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HIT Cancer

Carl S Rye, Nicola E A Chessum, Scott Lamont, Kurt G Pike, Paul Faulder, Julie Demeritt, Paul Kemmitt, Julie Tucker, Lorenzo Zani, Matthew D Cheeseman, Rosie Isaac, Louise Goodwin, Joanna Boros, Florence Raynaud, Angela Hayes, Alan T Henley, Emmanuel de Billy, Christopher J Lynch, Swee Y Sharp, Robert Te Poele, Lisa O' Fee, Kevin M Foote, Stephen Green, Paul Workman, Keith Jones
Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay...
August 1, 2016: MedChemComm
Michelangelo Fiorentino, Elisa Gruppioni, Francesco Massari, Francesca Giunchi, Annalisa Altimari, Chiara Ciccarese, Davide Bimbatti, Aldo Scarpa, Roberto Iacovelli, Camillo Porta, Sarhadi Virinder, Giampaolo Tortora, Walter Artibani, Riccardo Schiavina, Andrea Ardizzoni, Matteo Brunelli, Sakari Knuutila, Guido Martignoni
Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy...
October 10, 2016: Oncotarget
Romina J Pagliero, Diego S D'Astolfo, Daphne Lelieveld, Riyona D Pratiwi, Sonja Aits, Marja Jaattela, Nathaniel I Martin, Judith Klumperman, David A Egan
The lysosomal cell death (LCD) pathway is a caspase 3-independent cell death pathway that has been suggested as a possible target for cancer therapy, making the development of sensitive and specific high-throughput (HT) assays to identify LCD inducers highly desirable. In this study, we report a two-step HT screening platform to reliably identify such molecules. First, using a robust HT primary screen based on propidium iodide uptake, we identified compounds that kill through nonapoptotic pathways. A phenotypic image-based assay using a galectin-3 (Gal-3) reporter was then used to further classify hits based on lysosomal permeabilization, a hallmark of LCD...
October 2016: Assay and Drug Development Technologies
Asad Ali Shah, Akihiro Ito, Akiko Nakata, Minoru Yoshida
SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro...
2016: Biological & Pharmaceutical Bulletin
Ilenia Pellarin, Laura Arnoldo, Silvia Costantini, Silvia Pegoraro, Gloria Ros, Carlotta Penzo, Gianluca Triolo, Francesca Demarchi, Riccardo Sgarra, Alessandro Vindigni, Guidalberto Manfioletti
The HMGA1 architectural transcription factor is an oncogene overexpressed in the vast majority of human cancers. HMGA1 is a highly connected node in the nuclear molecular network and the key aspect of HMGA1 involvement in cancer development is that HMGA1 simultaneously confers cells multiple oncogenic hits, ranging from global chromatin structural and gene expression modifications up to the direct functional alterations of key cellular proteins. Interestingly, HMGA1 also modulates DNA damage repair pathways...
2016: PloS One
Weijia Chen, Piers D L Howe
Breast screening is an important tool for the early detection of breast cancers. However, tumours are typically present in less than 1% of mammograms. This low prevalence could cause radiologists to detect fewer tumours than they otherwise would, an issue known as the prevalence effect. The aim of our study was to investigate a novel breast screening protocol, designed to decrease the number of tumours missed by radiologists, without increasing their workload. We ran two laboratory-based experiments to assess the degree to which the novel protocol, called the catch trial (CT) protocol, resulted in greater sensitivity (d') than the double screener protocol (DS), currently utilised in Australia...
2016: PloS One
Jiuyang Liu, Jia Gao, Fudong Li, Rongsheng Ma, Qingtao Wei, Aidong Wang, Jihui Wu, Ke Ruan
BACKGROUND: The delineation of intrinsically weak interactions between novel targets and fragment screening hits has long limited the pace of hit-to-lead evolution. Rho guanine-nucleotide dissociation inhibitor 2 (RhoGDI2) is a novel target that lacks any chemical probes for the treatment of tumor metastasis. METHODS: Protein-observed and ligand-observed NMR spectroscopy was used to characterize the weak interactions between RhoGDI2 and fragment screening hits. RESULTS: We identified three hits of RhoGDI2 using streamlined NMR fragment-based screening...
October 6, 2016: Biochimica et Biophysica Acta
Wei-Lin Chen, Zhi-Hui Wang, Tao-Tao Feng, Dong-Dong Li, Chu-Hui Wang, Xiao-Li Xu, Xiao-Jin Zhang, Qi-Dong You, Xiao-Ke Guo
Protein lysine methyltransferase G9a is widely considered as an appealing antineoplastic target. Herein we present an integrated workflow combining shape-based virtual screening and structure-based molecular modification for the identification of novel G9a inhibitors. The shape-based similarity screening through ROCS overlay on the basis of the structure of UNC0638 was performed to identify CPUY074001 contained a 6H-anthra[1,9-cd]isoxazol-6-one scaffold as a hit. Analysis of the binding mode of CPUY074001 with G9a and 3D-QSAR results, two series compounds were designed and synthesized...
September 30, 2016: Bioorganic & Medicinal Chemistry
Jianqi Yang, Lance T Platt, Biswanath Maity, Katelin E Ahlers, Zili Luo, Zhibo Lin, Bandana Chakravarti, Stella-Rita Ibeawuchi, Ryan W Askeland, Jolanta Bondaruk, Bogdan A Czerniak, Rory A Fisher
Urinary bladder cancer (UBC) is largely caused by exposure to toxic chemicals including those in cigarette smoke (i.e. BBN). An activating SNP in RGS6 is associated with a pronounced reduction in UBC risk, especially among smokers. However, the mechanism underlying this reduction remains unknown. Here we demonstrate that RGS6 is robustly expressed in human urothelium, where urothelial cell carcinoma originates, and is downregulated in human UBC. Utilizing RGS6-/- mice we interrogated a possible role for RGS6 as a tumor suppressor using the BBN-induced bladder carcinogenesis model that closely recapitulates human disease...
October 4, 2016: Oncotarget
Ralf Ulrich Trappe, Marianne Sinn, Hanno Riess
There is only limited data for the use of direct oral anticoagulants (DOACs) in tumor patients and no data from prospective randomised trials comparing DOACs to the current standard care: low molecular weight heparine (LMWH). Therefore, DOACs must be used with caution and should be restricted to tumor patients with (1) contraindications for LMWH (e.g. HIT II, phobia of syringe) or (2) to the situations of prolonged anticoagulation after initial therapy with LMWH. Cancer-associated disorders as well as side effects of chemotherapy as nausea and emesis have to be considered as well as potential substance-specific interactions...
September 2016: Deutsche Medizinische Wochenschrift
Jesús García-Donas, Benoit Beuselinck, Lucía Inglada-Pérez, Osvaldo Graña, Patrick Schöffski, Agnieszka Wozniak, Oliver Bechter, Maria Apellániz-Ruiz, Luis Javier Leandro-García, Emilio Esteban, Daniel E Castellano, Aranzazu González Del Alba, Miguel Angel Climent, Susana Hernando, José Angel Arranz, Manuel Morente, David G Pisano, Mercedes Robledo, Cristina Rodriguez-Antona
The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10(-9) to 3 × 10(-3))...
July 7, 2016: JCI Insight
Elizabeth A Nardi, Lisa Korin Lentz, Katherine Winckworth-Prejsnar, Amy P Abernethy, Robert W Carlson
When used effectively, health information technology (HIT) can transform clinical care and contribute to new research discoveries. Despite advances in HIT and increased electronic health record adoption, many challenges to optimal use, interoperability, and data sharing exist. Data standardization across systems is limited, and scanned medical note documents result in unstructured data that make reporting on quality measures for reimbursement burdensome. Different policies and initiatives, including the Health Information Technology for Economic and Clinical Health Act, the Medicare Access and CHIP Reauthorization Act, and the National Cancer Moonshot initiative, among others, all recognize the impact that HIT can have on cancer care...
October 2016: Journal of the National Comprehensive Cancer Network: JNCCN
Disha Pathak, Navriti Chadha, Om Silakari
Proto-oncogene receptor tyrosine kinase ROS-1 plays a key role in regulating a variety of cancers mainly non-small cell lung cancer (NSCLC). The marketed ROS-1 inhibitors such as Crizotinib suffer from the tribulations of growing resistance due to mutations primarily Gly2032Arg in the ROS-1 protein. To curb the problem of resistance, researchers have developed inhibitors such as Lorlatinib against the mutant protein. The present study was designed to identify inhibitors against wild type (WT) as well as mutant ROS-1 protein that will offer a broader spectrum of activity...
September 29, 2016: Journal of Molecular Graphics & Modelling
Benedikt Schaefgen, Jörg Heil, Hannah Richter, Aba Harcos, Christina Gomez, Anne Stieber, Christof Sohn, Michael Golatta
This article explores the ability of sonographically guided, vacuum-assisted minimally invasive biopsy (VAB) to detect and remove ceramic clip markers from breast tissue. This is a feasibility pre-study for a clinical study using vacuum-assisted biopsy to predict pathologic complete response of breast cancer. Twenty-six ceramic clip markers were placed in five turkey breasts. Clip markers were then detected sonographically and removed using VAB by experienced physicians. Quality of visibility was graded by the performing doctors...
September 29, 2016: Ultrasound in Medicine & Biology
Antonio Coluccia, Sara Passacantilli, Valeria Famiglini, Manuela Sabatino, Alexandros Patsilinakos, Rino Ragno, Carmela Mazzoccoli, Lorenza Sisinni, Alato Okuno, Osamu Takikawa, Romano Silvestri, Giuseppe La Regina
Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested. Among these, derivative 21 exhibited an IC50 value of 7 microM, being the most active compound of the series. Furthermore, compounds 5 and 21 induced a dose-dependent growth inhibition in IDO1 expressing cancer cell lines HTC116 and HT29...
October 3, 2016: Journal of Medicinal Chemistry
Thomas C A Smith, Antony M Carr, Adam C Eyre-Walker
Across independent cancer genomes it has been observed that some sites have been recurrently hit by single nucleotide variants (SNVs). Such recurrently hit sites might be either (i) drivers of cancer that are postively selected during oncogenesis, (ii) due to mutation rate variation, or (iii) due to sequencing and assembly errors. We have investigated the cause of recurrently hit sites in a dataset of >3 million SNVs from 507 complete cancer genome sequences. We find evidence that many sites have been hit significantly more often than one would expect by chance, even taking into account the effect of the adjacent nucleotides on the rate of mutation...
2016: PeerJ
Angélique Vétillard, Wafa Bouzid
Animal venoms are complex mixtures containing simple organic molecules, proteins, peptides, and other bioactive elements with extraordinary biological properties associated with their ability to act on a number of molecular receptors in the process of incapacitating their target organisms. In such a context, arthropod venoms are invaluable sources of bioactive substances, with therapeutic interest but the limited availability of some venom such as those from ants, has restricted the potential that these biomolecules could represent...
2016: Biologie Aujourd'hui
Suraj Peri, Elena Caretti, Rossella Tricarico, Karthik Devarajan, Mitchell Cheung, Eleonora Sementino, Craig W Menges, Emmanuelle Nicolas, Lisa A Vanderveer, Sharon Howard, Peggy Conrad, James A Crowell, Kerry S Campbell, Eric A Ross, Andrew K Godwin, Anthony T Yeung, Margie L Clapper, Robert G Uzzo, Elizabeth P Henske, Christopher J Ricketts, Cathy D Vocke, W Marston Linehan, Joseph R Testa, Alfonso Bellacosa, Levy Kopelovich, Alfred G Knudson
Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC)...
September 22, 2016: Oncotarget
Terry D Crawford, F Anthony Romero, Kwong Wah Lai, Vickie Tsui, Alexander M Taylor, Gladys de Leon Boenig, Cameron L Noland, Jeremy Murray, Justin Ly, Edna F Choo, Thomas L Hunsaker, Emily W Chan, Mark Merchant, Samir Kharbanda, Karen E Gascoigne, Susan Kaufman, Maureen H Beresini, Jiangpeng Liao, Wenfeng Liu, Kevin X Chen, Zhongguo Chen, Andrew R Conery, Alexandre Côté, Hariharan Jayaram, Ying Jiang, James R Kiefer, Tracy Kleinheinz, Yingjie Li, Jonathan Maher, Eneida Pardo, Florence Poy, Kerry L Spillane, Fei Wang, Jian Wang, Xiaocang Wei, Zhaowu Xu, Zhongya Xu, Ivana Yen, Laura Zawadzke, Xiaoyu Zhu, Steven Bellon, Richard Cummings, Andrea G Cochran, Brian K Albrecht, Steven Magnuson
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0...
September 28, 2016: Journal of Medicinal Chemistry
Elliott J Brea, Claire Y Oh, Eusebio Manchado, Sadna Budhu, Ron S Gejman, George Mo, Patrizia Mondello, James E Han, Casey A Jarvis, David Ulmert, Qing Xiang, Aaron Y Chang, Ralph J Garippa, Taha Merghoub, Jedd D Wolchok, Neal Rosen, Scott W Lowe, David A Scheinberg
The major histocompatibility complex I (MHC-I) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped...
September 28, 2016: Cancer Immunology Research
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