DOCSLIB.ORG

Molecular Interactions of Erbb Receptor Tyrosine Kinases and Integrin Β1: Implications for Tumor Therapy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Interactions of Erbb Receptor Tyrosine Kinases and Integrin Β1: Implications for Tumor Therapy THESIS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (Ph.D.) Molecular interactions of ErbB receptor tyrosine kinases and integrin β1: implications for tumor therapy by Miklós Petrás Supervisor: Prof. János Szöllősi, D.Sc. Álmos Klekner, Ph.D. UNIVERSITY OF DEBRECEN DOCTORAL SCHOOL OF MOLECULAR MEDICINE DEBRECEN, 2013 Molecular interactions of ErbB receptor tyrosine kinases and integrin β1: implications for tumor therapy Miklós Petrás Ph.D. Thesis UNIVERSITY OF DEBRECEN MEDICAL AND HEALTH SCIENCE CENTER DEPARTMENT OF BIOPHYSICS AND CELL BIOLOGY DEPARTMENT OF NEUROSURGERY DEBRECEN, 2013. 2 Ph. D. thesis data Title: Molecular interactions of ErbB receptor tyrosine kinases and integrin β1: implications for tumor therapy Author: Miklós Petrás, M.D. Supervisors: Prof. János Szöllősi, D.Sc. Álmos Klekner, M.D., Ph.D. Doctoral School: "Molecular Medicine" at the University of Debrecen Head of Doctoral School: Prof. László Csernoch, D.Sc. Doctoral examination committee: Chairman: Prof. László Csernoch, D.Sc. Members: Prof. Ferenc Erdődi, D.Sc. Beáta Bugyi, Ph.D. Place and time of doctoral examination: Debrecen, 3 May 2013 Doctoral thesis committee: Chairman: Prof. László Csernoch, D.Sc. Reviewers: Prof. István Jóna, D.Sc. József Tóvári, Ph.D. Members: Prof. Ferenc Erdődi, D.Sc. Beáta Bugyi, Ph.D. Place and time of thesis defence: Debrecen, 3 May 2013 Key words: ErbB (EGFR), integrin, tyrosine kinase, FRET, trastuzumab, PI-3K/Akt, breast cancer, astrocytoma (glioblastoma) 3 "Because strait is the gate, and narrow is the way, which leadeth unto life, and few there be that find it." Matthew 7:14 Bible - King James Version, 1611 Oxford King James Bible (Authorized Version), 1769 4 CONTENTS ABBREVIATIONS ..................................................................................................................................... 7 1. INTRODUCTION................................................................................................................................... 9 2. MOLECULAR PATHOLOGY OF TUMORIGENESIS............................................................................. 11 2.1. The ErbB family of receptor tyrosine kinases.............................................................................11 2.2. The integrin family of cell adhesion molecules ..........................................................................13 2.3. Molecular markers and signal transduction pathways.................................................................15 2.4. Associations of ErbBs and interactions with integrin 1 ............................................................18 2.4.1. Homo- and heterodimerization of ErbB molecules ......................................................................... 18 2.4.2. Molecular interactions between ErbB and integrin 1 molecules .................................................. 19 2.5. Analysis of multi-faceted molecular interactions of membrane proteins....................................19 3. ERBB MOLECULES IN TUMOR DEVELOPMENT – THE MEDICAL ASPECT ..................................... 21 3.1. Alterations of ErbB2 in breast cancer .........................................................................................21 3.1.1. Epidemiology and diagnosis of breast cancers - a general outline................................................. 21 3.1.2. Treatment options for breast cancer ............................................................................................... 22 3.1.3. Therapy resistance to trastuzumab in the management of breast cancers ...................................... 23 3.2. Alterations of ErbB1 in astrocytoma...........................................................................................25 3.2.1. Epidemiology and diagnosis of astrocytomas - a general outline................................................... 25 3.2.2. Treatment options for astrocytoma.................................................................................................. 27 3.2.3. Therapy resistance to irradiation in the management of astrocytomas........................................... 28 4. OBJECTIVES...................................................................................................................................... 30 5. MATERIALS AND METHODS............................................................................................................. 31 5.1. Antibodies ...................................................................................................................................31 5.2. Labeling of cells with antibodies.................................................................................................32 5.3. Cell cultures.................................................................................................................................32 5.4. Fresh frozen sections...................................................................................................................33 5.5. Cellular Model Systems ..............................................................................................................33 5.5.1. Chromosome 7 transferred U251 NCI subclones............................................................................ 33 5.5.2. Stable erbB1 gene transfected U251 NCI subclones....................................................................... 34 5.6. Determination of radiosensitivity................................................................................................35 5.7. Flow cytometric determination of cell surface receptor expressions ..........................................36 5.8. Assessing the molecular interactions of ErbB and integrin molecules .......................................36 5.8.1. Fluorescence resonance energy transfer (FRET)............................................................................ 36 5.8.2. Flow cytometric fluorescence resonance energy transfer measurements (FCET) .......................... 37 5.8.3. Confocal microscopy....................................................................................................................... 38 5.8.4. Calculation of molecular colocalization ......................................................................................... 39 5.8.5. Acceptor photobleaching method (abFRET)................................................................................... 39 5.8.6. Donor photobleaching method (dbFRET)....................................................................................... 42 5.9. Stimulation of cells with EGF, heregulin and trastuzumab.........................................................43 5.10. Western blot analysis ................................................................................................................44 5.11. Statistical analysis .....................................................................................................................44 5 6. RESULTS............................................................................................................................................ 45 6.1. Interactions of ErbBs and integrin β1 on breast and gastric cancer cell lines.............................45 6.1.1. Lower ErbB2 expression is accompanied by higher integrin β1 levels........................................... 45 6.1.2. Colocalization of ErbB2, integrin β1 and lipid rafts upon treatments ............................................ 46 6.1.3. Crosslinking of integrin β1 or lipid rafts disrupts their colocalizations.......................................... 48 6.1.4. ErbB2 - integrin β1 interaction is independent of integrin β1 expression level .............................. 49 6.1.5. ErbB2-integrin β1 interaction do not alter trastuzumab-mediated phosphorylation ...................... 51 6.2. Associations of ErbBs are dynamically modulated by integrin β1 molecules -..........................52 application of the newly established two-sided FRET method..........................................................52 6.2.1. Excess integrin β1 inversely correlates with ErbB2 level on trastuzumab resistant cells............... 52 6.2.2. ErbB2 interactions are shifted towards heteroassociations with integrin β1.................................. 53 6.2.3. Model system for two-sided FRET (tsFRET)................................................................................... 54 6.2.4. Application of tsFRET: ErbB2 homoassociations are disintegrated by integrin β1 ....................... 57 6.2.5. Cell function related distribution of membrane receptors............................................................... 59 6.3. Molecular interactions of ErbB1 and integrin β1 molecules reliably predict clinical outcome and correlate with radioresistance of astrocytic tumors ..............................................................61 6.3.1. Higher ErbB1 and integrin β1 levels correlate with pronounced radioresistance.......................... 61 6.3.2. Overexpression of ErbB1 alone is also accompanied by higher integrin β1 levels......................... 62 6.3.3. Integrin β1 contributes to survival, whereas ErbB1 promotes colony forming ability.................... 62 6.3.4. Increased integrin β1 is critical for radioresistance avertible by inhibition of PI-3K .................... 63 6.3.5. ErbB1 interactions are shifted towards heteroassociations with integrin β1.................................. 64 FCET measurements: shift of balance towards ErbB1-integrin β1 heteroassociations............................ 64 tsFRET
Load more

Recommended publications
  • The Evolving Concept of Cancer and Metastasis Stem Cells
    JCB: Review The evolving concept of cancer and metastasis stem cells Irène Baccelli1,2 and Andreas Trumpp1,2 1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), D-69120 Heidelberg, Germany 2Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany The cancer stem cell (CSC) concept, which arose more review is to illustrate the current dynamic view of CSCs to fos- than a decade ago, proposed that tumor growth is sus- ter the development of better therapeutic approaches to target this highly complex and deadly disease. tained by a subpopulation of highly malignant cancerous cells. These cells, termed CSCs, comprise the top of the The classical concept of CSCs tumor cell hierarchy and have been isolated from many Adult regenerating tissues (such as the skin, the gastrointes- leukemias and solid tumors. Recent work has discovered tinal mucosa, or the hematopoietic system) are hierarchically Downloaded from that this hierarchy is embedded within a genetically het- organized (Murphy et al., 2005; Fuchs and Nowak, 2008; van erogeneous tumor, in which various related but distinct der Flier and Clevers, 2009; Seita and Weissman, 2010). At the top of the cellular organization, normal adult stem cells subclones compete within the tumor mass. Thus, geneti- maintain tissues during homeostasis and facilitate their regen- cally distinct CSCs exist on top of each subclone, revealing eration, for example in response to infection or to cell loss a highly complex cellular composition of tumors. The CSC due to injury. These physiological stem cells are defined by concept has therefore evolved to better model the complex their functional properties: they have the life-long capacity to jcb.rupress.org and highly dynamic processes of tumorigenesis, tumor self-renew (the ability to give rise to a new stem cell after cell relapse, and metastasis.
    [Show full text]
  • University of Groningen PET Imaging and in Silico Analyses to Support
    University of Groningen PET imaging and in silico analyses to support personalized treatment in oncology Moek, Kirsten DOI: 10.33612/diss.112978295 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2020 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Moek, K. (2020). PET imaging and in silico analyses to support personalized treatment in oncology. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.112978295 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 30-09-2021 06 The antibody-drug conjugate target landscape across a broad range of tumor types Kirsten L.
    [Show full text]
  • Review Article Cd44v6-Targeted Imaging of Head and Neck Squamous Cell Carcinoma: Antibody-Based Approaches
    Hindawi Contrast Media & Molecular Imaging Volume 2017, Article ID 2709547, 14 pages https://doi.org/10.1155/2017/2709547 Review Article CD44v6-Targeted Imaging of Head and Neck Squamous Cell Carcinoma: Antibody-Based Approaches Diana Spiegelberg1 and Johan Nilvebrant2 1 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden 2Division of Protein Technology, School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden Correspondence should be addressed to Diana Spiegelberg; [email protected] and Johan Nilvebrant; [email protected] Received 24 February 2017; Revised 23 April 2017; Accepted 21 May 2017; Published 20 June 2017 Academic Editor: Shasha Li Copyright © 2017 Diana Spiegelberg and Johan Nilvebrant. 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. Head and neck squamous cell carcinoma (HNSCC) is a common and severe cancer with low survival rate in advanced stages. Noninvasive imaging of prognostic and therapeutic biomarkers could provide valuable information for planning and monitoring of the different therapy options. Thus, there is a major interest in development of new tracers towards cancer-specific molecular targets to improve diagnostic imaging and treatment. CD44v6, an oncogenic variant of the cell surface molecule CD44, is a promising molecular target since it exhibits a unique expression pattern in HNSCC and is associated with drug- and radio-resistance. In this review we summarize results from preclinical and clinical investigations of radiolabeled anti-CD44v6 antibody-based tracers: full-length antibodies, Fab, F(ab )2 fragments, and scFvs with particular focus on the engineering of various antibody formats and choice of radiolabel for the use as molecular imaging agents in HNSCC.
    [Show full text]
  • Ep 3178848 A1
    (19) TZZ¥__T (11) EP 3 178 848 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 14.06.2017 Bulletin 2017/24 C07K 16/28 (2006.01) A61K 39/395 (2006.01) C07K 16/30 (2006.01) (21) Application number: 15198715.3 (22) Date of filing: 09.12.2015 (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AL AT BE BG CH CY CZ DE DK EE ES FI FR GB yet been filed GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Cueni, Leah Noëmi et al Designated Extension States: F. Hoffmann-La Roche AG BA ME Patent Department Designated Validation States: Grenzacherstrasse 124 MA MD 4070 Basel (CH) (71) Applicant: F. Hoffmann-La Roche AG 4070 Basel (CH) (54) TYPE II ANTI-CD20 ANTIBODY FOR REDUCING FORMATION OF ANTI-DRUG ANTIBODIES (57) The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent comprising administration of a Type II anti-CD20 antibody, e.g. obinutuzumab, to the subject prior to administration of the therapeutic agent. EP 3 178 848 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 178 848 A1 Description Field of the Invention 5 [0001] The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent.
    [Show full text]
  • Ep 3321281 A1
    (19) TZZ¥¥ _ __T (11) EP 3 321 281 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 16.05.2018 Bulletin 2018/20 C07K 14/79 (2006.01) A61K 38/40 (2006.01) A61K 38/00 (2006.01) A61K 38/17 (2006.01) (2006.01) (2006.01) (21) Application number: 17192980.5 A61K 39/395 A61K 39/44 C07K 16/18 (2006.01) (22) Date of filing: 03.08.2012 (84) Designated Contracting States: • TIAN, Mei Mei AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Coquitlam, BC V3J 7E6 (CA) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • VITALIS, Timothy PL PT RO RS SE SI SK SM TR Vancouver, BC V6Z 2N1 (CA) (30) Priority: 05.08.2011 US 201161515792 P (74) Representative: Gowshall, Jonathan Vallance Forresters IP LLP (62) Document number(s) of the earlier application(s) in Skygarden accordance with Art. 76 EPC: Erika-Mann-Strasse 11 12746240.6 / 2 739 649 80636 München (DE) (71) Applicant: biOasis Technologies Inc Remarks: Richmond BC V6X 2W8 (CA) •This application was filed on 25.09.2017 as a divisional application to the application mentioned (72) Inventors: under INID code 62. • JEFFERIES, Wilfred •Claims filed after the date of receipt of the divisional South Surrey, BC V4A 2V5 (CA) application (Rule 68(4) EPC). (54) P97 FRAGMENTS WITH TRANSFER ACTIVITY (57) The present invention is related to fragments of duction of the melanotransferrin fragment conjugated to human melanotransferrin (p97). In particular, this inven- a therapeutic or diagnostic agent to a subject.
    [Show full text]
  • Archivio Istituzionale Open Access Dell'università Di Torino Original
    AperTO - Archivio Istituzionale Open Access dell'Università di Torino Target therapies in recurrent or metastatic head and neck cancer: state of the art and novel perspectives. A systematic review This is a pre print version of the following article: Original Citation: Availability: This version is available http://hdl.handle.net/2318/1729977 since 2020-02-22T14:19:20Z Published version: DOI:10.1016/j.critrevonc.2019.05.002 Terms of use: Open Access Anyone can freely access the full text of works made available as "Open Access". Works made available under a Creative Commons license can be used according to the terms and conditions of said license. Use of all other works requires consent of the right holder (author or publisher) if not exempted from copyright protection by the applicable law. (Article begins on next page) 25 September 2021 Leonardo Muratori, Anna La Salvia, Paola Sperone, Massimo Di Maio Target therapies in recurrent or metastatic head and neck cancer: state of the art and novel perspectives. A systematic review. Abstract Recurrent or metastatic head and neck squamous-cell carcinomas (R/M HNSCC) are a group of cancers with a very poor prognosis. Many clinical trials testing novel target therapies in this setting are currently ongoing. We performed a systematic review focusing our attention on all clinical trials, ongoing or already published, concerning the use of novel drugs for treatment of R/M HNSCC. We found that the research of novel molecules effective in treatment of R/M HNSCC has been intense during last decade, and nowadays it is still very active.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0166697 A1 Bender (43) Pub
    US 2016O166697A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0166697 A1 Bender (43) Pub. Date: Jun. 16, 2016 (54) METHOD OF TREATING CANCER A619/00 (2006.01) A647/4 (2006.01) (71) Applicant: Intensity Therapeutics, Inc., Westport, A647/8 (2006.01) CT (US) A6II 45/06 (2006.01) A619/08 (2006.01) (72) Inventor: Lewis H. Bender, Redding, CT (US) A 6LX3/555 (2006.01) (52) U.S. Cl. (21) Appl. No.: 15/052,326 CPC. A61K47/12 (2013.01); A61 K9/08 (2013.01); 1-1. A61K 33/24 (2013.01); A61 K3I/555 (22) Filed: Feb. 24, 2016 (2013.01); A61 K47/14 (2013.01); A61K47/18 Related U.S. Application Data (2013.01); A61K 45/06 (2013.01); also (63) Continuation of application No. 14/280,036, filed on May 16, 2014, which is a continuation of application (57) ABSTRACT No. PCT/US2013/059841, filed on Sep. 15, 2013. The invention provides a method for treating cancer using a (60) Provisional application No. 61/779,509, filed on Mar. coadministration strategy that combines local codelivery of a 13, 2013, provisional application No. 61/707,733, therapeutic agent and an intracellular penetration enhancing filed on Sep. 28, 2012, provisional application No. agent, and optionally in further combination with local 61/703,890, filed on Sep. 21, 2012. administration of an immunotherapeutic agent, such as a cancer vaccine or NKTagonist. The invention also provides a Publication Classification method for treating cancer using an intracellular penetration enhancing agent. The methods of the invention aim to Sub (51) Int.
    [Show full text]
  • Investigating the Roles of CD44 and CD147 in Prostate Cancer Metastasis and Drug-Resistance
    Investigating the roles of CD44 and CD147 in prostate cancer metastasis and drug-resistance Jingli Hao A Thesis submitted for the Degree of Doctor of Philosophy St. George Clinical School Faculty of Medicine University of New South Wales April 2012 ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….................. COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only).
    [Show full text]
  • Immunogen, Inc. Regains Development and Commercialization Rights for Cantuzumab Mertansine
    ImmunoGen, Inc. Regains Development and Commercialization Rights for Cantuzumab Mertansine CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jan. 24, 2003--ImmunoGen, Inc. (Nasdaq: IMGN) today announced that the Company has regained the development and commercialization rights for cantuzumab mertansine (huC242-DM1), an anticancer product candidate. In 1999, the Company licensed these rights to SmithKline Beecham, which later became GlaxoSmithKline. Cantuzumab mertansine has been studied in Phase I clinical trials and found to be well tolerated. Initial evidence of biological activity also has been reported. ImmunoGen previously announced that GlaxoSmithKline had notified the Company that advancement of cantuzumab mertansine into Phase II studies was dependent on renegotiation of the product license agreement. Since then, the companies have been in negotiations. Mitchel Sayare, Ph.D., ImmunoGen Chairman and CEO, commented, "We've determined that it is not in the best interests of ImmunoGen to enter into a revised agreement with GlaxoSmithKline. ImmunoGen has regained all rights that were licensed to GlaxoSmithKline. We're excited about the prospects of licensing cantuzumab mertansine to a new marketing partner that would initiate a broad Phase II program for this important product candidate." No payments were made by either company for the return of the product rights to ImmunoGen. ImmunoGen holds the Investigational New Drug application (IND) for cantuzumab mertansine and has rights to all clinical data generated in the Phase I studies. The two companies will work together to ensure a smooth transition of all study data. Cantuzumab mertansine is a Tumor-Activated Prodrug (TAP) compound developed by ImmunoGen. It is composed of the humanized antibody huC242 and the cytotoxic agent DM1.
    [Show full text]
  • Considerations for the Nonclinical Safety Evaluation of Antibody–Drug Conjugates
    antibodies Review Considerations for the Nonclinical Safety Evaluation of Antibody–Drug Conjugates J. Edward Fisher, Jr. Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD 20993, USA; jedward.fi[email protected] Abstract: The targeted delivery of drugs by means of linking them to antibodies (Abs) to form antibody–drug conjugates (ADCs) has become an important approach in oncology and could po- tentially be used in other therapeutic areas. Targeted therapy is aimed at improving clinical efficacy while minimizing adverse reactions. The nonclinical safety assessment of ADCs presents several unique challenges involving the need to examine a complex molecule, each component of which can contribute to the effects observed, in appropriate animal models. Some considerations for the nonclinical safety evaluation of ADCs based on a literature review of ADCs in clinical development (currently or previously) are discussed. Keywords: antibody–drug conjugates; nonclinical safety studies; animal models; drivers of toxicity 1. Introduction In addition to the many therapeutic applications of unconjugated antibodies (Abs), the coupling of Abs to biologically active small molecules via chemical linkers to form antibody–drug conjugates (ADCs) has become an important strategy for increasing drug Citation: Fisher, J.E., Jr. specificity [1,2]. ADCs were initially developed to increase the effectiveness of chemother- Considerations for the Nonclinical apy and reduce its toxicity by delivering cytotoxic molecules directly to tumor cells while Safety Evaluation of Antibody–Drug avoiding damage to healthy cells. The majority of ADCs in clinical development combine Conjugates. Antibodies 2021, 10, 15. monoclonal Abs (mAbs) specific to surface antigens present on particular tumor cells https://doi.org/10.3390/antib10020015 with potent anti-cancer agents for oncology indications.
    [Show full text]
  • WO 2018/067987 Al 12 April 2018 (12.04.2018) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/067987 Al 12 April 2018 (12.04.2018) W !P O PCT (51) International Patent Classification: Published: A61K 39/00 (2006.01) A61K 47/22 (2006.01) — with international search report (Art. 21(3)) (21) International Application Number: — with sequence listing part of description (Rule 5.2(a)) PCT/US2017/055620 (22) International Filing Date: 06 October 2017 (06.10.2017) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 62/404,861 06 October 2016 (06.10.2016) US (71) Applicant: AMGEN INC. [US/US]; One Amgen Center Drive, Thousand Oaks, CA 91320-1799 (US). (72) Inventors: TERAN, Alona; 13715 Shenandoah Way, Moorpark, CA 93021 (US). MUNAIM, Qahera; 21025 Lemarsh Street, Unit #G42, Chatsworth, CA 913 11 (US). KHALAF, Nazer; 14 Lauf Street, Worcester, MA 01602 _ (US). KAUSHIK, Rahul, Rajan; 1660 Glider Court, Thou- = sand Oaks, CA 91320 (US). CLOGSTON, Christi, L.; = 601 Country View Place, Camarillo, CA 93010 (US). = CHRISTIAN, Twinkle, R.; 519 W. Gainsborough Road, = Apt. 303, Thousand Oaks, CA 91360 (US). CALLAHAN, — William, J.; 1104 Woodridge Avenue, Thousand Oaks, CA = 91362 (US). — (74) Agent: HONG, Julie, J. et al; Marshall, Gerstein Borun = LLP, 233 S. Wacker Drive, 6300 Willis Tower, Chicago, IL = 60606-6357 (US). = (81) Designated States (unless otherwise indicated, for every
    [Show full text]
  • Radioresistance in Head and Neck Squamous Cell Carcinoma — Possible Molecular Markers for Local Recurrence and New Putative Therapeutic Strategies
    Chapter 1 Radioresistance in Head and Neck Squamous Cell Carcinoma — Possible Molecular Markers for Local Recurrence and New Putative Therapeutic Strategies Federica Ganci, Andrea Sacconi, Valentina Manciocco, Giuseppe Spriano, Giulia Fontemaggi, Paolo Carlini and Giovanni Blandino Additional information is available at the end of the chapter http://dx.doi.org/10.5772/60081 1. Introduction Head and neck squamous cell carcinoma (HNSCC) comprises 5.5% of all incidence cancers and is the sixth leading cancer worldwide with approximately 600,000 cases reported annually [1, 2]. The vast majority of them are squamous cell carcinomas that originate in the epithelium of the oral cavity, pharynx and larynx. There is a higher incidence rate in males compared to females and the median age of patients with HNSCC is about 60 years [3]. The main risk factors for HNSCC are tobacco smoking and heavy use of alcohol. In particular, alcohol consumption and tobacco smoking have a synergic effect [4]. The contribution of tobacco exposure to HNSCC carcinogenesis is strongly correlated with the time and rate of the person who smokes and has showed to have site-specific differences according to the anatomical regions, with an increase in sensitivity from the oral cavity down to the larynx [5]. In addition, high-risk infection types of human papillomavirus (especially HPV-16 and 18) is emerging as a major cause of a subgroup of HNSCC, particularly those of the oropharynx and oral cavity [2, 6]. The traditional risk factors, tobacco and alcohol use, do not appear to play a contributing role in HPV-positive cancers [7].
    [Show full text]