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Cancer discovery

Hriday Bera, Sridevi Chigurupati
Thymidine phosphorylase (TP, EC, an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is extremely upregulated in a variety of solid tumours. The TP amplification is associated with concomitant overexpression of many angiogenic factors such as matrix metalloproteases (MMPs), interleukins (ILs), vascular endothelial growth factor (VEGF) etc., resulting in promotion of angiogenesis and cancer metastasis. In addition, overshooting TP level protects tumour cells from apoptosis and helps cell survival...
October 17, 2016: European Journal of Medicinal Chemistry
Shanshan Li, Wenda Zhang, Yanwei Yang, Ting Ma, Jianpeng Guo, Shanshan Wang, Wenying Yu, Lingyi Kong
Constitutive activation of STAT3 has been found in a wide variety of cancers and demonstrated as a very attractive therapeutic target. Disrupting both acetylation and phosphorylation of STAT3 protein was hypothesized to greatly deactivate STAT3, therefore, treating cancers. To demonstrate the hypothesis, two series of novel resveratrol-caffeic acid hybrids were designed aiming to regulate both acetylation and phosphorylation of STAT3 protein, which is also the first report of the synthetic inhibitors simultaneously regulating two biological reactions of STAT3 to our knowledge...
October 15, 2016: European Journal of Medicinal Chemistry
Claudiu T Supuran
The enzyme carbonic anhydrase (CA, EC is found in numerous organisms across the tree of life, with seven distinct classes known to date. CA inhibition can be exploited for the treatment of edema, glaucoma, seizures, obesity, cancer and infectious diseases. A myriad of CA inhibitor (CAI) classes and inhibition mechanisms have been identified over the past decade, mainly through structure-based drug design approaches. Five different CA inhibition mechanisms are presently known. Areas covered: Recent advances in structure-based CAI design are reviewed, with periodic table-based organization of inhibitor classes...
October 26, 2016: Expert Opinion on Drug Discovery
Binh Thanh Nguyen, Min Park, Jae-Chul Pyun, Young Sook Yoo, Min-Jung Kang
An assay for protein kinase C delta (PKCδ) activity based on the quantification of a synthetic substrate using capillary electrophoresis with laser-induced fluorescence detection was developed. The peptides labeled with fluorescein isothiocyanate F-ERK (where ERK is extracellular signal-regulated kinase) and the phosphorylated form, P-F-ERK, were utilized for the method development and validation. The migration time of F-ERK and P-F-ERK were 6.3 ± 0.1 and 8.7 ± 0.2 min, respectively. LOD and LOQ values of F-ERK were 2 and 6 ng/mL and those of P-F-ERK were 4 and 12 ng/mL...
October 26, 2016: Electrophoresis
Christine Jungk, Andreas Mock, Janina Exner, Christoph Geisenberger, Rolf Warta, David Capper, Amir Abdollahi, Sara Friauf, Bernd Lahrmann, Niels Grabe, Philipp Beckhove, Andreas von Deimling, Andreas Unterberg, Christel Herold-Mende
BACKGROUND: The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers. METHODS: mRNA microarray data of a discovery set (n = 36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore™ workflow...
October 26, 2016: BMC Medicine
Alessandro Morabito
The therapeutic scenario of patients with advanced non-small-cell lung cancer (NSCLC) has dramatically changed in recent years, thanks to the improvement in the knowledge of the biology of NSCLC, the discovery of targetable oncogenic drivers, and the availability of new effective drugs also for non oncogenic addicted patients, defined "wild-type" (WT). NSCLC has been the first epithelial neoplasm treated with a targeted first-line therapy in patients harbouring EGFR activating mutations or ALK rearrangements, and new targeted-based agents directed versus other molecular alterations are currently in development...
October 2016: Recenti Progressi in Medicina
Xin Yu, Heyi Zheng, Matthew T V Chan, William Ka Kei Wu
Highly up-regulated in liver cancer (HULC) was originally identified as the most overexpressed long non-coding RNA in hepatocellular carcinoma. Since its discovery, the aberrant up-regulation of HULC has been demonstrated in other cancer types, including gastric cancer, pancreatic cancer, osteosarcoma and hepatic metastasis of colorectal cancer. Recent discoveries have also shed new light on the upstream molecular mechanisms underlying HULC deregulation. As an oncogene, HULC promotes tumorigenesis by regulating multiple pathways, such as down-regulation of EEF1E1, promotion of abnormal lipid metabolism, and up-regulation of sphingosine kinase 1...
October 25, 2016: Journal of Cellular and Molecular Medicine
Yifan Cao, Hao Liu, Heng Zhang, Chao Lin, Ruochen Li, Songyang Wu, He Li, Hongyong He, Weijuan Zhang, Jiejie Xu
: Backround: Abnormal expression of CXC chemokine receptor 1 (CXCR1) has shown the ability to promote tumor angiogensis, invasion and metastasis in several cancers. The purpose of our curret study is to discover the clinical prognostic significance of CXCR1 in resectable gastric cancer. METHODS: 330 gastric cancer patients who underwent R0 gastrectomy with standard D2 lymphadenectomy at Zhongshan Hospital, Fudan University between 2007 and 2008 were enrolled. CXCR1 expression was evaluated with use of immunohistochemical staining...
October 21, 2016: Oncotarget
Nikhil Bhalla, Mirella Di Lorenzo, Pedro Estrela, Giordano Pula
Since the discovery of protein kinase activity in 1954, close to 600 kinases have been discovered that have crucial roles in cell physiology. In several pathological conditions, aberrant protein kinase activity leads to abnormal cell and tissue physiology. Therefore, protein kinase inhibitors are investigated as potential treatments for several diseases, including dementia, diabetes, cancer and autoimmune and cardiovascular disease. Modern semiconductor technology has recently been applied to accelerate the discovery of novel protein kinase inhibitors that could become the standard-of-care drugs of tomorrow...
October 22, 2016: Drug Discovery Today
Pritom Shah, Anne Cheasty, Caroline Foxton, Tony Raynham, Muddasar Farooq, Irene Farre Gutierrez, Aurore Lejeune, Michelle Pritchard, Andrew Turnbull, Leon Pang, Paul Owen, Susan Boyd, Alexandra Stowell, Allan Jordan, Niall M Hamilton, James R Hitchin, Martin Stockley, Ellen MacDonald, Mar Jimenez Quesada, Elisabeth Trivier, Jana Skeete, Huib Ovaa, Wouter H Moolenaar, Hamish Ryder
The autotoxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies...
October 14, 2016: Bioorganic & Medicinal Chemistry Letters
Lila E Mullany, Jennifer S Herrick, Roger K Wolff, John R Stevens, Martha L Slattery
Smoking is known to influence messenger RNA (mRNA) expression in colorectal cancer (CRC) cases. As microRNAs (miRNAs) are known repressors of mRNAs, we hypothesize that smoking may influence miRNA expression, thus altering mRNA expression. Our sample consisted of 1447 CRC cases that had normal colorectal mucosa and carcinoma miRNA data and lifestyle data. We examined current smoking, current versus never and former versus never (C/F/N) smoking(1), and pack-years smoked with miRNA expression in normal mucosa as well as differential miRNA expression between paired normal and carcinoma tissue for colon and rectal tissue to determine associations between smoking and miRNA expression...
October 22, 2016: Cancer Epidemiology
Ting Qu, Yan-Ping Li, Xiao-Hong Li, Yan Chen
The present study aimed to systematically examine the molecular mechanisms of papillary thyroid cancer (PTC), and identify potential biomarkers and drugs for the treatment of PTC. Two microarray data sets (GSE3467 and GSE3678), containing 16 PTC samples and 16 paired normal samples, were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Analysis package. Subsequently, the common DEGs were screened for functional and pathway enrichment analysis using the Database for Annotation Visualization and Integrated Discovery...
October 19, 2016: Molecular Medicine Reports
Mahmoud A Alfaqih, Emma H Allott, Robert J Hamilton, Michael R Freeman, Stephen J Freedland
An increasing amount of data supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. Use of these agents seems to also be associated with improved prostate- cancer-specific survival, particularly in men undergoing radiotherapy, suggesting usefulness of statins in secondary and tertiary prevention. Some study results might be influenced by increased PSA screening and health-conscious behaviour in statin users but these factors are unlikely to completely account for observed beneficial effects...
October 25, 2016: Nature Reviews. Urology
Marie Eliade, Jeremy Skrzypski, Amandine Baurand, Caroline Jacquot, Geoffrey Bertolone, Catherine Loustalot, Charles Coutant, France Guy, Pierre Fumoleau, Yannis Duffourd, Laurent Arnould, Alexandra Delignette, Marie-Martine Padéano, Côme Lepage, Géraldine Raichon-Patru, Axelle Boudrant, Marie-Christine Bône-Lépinoy, Anne-Laure Villing, Aurélie Charpin, Karine Peignaux, Sandy Chevrier, Frédérique Vegran, François Ghiringhelli, Romain Boidot, Nicolas Sevenet, Sarab Lizard, Laurence Faivre
Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1/2 testing. Next generation sequencing and the recent discovery of new genes involved in HBOC now permit the transfer of genomic capture targeting multiple candidate genes from research to clinical use. However, the implications for the management of patients and their families have not been extensively studied, in particular since some of these genes are not well-established cancer predisposing genes...
October 15, 2016: Oncotarget
Zain A Sobani, Ashwin Sawant, Mikram Jafri, Amit Keith Correa, Ibrahim Halil Sahin
Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency...
October 10, 2016: World Journal of Clinical Oncology
Junmin Zhang, Juan Yao, Shoujiao Peng, Xinming Li, Jianguo Fang
Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders...
October 21, 2016: Biochimica et Biophysica Acta
Peter M Fischer
Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult-even for those working in the field-easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation...
October 24, 2016: Medicinal Research Reviews
M C Gouveia, J P Vella, F R Cafeo, F L Affonso Fonseca, M R Bacci
OBJECTIVE: Irisin is a muscle-secreted protein released into the circulation by cleavage of fibronectin type III domain containing protein 5(FNDC5). Since its discovery in 2012, it has been the subject of many researches due to its physiological role. It is believed that understanding irisin's function may be the key to comprehend many diseases and their development. The aim of this study is to perform a systematic review in order to establish whether there is an association of irisin's levels with obesity, diabetes mellitus, non-alcoholic steatohepatitis, chronic kidney disease and cancer in terms of prognosis...
October 2016: European Review for Medical and Pharmacological Sciences
Hyunjin Kim, Sang-Min Choi, Sanghyun Park
When a gene shows varying levels of expression among normal people but similar levels in disease patients or shows similar levels of expression among normal people but different levels in disease patients, we can assume that the gene is associated with the disease. By utilizing this gene expression heterogeneity, we can obtain additional information that abets discovery of disease-associated genes. In this study, we used collaborative filtering to calculate the degree of gene expression heterogeneity between classes and then scored the genes on the basis of the degree of gene expression heterogeneity to find "differentially predicted" genes...
October 19, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Yana K Rennie, Patrick J McIntyre, Tito Akindele, Richard Bayliss, Andrew G Jamieson
Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein-protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly, and is a promising target for anti-cancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker...
October 24, 2016: ACS Chemical Biology
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