DOCSLIB.ORG

Exploring the Therapeutic Potential of Protein Tyrosine Phosphatase Inhibition in Neuroblastoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Exploring the therapeutic potential of protein tyrosine phosphatase inhibition in neuroblastoma Elsa Irving University College London Great Ormond Street Institute of Child Health A thesis submitted for the degree of Doctor of Philosophy 1 I, Elsa Irving, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Neuroblastoma accounts for 15% of paediatric cancer deaths and there is an urgent need for improved therapeutic strategies. Phosphotyrosine signalling, regulated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is critical for virtually all aspects of cell behaviour, and is commonly perturbed in cancer. We have previously shown that pan-inhibition of PTPs using oxidovanadium induces cytotoxicity in a panel of neuroblastoma cell lines. We therefore hypothesise that there exist specific PTPs that promote tumour cell survival, and that their specific or pan-inhibition may be beneficial for the treatment of neuroblastoma. Whilst promising preclinical data using vanadium-derived compounds in in vitro and in vivo models of cancer has been reported, clinical trials have been prevented in part due to concerns surrounding off-target tissue toxicity. I have taken several approaches to harness the cytotoxic properties of oxidovanadium, and PTP inhibition, with the aim to develop new therapeutic strategies for neuroblastoma. The tumour-promoting roles of specific PTPs were investigated using loss-of-function approaches including RNAi and CRISPR/Cas9 gene knockout. The dual specificity phosphatase CDC14B was identified as a potential candidate, although further validation studies need to be considered for this enzyme to be taken forward as a potential therapeutic target. In a parallel study, the first genome-wide transcriptomic analysis in neuroblastoma cells treated with oxidovanadium has revealed a potential role for cAMP signalling in bismaltolato oxidovanadium (BMOV)-induced cytotoxicity. This pathway and others that are affected by oxidovanadium may be a source of useful therapeutic targets for neuroblastoma in the future. Finally, I have shown for the first time that hydrophobic oxidovanadium can be packaged into liposomes and maintains its cytotoxicity when delivered to neuroblastoma cells. This presents a novel opportunity to deliver vanadium with potentially fewer safety concerns, whilst retaining its broad activity and high levels of anti-cancer efficacy. 3 Impact Statement The aim of this project was to explore the potential of targeting protein tyrosine phosphatase (PTP) signalling for the treatment of neuroblastoma and to deliver new conceptual approaches and opportunities for future therapies. We believe that there is enormous therapeutic potential in targeting PTPs. These enzymes, along with their functional partners, protein tyrosine kinases, are responsible for the regulation of tyrosine phosphorylation, which is vital for proper cell function, and its deregulation is implicated in a broad spectrum of human diseases including cancer. PTPs are increasingly being positively implicated in tumourigenesis and cancer progression, and several have now been labelled as bona fide oncogenes in several tumour types including neuroblastoma. We therefore suggest that therapeutic inhibition of these, and other yet to be identified PTPs, will be useful in developing much needed improved therapeutic strategies for high-risk neuroblastoma. Here I present data indicating that targeting of specific pro-tumour PTPs, as well as pan-PTP inhibition using vanadium-derived compounds may be of benefit for neuroblastoma treatment. I utilised genomic technologies including siRNA and shRNA-mediated gene knockdown, and CRISPR/Cas9-mediated gene deletion, to identify specific PTPs that are required for growth and/or survival of neuroblastoma cell lines. If confirmed in vivo, therapeutic targeting of these enzymes may have significant clinical impact. Vanadium-derived compounds are considered broad-spectrum inhibitors of the entire PTP superfamily and have been of interest in disease research including cancer for many decades. Despite considerable research efforts reporting anti-cancer activity in in vitro and in vivo tumour models, and even human clinical trials in the diabetes setting, vanadium compounds have yet to achieve clinical approval, due in part to concerns regarding the safety of their use in humans. Here I attempted to deconvolute the mechanisms driving oxidovanadium cytotoxicity, using genome-wide transcriptomics. These data revealed a broad range of transcriptional changes, suggesting that several effector pathways likely contribute to the observed cytotoxicity. One such 4 pathway was identified as cAMP signalling, and early validation suggests that cAMP signalling is activated by oxidovanadium and may be involved in cytotoxicity. Targeting of this pathway and other oxidovanadium effectors may be useful in the treatment of neuroblastoma. Both the targeting of specific pro-tumour PTPs and BMOV effectors are reductionist approaches to harness the cytotoxicity associated with oxidovanadium-mediated pan-PTP inhibition. An alternative approach is the therapeutic use of oxidovanadium itself. Here I present a novel hydrophobic oxidovanadium liposomal formulation that can be delivered to neuroblastoma cells in culture. This nanoparticle formulation may allow safer delivery of oxidovanadium to tumour cells in vivo, both by enhancing the efficiency of delivery and reducing off-target tissue toxicities. These formulations may be useful not only in the treatment of neuroblastoma but also in other cancers, as well as other diseases related to PTP signalling, namely diabetes, where vanadium-derived compounds have previously been trialled. My research will therefore raise the profile of PTP signalling as a therapeutic target in the cancer field and will also promote new thinking about how to utilize the cytotoxic potential of oxidovanadium for cancer and other disease treatment. 5 Acknowledgements I would first like to thank Andy Stoker. Your calming influence, patience, enthusiasm, and willingness to help is inspirational, and I truly couldn’t have hoped for a better supervisor. I also owe a huge thank you to Vruti Patel. I am so glad that you joined the lab, your advice, and let’s face it counselling, really has helped me through to the end! I am also very grateful for the help of many other scientists based at ICH. In particular, thank you to JP for his support and advice, Aris and Ruhina for synthesising my liposomes, and Simon and Mike for their help with HPLC. I have made great friends during my time at ICH, who have supported me enormously. I’d especially like to thank all ‘residents’ of office W2.04 past and present. Amy, Vruti, Aara, Lisa, and Elliot, you are all fantastic people and you deserve medals for putting up with me during writing this thesis! Lucy, we’ve been in it together since day one, and we’ve done it! (And Amy you will too!). I hope I will be lucky enough to work with a group of people just as fun, driven, kind, and coffee and cake dependent again. Most importantly, thank you to my amazing family and friends in London and further afield, who have supported me unconditionally. Catherine, you’ve been my cheer leader! Thank you for your pep talks over coffee and breakfast, you’ve kept me sane (ish!). I will be forever grateful to the Flahertys for welcoming me into their wonderful home and providing me with endless fun and distraction. I have been so lucky to come home to supportive family, lovely food and a comforting home every day. Owen, thank you for always telling me I can do this and for reminding me that ‘No stress is best!’. 2018 has been a very challenging year but, thanks to you, also one of my best! Alice, you know me better than I know myself, and never fail to make me smile during meltdowns, however ridiculous they may seem! You and Dicken have been inspiring and encouraging me for my whole life, and this PhD has been no different. Finally, thank you to my parents. Mum and John, you have supported me in everything I have achieved, and have always told me I can do anything I put my mind to. I love you both, and if there is one thing I know, it is that this PhD would not have been possible without your love and support. 6 Table of contents Abstract ........................................................................................................ 3 Impact Statement ......................................................................................... 4 Acknowledgements ..................................................................................... 6 List of figures ............................................................................................. 12 List of tables ............................................................................................... 12 Abbreviations ............................................................................................. 17 Chapter 1. Introduction.............................................................................. 21 1.1. Neuroblastoma .................................................................................. 22 1.1.1. Incidence and clinical presentation ............................................. 22 1.1.2. Disease classification and treatment ........................................... 24 1.1.3. MYCN amplification ...................................................................
Recommended publications
  • Clinical and Biological Features of PTPN2-Deleted Adult and Pediatric T-Cell Acute Lymphoblastic Leukemia

    Clinical and Biological Features of PTPN2-Deleted Adult and Pediatric T-Cell Acute Lymphoblastic Leukemia

    REGULAR ARTICLE Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia Marion Alcantara,1 Mathieu Simonin,1-3 Ludovic Lhermitte,1 Aurore Touzart,1 Marie Emilie Dourthe,1,4 Mehdi Latiri,1 Nathalie Grardel,5 Jean Michel Cayuela,6 Yves Chalandon,7 Carlos Graux,8 Herve´ Dombret,9 Norbert Ifrah,10 Arnaud Petit,2,3 Elizabeth Macintyre,1 Andre´ Baruchel,4 Nicolas Boissel,9 and Vahid Asnafi1 1Universite´ Paris Descartes Sorbonne Cite,´ Institut Necker-Enfants Malades, Institut National de Recherche Medicale´ U1151, Laboratory of Onco-Hematology, Assistance Publique–Hopitauxˆ de Paris, Hopitalˆ Necker Enfants-Malades, Paris, France; 2Department of Pediatric Hematology and Oncology, Assistance Publique–Hopitauxˆ de Paris, Groupe Hospitalier des Hopitauxˆ Universitaires Est Parisien, Armand Trousseau Hospital, Paris, France; 3Sorbonne Universites,´ Universite´ Pierre et Marie Curie Universite´ Paris 06, Unite´ Mixte de Recherche S 938, Centre de Recherche Saint-Antoine, Groupe de Recherche (GRC) Clinique n°07, GRC Myeloprolif´ erations´ aigues¨ et chroniques, Paris, France; 4Department of Pediatric Hematology and Immunology, Assistance Publique–Hopitauxˆ de Paris, Hopitalˆ Universitaire Robert-Debre,´ Paris, France; 5Laboratory of Hematology, Centre Hospitalier Regional´ Universitaire de Lille, Lille, France; 6Laboratory of Hematology, Saint-Louis Hospital, Assistance Publique–Hopitauxˆ de Paris, Paris, France; 7Swiss Group for Clinical Cancer Research, Bern, Hopitalˆ Universitaire, Geneva, Switzerland; 8Universite´ Catholique de Louvain, Centre Hospitalier Universitaire, Namur, Yvoir, Belgium; 9Adolescent and Young Adult Hematology Unit, Saint-Louis Hospital, Assistance Publique–Hopitauxˆ de Paris, Paris, France; and 10Centre Hospitalier Universitaire d’Angers, Angers, France Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be Key Points a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL).
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
  • Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase As a Molecular Target for Ovarian Cancer

    Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase As a Molecular Target for Ovarian Cancer

    biomolecules Article Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer John S. Lazo 1,2,* , Elizabeth R. Sharlow 1,2,*, Robert Cornelison 1,2, Duncan J. Hart 1, Danielle C. Llaneza 1, Anna J. Mendelson 1, Ettore J. Rastelli 3 , Nikhil R. Tasker 3, Charles N. Landen, Jr. 4 and Peter Wipf 3 1 Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; [email protected] (R.C.); [email protected] (D.J.H.); [email protected] (D.C.L.); [email protected] (A.J.M.) 2 KeViRx, Inc., Charlottesville, VA 22904, USA 3 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (E.J.R.); [email protected] (N.R.T.); [email protected] (P.W.) 4 Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA 22908, USA; [email protected] * Correspondence: [email protected] or [email protected] (J.S.L.); [email protected] (E.R.S.); Tel.: +1-434-243-1936 (J.S.L.); +1-434-243-1937 (E.R.S.) Abstract: High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines Citation: Lazo, J.S.; Sharlow, E.R.; compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor Cornelison, R.; Hart, D.J.; Llaneza, and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of D.C.; Mendelson, A.J.; Rastelli, E.J.; JMS-053-based analogs in OvCa cell line-based phenotypic assays.
  • Review Article PTEN Gene: a Model for Genetic Diseases in Dermatology

    Review Article PTEN Gene: a Model for Genetic Diseases in Dermatology

    The Scientific World Journal Volume 2012, Article ID 252457, 8 pages The cientificWorldJOURNAL doi:10.1100/2012/252457 Review Article PTEN Gene: A Model for Genetic Diseases in Dermatology Corrado Romano1 and Carmelo Schepis2 1 Unit of Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, 94018 Troina, Italy 2 Unit of Dermatology, I.R.C.C.S. Associazione Oasi Maria Santissima, 94018 Troina, Italy Correspondence should be addressed to Carmelo Schepis, [email protected] Received 19 October 2011; Accepted 4 January 2012 Academic Editors: G. Vecchio and H. Zitzelsberger Copyright © 2012 C. Romano and C. Schepis. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PTEN gene is considered one of the most mutated tumor suppressor genes in human cancer, and it’s likely to become the first one in the near future. Since 1997, its involvement in tumor suppression has smoothly increased, up to the current importance. Germline mutations of PTEN cause the PTEN hamartoma tumor syndrome (PHTS), which include the past-called Cowden, Bannayan- Riley-Ruvalcaba, Proteus, Proteus-like, and Lhermitte-Duclos syndromes. Somatic mutations of PTEN have been observed in glioblastoma, prostate cancer, and brest cancer cell lines, quoting only the first tissues where the involvement has been proven. The negative regulation of cell interactions with the extracellular matrix could be the way PTEN phosphatase acts as a tumor suppressor. PTEN gene plays an essential role in human development. A recent model sees PTEN function as a stepwise gradation, which can be impaired not only by heterozygous mutations and homozygous losses, but also by other molecular mechanisms, such as transcriptional regression, epigenetic silencing, regulation by microRNAs, posttranslational modification, and aberrant localization.
  • Inflammatory Cytokine Signalling by Protein Tyrosine Phosphatases in Pancreatic Β-Cells

    Inflammatory Cytokine Signalling by Protein Tyrosine Phosphatases in Pancreatic Β-Cells

    59 4 W J STANLEY and others PTPN1 and PTPN6 modulate 59: 4 325–337 Research cytokine signalling in β-cells Differential regulation of pro- inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells William J Stanley1,2, Prerak M Trivedi1,2, Andrew P Sutherland1, Helen E Thomas1,2 and Esteban N Gurzov1,2,3 Correspondence should be addressed 1 St. Vincent’s Institute of Medical Research, Melbourne, Australia to E N Gurzov 2 Department of Medicine, St. Vincent’s Hospital, The University of Melbourne, Melbourne, Australia Email 3 ULB Center for Diabetes Research, Universite Libre de Bruxelles (ULB), Brussels, Belgium esteban.gurzov@unimelb. edu.au Abstract Type 1 diabetes (T1D) is characterized by the destruction of insulin-producing β-cells Key Words by immune cells in the pancreas. Pro-inflammatory including TNF-α, IFN-γ and IL-1β f pancreatic β-cells are released in the islet during the autoimmune assault and signal in β-cells through f protein tyrosine phosphorylation cascades, resulting in pro-apoptotic gene expression and eventually phosphatases β-cell death. Protein tyrosine phosphatases (PTPs) are a family of enzymes that regulate f PTPN1 phosphorylative signalling and are associated with the development of T1D. Here, we f PTPN6 observed expression of PTPN6 and PTPN1 in human islets and islets from non-obese f cytokines diabetic (NOD) mice. To clarify the role of these PTPs in β-cells/islets, we took advantage f inflammation Journal of Molecular Endocrinology of CRISPR/Cas9 technology and pharmacological approaches to inactivate both proteins. We identify PTPN6 as a negative regulator of TNF-α-induced β-cell death, through JNK- dependent BCL-2 protein degradation.
  • Molecular and Genetic Medicine

    Molecular and Genetic Medicine

    Bertazzi et al., J Mol Genet Med 2015, 8:2 Molecular and Genetic Medicine http://dx.doi.org/10.4172/1747-0862.1000116 Review Article Open Access Myotubularin MTM1 Involved in Centronuclear Myopathy and its Roles in Human and Yeast Cells Dimitri L. Bertazzi#, Johan-Owen De Craene# and Sylvie Friant* Department of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg and CNRS, France #Authors contributed equally to this work. *Corresponding author: Friant S, Department of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg and CNRS, 67084 Strasbourg, France, E-mail: [email protected] Received date: April 17, 2014; Accepted date: July 21, 2014; Published date: July 28, 2014 Copyright: © 2014 Bertazzi DL, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Mutations in the MTM1 gene, encoding the phosphoinositide phosphatase myotubularin, are responsible for the X-linked centronuclear myopathy (XLCNM) or X-linked myotubular myopathy (XLMTM). The MTM1 gene was first identified in 1996 and its function as a PtdIns3P and PtdIns(,5)P2 phosphatase was discovered in 2000. In recent years, very important progress has been made to set up good models to study MTM1 and the XLCNM disease such as knockout or knockin mice, the Labrador Retriever dog, the zebrafish and the yeast Saccharomyces cerevisiae. These helped to better understand the cellular function of MTM1 and of its four conserved domains: PH-GRAM (Pleckstrin Homology-Glucosyltransferase, Rab-like GTPase Activator and Myotubularin), RID (Rac1-Induced recruitment Domain), PTP/DSP (Protein Tyrosine Phosphatase/Dual-Specificity Phosphatase) and SID (SET-protein Interaction Domain).
  • The Expression Patterns and the Prognostic Roles of PTPN Family Members in Digestive Tract Cancers

    The Expression Patterns and the Prognostic Roles of PTPN Family Members in Digestive Tract Cancers

    Preprint: Please note that this article has not completed peer review. The expression patterns and the prognostic roles of PTPN family members in digestive tract cancers CURRENT STATUS: UNDER REVIEW Jing Chen The First Affiliated Hospital of China Medical University Xu Zhao Liaoning Vocational College of Medicine Yuan Yuan The First Affiliated Hospital of China Medical University Jing-jing Jing The First Affiliated Hospital of China Medical University [email protected] Author ORCiD: https://orcid.org/0000-0002-9807-8089 DOI: 10.21203/rs.3.rs-19689/v1 SUBJECT AREAS Cancer Biology KEYWORDS PTPN family members, digestive tract cancers, expression, prognosis, clinical features 1 Abstract Background Non-receptor protein tyrosine phosphatases (PTPNs) are a set of enzymes involved in the tyrosyl phosphorylation. The present study intended to clarify the associations between the expression patterns of PTPN family members and the prognosis of digestive tract cancers. Method Expression profiling of PTPN family genes in digestive tract cancers were analyzed through ONCOMINE and UALCAN. Gene ontology enrichment analysis was conducted using the DAVID database. The gene–gene interaction network was performed by GeneMANIA and the protein–protein interaction (PPI) network was built using STRING portal couple with Cytoscape. Data from The Cancer Genome Atlas (TCGA) were downloaded for validation and to explore the relationship of the PTPN expression with clinicopathological parameters and survival of digestive tract cancers. Results Most PTPN family members were associated with digestive tract cancers according to Oncomine, Ualcan and TCGA data. For esophageal carcinoma (ESCA), expression of PTPN1, PTPN4 and PTPN12 were upregulated; expression of PTPN20 was associated with poor prognosis.
  • The Regulatory Roles of Phosphatases in Cancer

    The Regulatory Roles of Phosphatases in Cancer

    Oncogene (2014) 33, 939–953 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW The regulatory roles of phosphatases in cancer J Stebbing1, LC Lit1, H Zhang, RS Darrington, O Melaiu, B Rudraraju and G Giamas The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies. Oncogene (2014) 33, 939–953; doi:10.1038/onc.2013.80; published online 18 March 2013 Keywords: cancer; phosphatases; solid tumours GASTROINTESTINAL MALIGNANCIES abs in sera were significantly associated with poor survival in Oesophageal cancer advanced ESCC, suggesting that they may have a clinical utility in Loss of PTEN (phosphatase and tensin homologue deleted on ESCC screening and diagnosis.5 chromosome 10) expression in oesophageal cancer is frequent, Cao et al.6 investigated the role of protein tyrosine phosphatase, among other gene alterations characterizing this disease. Zhou non-receptor type 12 (PTPN12) in ESCC and showed that PTPN12 et al.1 found that overexpression of PTEN suppresses growth and protein expression is higher in normal para-cancerous tissues than induces apoptosis in oesophageal cancer cell lines, through in 20 ESCC tissues.
  • Targeting Protein Tyrosine Phosphatases in Cancer Lakshmi Reddy Bollu, Abhijit Mazumdar, Michelle I

    Targeting Protein Tyrosine Phosphatases in Cancer Lakshmi Reddy Bollu, Abhijit Mazumdar, Michelle I

    Published OnlineFirst January 13, 2017; DOI: 10.1158/1078-0432.CCR-16-0934 Molecular Pathways Clinical Cancer Research Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer Lakshmi Reddy Bollu, Abhijit Mazumdar, Michelle I. Savage, and Powel H. Brown Abstract The aberrant activation of oncogenic signaling pathways is a act as tumor suppressor genes by terminating signal responses universal phenomenon in cancer and drives tumorigenesis and through the dephosphorylation of oncogenic kinases. More malignant transformation. This abnormal activation of signal- recently, it has become clear that several PTPs overexpressed ing pathways in cancer is due to the altered expression of in human cancers do not suppress tumor growth; instead, they protein kinases and phosphatases. In response to extracellular positively regulate signaling pathways and promote tumor signals, protein kinases activate downstream signaling path- development and progression. In this review, we discuss both ways through a series of protein phosphorylation events, ulti- types of PTPs: those that have tumor suppressor activities as mately producing a signal response. Protein tyrosine phospha- well as those that act as oncogenes. We also discuss the tases (PTP) are a family of enzymes that hydrolytically remove potential of PTP inhibitors for cancer therapy. Clin Cancer Res; phosphate groups from proteins. Initially, PTPs were shown to 23(9); 1–7. Ó2017 AACR. Background in cancer and discuss the current status of PTP inhibitors for cancer therapy. Signal transduction is a complex process that transmits extra- PTPs belong to a superfamily of enzymes that hydrolytically cellular signals effectively through a cascade of events involving remove phosphate groups from proteins (2).
  • (12) United States Patent (10) Patent No.: US 7,662,770 B2 Kinch (45) Date of Patent: Feb

    (12) United States Patent (10) Patent No.: US 7,662,770 B2 Kinch (45) Date of Patent: Feb

    USOO766277OB2 (12) United States Patent (10) Patent No.: US 7,662,770 B2 Kinch (45) Date of Patent: Feb. 16, 2010 (54) LOW MOLECULARWEIGHT PROTEIN WO WOO1? 12172 A1 2, 2001 TYROSINE PHOSPHATASE (LMW-PTP) ASA WO WO 01/12840 A2 2, 2001 DAGNOSTIC AND THERAPEUTIC TARGET WO WOO3,O94859 A2 11/2003 WO WOO3,O993 13 A1 12/2003 75 WO WO 2004/O14292 A2 2, 2004 (75) Inventor: Michael S. Kinch, Laytonville, MD WO WO 2004/O14292 A3 2, 2004 WO WO 2005/051307 A2 6, 2005 (73) Assignee: Purdue Research Foundation, West W W SE A. 3. LaFayette, IN (US) WO WO 2005/055948 A3 6, 2005 - WO WO 2005/056766 A2 6, 2005 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 350 days. Carles-Kinchet al., “Antibody targeting of the EphA2tyrosine kinase inhibits malignant cell behavior.” May 15, 2002 Cancer Research (21) Appl. No.: 10/515,358 62(10):2840-2847. Parket al., “Low-molecular-weight protein tyrosine phosphatase is a (22) PCT Filed: May 22, 2003 positive component of the fibroblast growth factor receptor signaling pathway.” May 15, 2002 Molecular and Cellular Biology (86). PCT No.: PCT/USO3A16269 22(10):3404-3414. Souza et al., “From immune response to cancer: a spot on the low S371 (c)(1), molecular weight protein tyrosine phosphatase.” Apr. 2009 Cellular (2), (4) Date: Aug. 11, 2005 and Molecular Life Sciences 66(6):1140-1153. Available online on Nov. 11, 2008. (87) PCT Pub.
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease

    Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease

    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................
  • Application of Microrna Database Mining in Biomarker Discovery and Identification of Therapeutic Targets for Complex Disease

    Application of Microrna Database Mining in Biomarker Discovery and Identification of Therapeutic Targets for Complex Disease

    Article Application of microRNA Database Mining in Biomarker Discovery and Identification of Therapeutic Targets for Complex Disease Jennifer L. Major, Rushita A. Bagchi * and Julie Pires da Silva * Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; [email protected] * Correspondence: [email protected] (R.A.B.); [email protected] (J.P.d.S.) Supplementary Tables Methods Protoc. 2021, 4, 5. https://doi.org/10.3390/mps4010005 www.mdpi.com/journal/mps Methods Protoc. 2021, 4, 5. https://doi.org/10.3390/mps4010005 2 of 25 Table 1. List of all hsa-miRs identified by Human microRNA Disease Database (HMDD; v3.2) analysis. hsa-miRs were identified using the term “genetics” and “circulating” as input in HMDD. Targets CAD hsa-miR-1 Targets IR injury hsa-miR-423 Targets Obesity hsa-miR-499 hsa-miR-146a Circulating Obesity Genetics CAD hsa-miR-423 hsa-miR-146a Circulating CAD hsa-miR-149 hsa-miR-499 Circulating IR Injury hsa-miR-146a Circulating Obesity hsa-miR-122 Genetics Stroke Circulating CAD hsa-miR-122 Circulating Stroke hsa-miR-122 Genetics Obesity Circulating Stroke hsa-miR-26b hsa-miR-17 hsa-miR-223 Targets CAD hsa-miR-340 hsa-miR-34a hsa-miR-92a hsa-miR-126 Circulating Obesity Targets IR injury hsa-miR-21 hsa-miR-423 hsa-miR-126 hsa-miR-143 Targets Obesity hsa-miR-21 hsa-miR-223 hsa-miR-34a hsa-miR-17 Targets CAD hsa-miR-223 hsa-miR-92a hsa-miR-126 Targets IR injury hsa-miR-155 hsa-miR-21 Circulating CAD hsa-miR-126 hsa-miR-145 hsa-miR-21 Targets Obesity hsa-mir-223 hsa-mir-499 hsa-mir-574 Targets IR injury hsa-mir-21 Circulating IR injury Targets Obesity hsa-mir-21 Targets CAD hsa-mir-22 hsa-mir-133a Targets IR injury hsa-mir-155 hsa-mir-21 Circulating Stroke hsa-mir-145 hsa-mir-146b Targets Obesity hsa-mir-21 hsa-mir-29b Methods Protoc.