammers, Charles M Rudin, Michael A Carducci, Sushant K Kachhap
Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. This provides opportunities for combination therapy: agents that further disable these pathways through inhibition of residual gene function are speculated to enhance cell death in combination with HDACIs. A previous study from our group indicated that mitotic checkpoint kinases such as PLK1 and Aurora A are downregulated by HDACIs...
October 2014: Cancer Medicine
Charlotte Svensson, Jens Ceder, Diego Iglesias-Gato, Yin-Choy Chuan, See Tong Pang, Anders Bjartell, Roxana Merino Martinez, Laura Bott, Leszek Helczynski, David Ulmert, Yuzhuo Wang, Yuanjie Niu, Colin Collins, Amilcar Flores-Morales
The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds chromatin regions containing well-characterized cis-elements known to mediate REST transcriptional repression, while cell imaging studies confirmed that REST and AR closely co-localize in vivo. Androgen-induced gene repression also involves modulation of REST protein turnover through actions on the ubiquitin ligase β-TRCP...
January 2014: Nucleic Acids Research
Ram V Roy, Suman Suman, Trinath P Das, Joe E Luevano, Chendil Damodaran
Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer. Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including prostate cancer are increasing. The present study focused on the cell cycle regulatory potential of the withanolide withaferin A (1) on prostate cancer cells. Compound 1 induced G2/M arrest in both prostate cancer cell lines (PC-3 and DU-145) when treated for 48 h. The G2/M arrest was accompanied by upregulation of phosphorylated Wee-1, phosphorylated histone H3, p21, and Aurora B...
October 25, 2013: Journal of Natural Products
Wei He, Min-Guang Zhang, Xiao-Jing Wang, Shan Zhong, Yuan Shao, Yu Zhu, Zhou-Jun Shen
The palliative therapy effect by docetaxel for CRPC patients makes it urgent to improve the therapy. It was suggested that PI3K and androgen receptor-directed combination therapy may be effective for prostate cancer (PCa) patients PTEN negative. However, for those patients PTEN positive, the mechanism of anti-apoptosis survival of cancer cells is not yet well defined. Amplification of AURKA has been detected in 5% of PCa. In this work, Du145, a PTEN positive PCa cell model, was employed to investigate the role of aurora kinase a (AURKA) on cell growth...
2013: American Journal of Translational Research
Michel D Wissing, Paul J van Diest, Elsken van der Wall, Hans Gelderblom
INTRODUCTION: Metastatic castrate-resistant prostate cancer (mCRPC) is the second deadliest cancer in men. The group of taxanes, which target microtubules of mitotic cells, is currently the only chemotherapy which has proven to increase overall survival in mCRPC patients. Other mitotic inhibitors are being explored for their clinical potential in mCRPC treatment. AREAS COVERED: In this review, we summarize recent developments in the application of mitotic inhibitors for mCRPC from a clinical perspective...
May 2013: Expert Opinion on Investigational Drugs
Raheleh Toughiri, Xiang Li, Quansheng Du, Charles J Bieberich
Aurora-A is a serine/threonine kinase that has oncogenic properties in vivo. The expression and kinase activity of Aurora-A are up-regulated in multiple malignancies. Aurora-A is a key regulator of mitosis that localizes to the centrosome from the G2 phase through mitotic exit and regulates mitotic spindle formation as well as centrosome separation. Overexpression of Aurora-A in multiple malignancies has been linked to higher tumor grade and poor prognosis through mechanisms that remain to be defined. Using an unbiased proteomics approach, we identified the protein nuclear mitotic apparatus (NuMA) as a robust substrate of Aurora-A kinase...
April 2013: Journal of Cellular Biochemistry
Ana Aparicio, Christopher J Logothetis, Sankar N Maity
Small cell prostate carcinoma is a lethal variant of castration-resistant prostate cancer. Beltran and colleagues identified overexpression and amplification of both aurora kinase A (AURKA) and the MYCN proto-oncogene in the small cell prostate carcinomas and propose Aurora kinase A as a potential therapeutic target in this disease subset.
November 2011: Cancer Discovery
Himisha Beltran, David S Rickman, Kyung Park, Sung Suk Chae, Andrea Sboner, Theresa Y MacDonald, Yuwei Wang, Karen L Sheikh, Stéphane Terry, Scott T Tagawa, Rajiv Dhir, Joel B Nelson, Alexandre de la Taille, Yves Allory, Mark B Gerstein, Sven Perner, Kenneth J Pienta, Arul M Chinnaiyan, Yuzhuo Wang, Colin C Collins, Martin E Gleave, Francesca Demichelis, David M Nanus, Mark A Rubin
UNLABELLED: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings on tumors from a large cohort of patients (37 NEPC, 169 PCA, 22 BEN) using IHC and FISH. We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA, respectively, and evidence that that they cooperate to induce a neuroendocrine phenotype in prostate cells...
November 2011: Cancer Discovery
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