DOCSLIB.ORG

Presentation: Yusuke Nakamura

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Presentation: Yusuke Nakamura From Cancer Genomics to Cancer Treatment : from hope to reality Yusuke Nakamura Human Genome Center Institute of Medical Science The University of Tokyo International HapMap Consortium October 27, 2005 Construction of public database for genetic variations in human Country Genotyping Center %Genome Chromosome Platform Japan RIKEN 24.3% 5, 11, 14, 15, 16, 17, 19 Third Wave Invader Wellcome Trust Sanger UK 23.7% 1, 6, 10, 13, 20 Illumina BeadArray Institute McGill Univ. / Genome Canada 10.1% 2, 4p Illumina BeadArray QuebecWe Innovation (The Centre SNP Research Center in RIKEN) Sequenom MassExtend, China Chinesecontributed HapMap Consortium the largest9.5% 3, SNP8p, 21 data (24.3%) contributed the largest SNP data (24.3%)Illumina BeadArray Illumina among the16.1% SNP 8q,typing 9, 18q, 22, centers X Illumina BeadArray Broad Institute of Harvard and in this paper Sequenom MassExtend, 9.7% 4q, 7q, 18p, Y, mtDNA MIT Illumina BeadArray USA Baylor College of Medicine 4.6% 12 ParAllele MIP PerkinElmer AcycloPrime- UCSF / Washington Univ. 2.0% 7p FP High-denstity Perlegen Sciences All oligonucleotide array Biobank Japan Sample Collection at February 29, 2008 Hyperlipidemia 42,354 Prostate cancer 5,839 Leukemia 1,597 Diabetes 39,982 Periodontitis 5,652 Esophageal cancer 1,461 Cataract 19,070 Pollinosis 5,572 Cervical caner 1,405 Cerebral infarction 16,012 Glaucoma 5,257 Hepatitis B 1,391 Arrhythmia 15,440 Lung cancer 4,845 Uterine corpus cancer 1,189 Stable angina pectoris 14,855 Unstable angina pectoris 4,161 Nephrotic syndrome 1,038 MyocardialWe Infarction have 12,956 genotyped Rheumatoid arthritis more than 4,155 Ovarian15,000 cancer patients 976 BronchialWe asthma have 8,657genotyped Atopic dermatitis more than2,967 Tuberculosis15,000 patients 894 Cardiac failure 7,438 COPDat 250K-550K 2,797SNPs Keloid 814 Breast cancer 7,349 Cerebral aneurysm 2,735 ALS 788 Colorectal cancer 6,957 Arteriosclerotic obliterans 2,609 ILD 780 Gastric cancerA 6,869 total Liver cirrhosisof 6-billion data-points.2,494 Drug-induced hypersensitivity 598 Urinary stone 6,605 Liver cancer 2,452 Pancreatic cancer 531 Osteoporosis 6,412 Hyperthyroidism 2,320 CCC 503 Myoma uteri 5,988 Epilepsy 2,250 Febrile seizures 475 Hepatitis C 5,962 Endometriosis 1,827 Total 295,278 ICIC askedasked 235,841 235,841 patientspatients TotalTotal Cases Cases 295,278 295,278 cases cases ICIC obtainedobtained 201,805 201,805 patientspatients WithdrawnWithdrawn 172 172 individuals individuals （（85.6%)85.6%) Genes isolated through genome-wide association studies in RIKEN and University of Tokyo Myocardial Infarction LTA Nature Genetics 2002 LGALS2 Nature 2004 PSMA6 Nature Genetics 2006 Rheumatoid Arthritis PADI4 Nature Genetics 2003 SLC22A4 Nature Genetics 2003 FcRH3 Nature Genetics 2005 Diabetic nephropathySLC12A3 Diabetes 2003 ELMO1 Diabetes 2005 (Diabetes) KCNQ1 Nature Genetics 2008 IgA nephropathy SEL-L,-E Am J Hum Genet 2002 Osteoarthritis Asporin Nature Genetics 2005 Calmodulin 1 Human Mol. Gen 2005 GDF5 Nature Genetics 2007 DVWA Nature Genetics 2008 Disc herniation CILP Nature Genetics 2005 Brain Infarction PRKCH1 Nature Genetics 2007 Kawasaki disease ITPKC Nature Genetics 2008 Crohn disease TNSF15 Human Mol. Gen 2005 Colon cancer multipel genes Nature Genetics 2008 Lung fibrosis TERT JMG 2008 Hapmap Nature 2003 Nature 2005 Nature 2007 From molecular targets to antianti-cancer-cancer drugs SMC Antibody Dominant-negative Target Peptide Molecules peptide Molecules vaccine Anti-sense DNA Cell Gene siRNA Therapy Therapy From molecular targets to antianti-cancer-cancer drugs SMC Antibody Dominant-negative Target Peptide Molecules peptide Molecules vaccine Anti-sense DNA Cell Gene siRNA Therapy Therapy IsolationIsolation ofof molecularmolecular targetstargets forfor cancercancer treatmenttreatment usingusing clinicalclinical materialsmaterials cDNA microarray consisting of 32,000 genes ComparisonComparison ofof expressionexpression ExpressionExpression profilesprofiles ofof profilesprofiles ofof cancercancer andand 3030 normalnormal humanhuman correspondingcorresponding normalnormal tissuestissues tissuestissues Selection of novel molecular targets DiagnosisDiagnosis TreatmentTreatment TumorTumor MarkerMarker SmallSmall molecularmolecular compoundcompound PredictionPrediction toto MonoclonalMonoclonal AntibodyAntibody chemosensitivitychemosensitivity PeptidePeptide VaccineVaccine siRNAsiRNA cDNAcDNA MicroarrayMicroarray systemsystem High-density spotting Cancer 20000 spots/glass Normal tissue tissue ＬＭＭ ＬＭＭ Cancer cells Normal ductal cells T7-based RNA Amplification T7-based RNA Amplification （2-rounds） （2-rounds） aRNA aRNA labeling labeling Cy5 Cy3 co-hybridization Number of clinical samples analyzed by cDNA microarray Tissue Number Tissue Number Lung 126 Bile duct 45 Breast 135 Uterus 44 Soft Tissue 101 ALL 25 AML 87 Kidney 25 Colon 78 Endometriosis 23 CML 84 Liver 20 Ovary 59 Pancreas 20 Malignant lymphoma 54 Melanoma 20 Prostate 54 Thyroid 20 Stomach 51 Neuroblastoma 16 Bladder 55 Testis 13 Eshophagus 45 TOTAL 1200 Criteria for selection of candidate targets for drug development (S) Small molecular compound (P) Peptide vaccine (R) siRNA (A) Antibody 1. Genes which were highly over-expressed in a large proportion of clinical cancer samples examined (S, P, R, A) 2. Genes which were expressed in none of important vital organs; ideally not expressed in any organs (S, P, R, A) 3. Genes whose expressions are essential for cell survival (S, R, A?) 4. Cytoplasmic membrane protein, Secreted protein (A) Development of anti-FZD10 antibody therapy for Synovial Sarcoma Chikako Fukukawa Satoshi Nagayama Toyomasa Katagiri Frizzled Homologue 10 (FZD10) RT-PCR C S SS S MFH LMS L M Synovial Sarcoma MPNST cell lines 123456789101112131514 16 17 18 19 20 21 22 23 24 25 26 27 28 FZD10 b2MG Northern Blotting SS CL Srug. Frizzled family (Wnt signal) Lung Kidney Brain Liver Heart Pancreas SS582 SS487 Placenta HS-SY-2 YaFuSS Bone marrow Bone Wnt? 9.5 7.5 SS cell 4.4 2.37 1.35 SS ; Synovial Sarcoma FZD10 Protein expression of FZD10 in colon cancer 03-24640 FZD10 expression in colon cancer 34 41 59 69 123 124 128 129 141 146 147 NTNTNTNTNTNTNTNTNTNPr MN Pr M FZD10 β2MG 149 150 151 153 154 155 201 NMPr NMPr NMPr NMPr NPPr NNTrSS FZD10 β2MG 04-26192 04-25950 Paraffin slides EDTA buffer (pH9.0) 125oC, 30sec α-FZD10 mAb 92-13 20μg/mL, 4oC, O/N Celler Immunization Monoclonal antibody recognizing a complex structure Cells (COS-7 etc.) transfection Ag pCAGGS-FZD10 (FL)-myc･His Immunization to mouse Monoclonal Antibody Hybrydoma Antibody stayed at tumor lesion at 5 days after injection InternalizationInternalization ofof anti-FDZ10anti-FZD10 antibodyantibody FZD10(+) FZD10(-) SYO-1 YaFuSS LoVo No Tx No 92-13 93-22 In vivo effect of Y90-anti-FZD10 Antibody Day 0 Day 5 Day 9 Day 40 Day 54 90Y-anti-FZD10 Day 0 Day 9 Day 33 Day 40 Day 54 90Y-anti-FZD10 Day 0 Day 9 90Y-CD20-Ab In vivo effect of Y90-anti-FZD10 Antibody Balb-c/nu (male) / SYO-1 tumor 90Y - DTPA - antibody 100uCi Intraveneous injection Single injection on Day0 7 Non-Labeled 92-13 (n=5) Non-treated (n=5) 6 ) 3 5 4 3 Tumor Volume(cm 2 90Y - 92-13 (n=11) 1 0 0 5 10 15 20 25 30 35 40 Days Injection 11 / 11 4 / 11 DevelopmentDevelopment of cancercancer peptidepeptide vaccine andand ConstructionConstruction ofof TRTR networknetwork inin JapanJapan Types of Cancer Vaccines • Antigen/adjuvant vaccines • Whole cell cancer vaccines • Dendritic cell (DC) vaccines • Idiotype vaccines RecentRecent advancesadvances forfor cancercancer vaccinevaccine • 1991 Discovery of Tumor specific antigen (T. Boon, Science) • 1995 Clinical Trial against melanoma (Int J Cancer) • 1998 IL-2 + Peptides (Rosenberg, Nature Med) DC + Peptide (Nestle, Nature Med) • 2004 Less than 3% response rate for advanced cancer (Rosenberg, Nature Med) • 2006 33%33% reductionreduction ofof recurrencerecurrence forfor lunglung cancercancer afterafter surgerysurgery (GSK,(GSK, ASCO)ASCO) 50%50% reductionreduction ofof recurrencerecurrence forfor breastbreast cancercancer afterafter surgerysurgery (Peoples,(Peoples, SanSan AntonioAntonio Int.Int. BreastBreast CancerCancer Meeting)Meeting) Expectation to Cancer Vaccine Treatment 100 1998 Promising Results on 2015 Approval melanonma of 15-20 Vac. 2007 Effect on reduction 0 of recurrence 1991 Tumor antigen 2003 Rosenberg report -100 1990 2000 2010 2020 AppropriateCancer Vaccine Cancer Treatment Vaccine atTreatment present 10-cm tumor = 1011-12 cells CTL CTL CTL CTL＜＜＜＜＜Cancer＜＜＜＜＜CancerCancer CellsCells 10000 cells Peripheral Lym 1010 cells CTL=106-7 cells CTL Vaccine Treatment at an earlier stage of cancer Canc er Canc CTL er CTL Canc Canc er er CTL Canc CTL Canc Canc er CTL er er Canc CTL er CTL Canc er CTL CTL CTL Canc er Canc er CTL CancerFurther Vaccine enhancement Treatment of CTL at activity present CTL CTL CTL CTL CTL＜＜＜＜＜Cancer＜＜＜＜＜Cancer Cells 10000 cells CTL FurtherTo overcom enhancement the present of CTL status activity CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL １．Improvement of CTL inductionCTL CTL CTL CTL CTL ２．BestCTL selection of antigen CTL CTL CTL CTL UnevenCTL precursor T cell population CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL ３．Regulation of Treg CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL CTL DevelopmentDevelopment of cancer vaccinevaccine Development of cancer vaccines using novel tumortumor-specific-specific oncoantigensoncoantigens identifiedidentified through genome-widegenome-wide cDNAcDNA microarraymicroarray analysisanalysis andand subsequent“Oncoantigen” functional analysis is defined
Load more

Recommended publications
  • Characterization of Increasing Stages of Invasiveness Identifies Stromal/Cancer Cell Crosstalk in Rat Models of Mesothelioma
    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 23), pp: 16311-16329 Research Paper Characterization of increasing stages of invasiveness identifies stromal/cancer cell crosstalk in rat models of mesothelioma Joëlle S. Nader1, Jérôme Abadie1,2, Sophie Deshayes1, Alice Boissard3,4, Stéphanie Blandin5, Christophe Blanquart1, Nicolas Boisgerault1, Olivier Coqueret3,4, Catherine Guette3,4, Marc Grégoire1 and Daniel L. Pouliquen1 1CRCINA, INSERM, Université d’Angers, Université de Nantes, Nantes, France 2ONIRIS, Nantes, France 3CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France 4ICO, Angers, France 5Plate-Forme MicroPICell, SFR François Bonamy, Université de Nantes, France Correspondence to: Daniel L. Pouliquen, email: [email protected] Keywords: stroma; invasiveness; sarcomatoid mesothelioma; immune cells; rat model Received: November 08, 2017 Accepted: February 25, 2018 Published: March 27, 2018 Copyright: Nader et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Sarcomatoid mesothelioma (SM) is a devastating cancer associated with one of the poorest outcome. Therefore, representative preclinical models reproducing different tumor microenvironments (TME) observed in patients would open up new prospects for the identification of markers and evaluation of innovative therapies. Histological analyses
    [Show full text]
  • Mediated Enamel Mineralization
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Archivio della ricerca- Università di Roma La Sapienza [Frontiers In Bioscience, Landmark, 22, 1289-1329, March 1, 2017] The crossroads between cancer immunity and autoimmunity: antibodies to self antigens Monica Benvenuto1, Rosanna Mattera1, Laura Masuelli2, Ilaria Tresoldi1, Maria Gabriella Giganti1, Giovanni Vanni Frajese3, Vittorio Manzari1, Andrea Modesti1,4, Roberto Bei1,4 1Department of Clinical Sciences and Translational Medicine, University of Rome, Tor Vergata, Rome, 00133 Italy, 2Department of Experimental Medicine, University of Rome, Sapienza, Rome, 00164 Italy, 3Department of Sports Science, Human and Health, University of Rome ‘Foro Italico’, Rome, 00135 Italy, 4Center for Regenerative Medicine, (CIMER), University of Rome “Tor Vergata”, Rome, 00133 Italy TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Immune response to self antigens in cancer patients partly covers that characteristic of patients with autoimmune diseases 4. Features of self antigens involved in the autoreactive immune response: immunological properties and abnormal expression 5. Biological activities of autoantibodies to self antigens 6. Association of autoantibodies to self antigens with paraneoplastic autoimmune syndromes 7. Role of autoantibodies to self antigens as biomarkers for cancer detection and cancer patients prognosis 8. Paraneoplastic neurological syndromes, effects of therapy targeting immune-checkpoint receptors and Tregs dysregulation in autoimmune disease patients: the crossroad between autoimmunity and immune response in cancer patients 9. Conclusions 10. Acknowledgment 11. References 1. ABSTRACT The production of autoantibodies to self meaning of autoantibodies to self antigens detected in antigens is dependent on the failure of immune cancer and autoimmune disease patients.
    [Show full text]
  • Vaccines and Other Immunological Approaches for Cancer Immunoprevention
    Current Drug Targets, 2011, 12, 1957-1973 1957 Vaccines and Other Immunological Approaches for Cancer Immunoprevention Pier-Luigi Lollini*,1, Giordano Nicoletti2, Lorena Landuzzi2, Federica Cavallo3, Guido Forni3, Carla De Giovanni4 and Patrizia Nanni4 1Department of Hematology and Oncological Sciences, University of Bologna; 2Rizzoli Orthopedic Institute, Bologna; 3Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin; 4Department of Experimental Pathology, University of Bologna, Italy Abstract: The immune system effectively prevents cancer, whereas severe immunodepression increases its incidence. Cancer immunoprevention is a strategy based on the concept that enhancement of tumor immunity in healthy individuals reduces cancer risk. It can be viewed as a kind of chemoprevention. For cancer immunoprevention, the cancer universe can be neatly divided between tumors caused - directly or indirectly - by infectious agents and all other tumors. Immunoprevention of tumors caused by infectious agents is already implemented at the population level for hepatitis B virus (HBV)-related hepatocellular carcinoma and for tumors caused by human papillomaviruses (HPV), like cervical carcinoma. Now the challenge is to develop immunological strategies to prevent the bulk (>80%) of human tumor burden, unrelated to infections. Both vaccines against tumor antigens and immune modulators can prevent tumor onset in cancer- prone mice. These studies outlined the target antigens and the molecular and cellular mechanisms
    [Show full text]
  • Identification of Biomarkers in Colon Cancer Based on Bioinformatic Analysis
    4895 Original Article Identification of biomarkers in colon cancer based on bioinformatic analysis Ying Zhu1#^, Leitao Sun2#^, Jieru Yu3, Yuying Xiang1^, Minhe Shen2^, Harpreet S. Wasan4^, Shanming Ruan2^, Shengliang Qiu2^ 1The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China; 2Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China; 3College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China; 4Department of Cancer Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK Contributions: (I) Conception and design: Y Zhu, L Sun; (II) Administrative support: M Shen, S Ruan, S Qiu; (III) Provision of study materials or patients: Z Ying, L Sun; (IV) Collection and assembly of data: J Yu, Y Xiang; (V) Data analysis and interpretation: Ying Zhu, Leitao Sun, Harpreet S. Wasan, S Qiu, S Ruan; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Shengliang Qiu. Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Shangcheng, Hangzhou 310006, China. Email: [email protected]; Shanming Ruan. Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Shangcheng, Hangzhou 310006, China. Email: shanmingruan@ zcmu.edu.cn. Background: Colon cancer is one of the most common cancers in the world. Targeting biomarkers is helpful for the diagnosis and treatment of colon cancer. This study aimed to identify biomarkers in colon cancer, in addition to those that have already been reported, using microarray datasets and bioinformatics analysis.
    [Show full text]
  • Vaccines Against Human HER2 Prevent Mammary Carcinoma in Mice Transgenic for Human HER2
    De Giovanni et al. Breast Cancer Research 2014, 16:R10 http://breast-cancer-research.com/content/16/1/R10 RESEARCH ARTICLE Open Access Vaccines against human HER2 prevent mammary carcinoma in mice transgenic for human HER2 Carla De Giovanni1,2, Giordano Nicoletti3, Elena Quaglino4, Lorena Landuzzi3, Arianna Palladini1, Marianna Lucia Ianzano1, Massimiliano Dall’Ora1, Valentina Grosso1, Dario Ranieri1, Roberta Laranga1, Stefania Croci1, Augusto Amici5, Manuel L Penichet6, Manuela Iezzi7, Federica Cavallo4, Patrizia Nanni1,2* and Pier-Luigi Lollini1,2 Abstract Introduction: The availability of mice transgenic for the human HER2 gene (huHER2) and prone to the development of HER2-driven mammary carcinogenesis (referred to as FVB-huHER2 mice) prompted us to study active immunopreventive strategies targeting the human HER2 molecule in a tolerant host. Methods: FVB-huHER2 mice were vaccinated with either IL-12-adjuvanted human HER2-positive cancer cells or DNA vaccine carrying chimeric human-rat HER2 sequences. Onset and number of mammary tumors were recorded to evaluate vaccine potency. Mice sera were collected and passively transferred to xenograft-bearing mice to assess their antitumor efficacy. Results: Both cell and DNA vaccines significantly delayed tumor onset, leading to about 65% tumor-free mice at 70 weeks, whereas mock-vaccinated FVB-huHER2 controls developed mammary tumors at a median age of 45 weeks. In the DNA vaccinated group, 65% of mice were still tumor-free at about 90 weeks of age. The number of mammary tumors per mouse was also significantly reduced in vaccinated mice. Vaccines broke the immunological tolerance to the huHER2 transgene, inducing both humoral and cytokine responses.
    [Show full text]
  • Archivio Istituzionale Open Access Dell'università Di Torino Original Citation
    AperTO - Archivio Istituzionale Open Access dell'Università di Torino Bovine herpesvirus 4-based vector delivering a hybrid rat/human HER-2 oncoantigen efficiently protects mice from autochthonous Her-2+mammary cancer This is the author's manuscript Original Citation: Availability: This version is available http://hdl.handle.net/2318/1542810 since 2017-05-16T11:42:46Z Published version: DOI:10.1080/2162402X.2015.1082705 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) 04 October 2021 This is an author version of the contribution published on: Sarah Jacca, Valeria Rolih, Elena Quaglino, Valentina Franceschi, Giulia Tebaldi, Elisabetta Bolli, Alfonso Rosamilia, Simone Ottonello, Federica Cavallo & Gaetano Donofrio Bovine herpesvirus 4-based vector delivering a hybrid rat/human HER-2 oncoantigen efficiently protects mice from autochthonous Her-2+ mammary cancer. In Oncoimmunology, 2015 The definitive version is available at: DOI: 10.1080/2162402X.2015.1082705 1 Bovine herpesvirus 4-based vector delivering a hybrid rat/human HER-2 oncoantigen 2 efficiently protects mice from autochthonous Her-2+ mammary cancer. 3 4 Sarah JaccaaΔ, Valeria RolihbΔ, Elena QuaglinobΔ, Valentina Franceschia, Giulia Tebaldia, Elisabetta 5 Bollib, Alfonso Rosamiliaa, Simone Ottonelloc, Federica Cavallob* and Gaetano Donofrioa* 6 7 aDepartment of Medical-Veterinary Science, University of Parma, Parma, Italy.
    [Show full text]
  • Induce Immunogenic Cell Death Through On-Target Effects
    www.nature.com/cddis ARTICLE OPEN Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects 1,2,3 1,2,3 1,2 1,2 1,2 4 Adriana Petrazzuolo , Maria Perez-Lanzon , Isabelle✉ Martins , Peng Liu , Oliver Kepp , Véronique Minard-Colin , Maria Chiara Maiuri 1,2 and Guido Kroemer 1,2,5,6,7 © The Author(s) 2021 Immunogenic cell death (ICD) is clinically relevant because cytotoxicants that kill malignant cells via ICD elicit anticancer immune responses that prolong the effects of chemotherapies beyond treatment discontinuation. ICD is characterized by a series of stereotyped changes that increase the immunogenicity of dying cells: exposure of calreticulin on the cell surface, release of ATP and high mobility group box 1 protein, as well as a type I interferon response. Here, we examined the possibility that inhibition of an oncogenic kinase, anaplastic lymphoma kinase (ALK), might trigger ICD in anaplastic large cell lymphoma (ALCL) in which ALK is activated due to a chromosomal translocation. Multiple lines of evidence plead in favor of specific ICD-inducing effects of crizotinib and ceritinib in ALK-dependent ALCL: (i) they induce ICD stigmata at pharmacologically relevant, low concentrations; (ii) can be mimicked in their ICD-inducing effects by ALK knockdown; (iii) lose their effects in the context of resistance-conferring ALK mutants; (iv) ICD-inducing effects are mimicked by inhibition of the signal transduction pathways operating downstream of ALK. When ceritinib-treated murine ALK-expressing ALCL cells were inoculated into the left flank of immunocompetent syngeneic mice, they induced an immune response that slowed down the growth of live ALCL cells implanted in the right flank.
    [Show full text]
  • Early Assessment of Colorectal Cancer by Quantifying Circulating Tumor Cells in Peripheral Blood: ECT2 in Diagnosis of Colorectal Cancer
    Article Early Assessment of Colorectal Cancer by Quantifying Circulating Tumor Cells in Peripheral Blood: ECT2 in Diagnosis of Colorectal Cancer Chih-Jung Chen 1,2,3, Wen-Wei Sung 2,3,4,5,6, Hung-Chang Chen 7, Yi-Jye Chern 8, Hui-Ting Hsu 1, Yueh-Min Lin 1,2, Shu-Hui Lin 1,2,9, Konan Peck 8,*,† and Kun-Tu Yeh 1,3,* 1 Department of Surgical Pathology, Changhua Christian Hospital, Changhua 8864, Taiwan; [email protected] (C.-J.C.); [email protected] (H.-T.H.); [email protected] (Y.-M.L.); [email protected] (S.-H.L.) 2 Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 88637, Taiwan; [email protected] 3 School of Medicine, Chung Shan Medical University, Taichung 8864, Taiwan 4 Department of Urology, Chung Shan Medical University Hospital, Taichung 8864, Taiwan 5 Institute of Medicine, Chung Shan Medical University, Taichung 8864, Taiwan 6 Department of Medical Education, Chung Shan Medical University Hospital, Taichung 8864, Taiwan 7 Department of Colon and Rectal Surgery, Changhua Christian Hospital, Changhua, Taiwan; [email protected] 8 Institute of Biomedical Sciences, Academia Sinica, Taipei 8862, Taiwan; [email protected] 9 Institute of Medicine, Chung Shan Medical University, Taichuang 8864, Taiwan * Correspondence: [email protected] (K.P.); [email protected] (K.-T.Y.); Tel.: +886-4-7238595 (ext. 4830) (K.-T.Y.) † The author, Konan Peck, was deceased during study. Academic Editor: William Chi-shing Cho Received: 13 January 2017; Accepted: 24 March 2017; Published: 31 March 2017 Abstract: Circulating tumor cells (CTCs) in peripheral blood is an indication of poor prognosis for patients with different cancer types.
    [Show full text]
  • Header Type (Not APS)
    New developments in the treatment of anaplastic lymphoma kinase-driven malignancies Luca Mologni & Carlo Gambacorti-Passerini* Dept. Clinical Medicine and Prevention, University of Milano-Bicocca, Via Cadore 48 – 20900 Monza, Italy *Author for correspondence: E-mail: [email protected] Keywords: ALK, tyrosine kinase, crizotinib, lymphoma, NSCLC, targeted therapy Disclosure Carlo Gambacorti-Passerini is PI in the Pfizer protocol A8081013 at the Investigational Site, Monza, Italy. The anaplastic lymphoma kinase (ALK) has been recognized as a therapeutic target in several neoplasias, including anaplastic large cell lymphoma (ALCL), non-small-cell lung cancer (NSCLC), neuroblastoma and colorectal cancer. Both chromosomal rearrangements, leading to the expression of fusion kinases, and kinase-activating point mutations, have been found to trigger the oncogenic activation of ALK. ALK-positive cancers are highly dependent on ALK catalytic activity. Since the normal, wild-type ALK gene is expressed at low levels in a limited population of nervous tissue cells, the targeting of oncogenic ALK proteins has great therapeutic value. Hence, a large effort is ongoing worldwide to develop small-molecule inhibitors of ALK kinase. One compound has been approved for the treatment of ALK+ NSCLC and a number of second- generation compounds is undergoing clinical evaluation. Here, we review the molecular biology of normal and oncogenic ALK, its involvement in the pathogenesis of cancer and the current status of ALK inhibitors research, including preclinical and clinical development and acquired resistance to ALK inhibition. The results obtained so far in ALK+ tumors emphasize the importance of deep understanding of the genetic alterations that cause transformation, in order to achieve major advances in cancer therapy.
    [Show full text]
  • Oncogenic Kinase NPM/ALK Induces Through STAT3 Expression of Immunosuppressive Protein CD274 (PD-L1, B7-H1)
    Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1) Michal Marzeca, Qian Zhanga, Ami Goradiaa, Puthiyaveettil N. Raghunatha, Xiaobin Liua, Michele Paesslera, Hong Yi Wanga, Maria Wysockab, Mangeng Chengc, Bruce A. Ruggeric, and Mariusz A. Wasika,1 Departments of aPathology and Laboratory Medicine and bDermatology, University of Pennsylvania, Philadelphia, PA 19104 and cCephalon, West Chester, PA 19380 Communicated by Peter C. Nowell, University of Pennsylvania School of Medicine, Philadelphia, PA, October 29, 2008 (received for review August 27, 2008) The mechanisms of malignant cell transformation caused by the involved in immune evasion in malignancy, as cells of various oncogenic, chimeric nucleophosmin (NPM)/anaplastic lymphoma tumor types have been shown to aberrantly express CD274 and, kinase (ALK) remain only partially understood, with most of the seemingly to a lesser degree, CD273. previous studies focusing mainly on the impact of NPM/ALK on cell Here we report that ALKϩTCL cells universally express survival and proliferation. Here we report that the NPM/ALK- CD274. The CD274 expression is induced in these malignant carrying T cell lymphoma (ALK؉TCL) cells strongly express the cells by the NPM/ALK tyrosine kinase. NPM/ALK triggers the immunosuppressive cell-surface protein CD274 (PD-L1, B7-H1), as expression by activating STAT3, which in turn acts as a determined on the mRNA and protein level. The CD274 expression transcriptional activator of the CD274 gene. These findings is strictly dependent on the expression and enzymatic activity of identify a unique role of NPM/ALK and STAT3 in inducing NPM/ALK, as demonstrated by inhibition of the NPM/ALK function tumor immune evasion, and demonstrate the direct role of an -in ALK؉TCL cells by the small molecule ALK inhibitor CEP-14083 oncogenic protein in controlling the expression of an immu and by documenting CD274 expression in IL-3-depleted BaF3 cells nosuppressive cell-surface protein.
    [Show full text]
  • Predictive Biomarkers for the Efficacy of Peptide Vaccine Treatment
    Shindo et al. Journal of Experimental & Clinical Cancer Research (2017) 36:36 DOI 10.1186/s13046-017-0509-1 RESEARCH Open Access Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer Yoshitaro Shindo1, Shoichi Hazama1,2, Nobuaki Suzuki1, Haruo Iguchi3, Kazuhiro Uesugi3, Hiroaki Tanaka4, Atsushi Aruga5, Takashi Hatori5, Hidenobu Ishizaki6, Yuzo Umeda7, Toshiyoshi Fujiwara7, Tetsuya Ikemoto8, Mitsuo Shimada8, Kazuhiko Yoshimatsu9, Hiroko Takenouchi1, Hiroto Matsui1, Shinsuke Kanekiyo1, Michihisa Iida1, Yasunobu Koki10, Hideki Arima10, Hiroyuki Furukawa10, Tomio Ueno1, Shigefumi Yoshino1, Tomonobu Fujita11, Yutaka Kawakami11, Yusuke Nakamura12, Masaaki Oka13 and Hiroaki Nagano1* Abstract Background: The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments. Methods: From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402- unmatched group. Results: Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group .
    [Show full text]
  • Cancer Vaccine Therapy Based on Peptides Masahiro Katsuda, Hiroki Yamaue* Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
    Trends in Immunotherapy (2017) Volume 1 Issue 1, pp.10–18. doi: 10.24294/ti.v1i1.41 Review article Cancer vaccine therapy based on peptides Masahiro Katsuda, Hiroki Yamaue* Second Department of Surgery, Wakayama Medical University, Wakayama, Japan ABSTRACT Following numerous unequivocal clinical failures, immunotherapy has become an attractive therapeutic modality. Peptide vaccines are cost-effective compared to other vaccine approaches, and effective epitopes eliciting strong immune response can be selected experimentally in silico and ex vivo. However, the clinical benefits of cancer peptides vaccine have been disappointing in most studies; therefore, we need to prove the clinical beneficial effects for cancer treatment following induction of more powerful cytotoxic T lymphocytes (CTLs). First, the choice of ideal target antigen is essential. Epitopes derived from tumor-associated antigens (TAAs), oncoantigens, vascular endothelial cells and neoantigens are then developed. In particular, whole- exome sequencing enables us to identify the epitopes of neoantigens. The choice of therapeutic objectives is also important and peptide vaccines might be better to be developed as preventative vaccines. Dendritic cells (DCs) vaccine pulsed with peptides is an approach to induce powerful CTLs and might overcome several disadvantages of peptide vaccines as monotherapy. Targeting vaccine therapy against DC subsets in vivo is under development. Keywords: immunotherapy; peptide vaccine; tumor-associated antigen; oncoantigen; VEGFR2; neoantigen; dendritic cells ARTICLE INFO Received: April 17, 2017 Introduction Accepted: May 2, 2017 Available online: May 16, 2017 It is well established that the immune system against cancer can be spontaneously activated. In melanoma, renal cancer, breast cancer and *CORRESPONDING AUTHOR ovarian cancer, the tumor-infiltrating lymphocytes (TILs) in tumor micro- Hiroki Yamaue, Second Department [1,2] of Surgery, Wakayama Medical environment are positively related to long survival .
    [Show full text]