Cancer Proteomics

Cancer Drug Discovery

and Development

Beverly A. Teicher, Series Editor

Checkpoint Responses in CancerTherapy, edited by Wei Dai, 2008

Cancer Proteomics: From Bench toBedside, edited by Sayed S. Daoud,2008

Antiangiogenic Agents in CancerTherapy, Second Edition, editedby Beverly A. Teicher and Lee M.Ellis, 2007

Apoptosis and Senescence in CancerChemotherapy andRadiotherapy, Second Edition,edited by David A. Gerwitz, ShawnEdan Holtz, and Steven Grant,2007

Molecular Targeting in Oncology,edited by Howard L. Kaufman,Scott Wadler, and Karen Antman,2007

In Vivo Imaging of Cancer Therapy,edited by Anthony F. Shields andPatricia Price, 2007

Transforming Growth Factor-� inCancer Therapy, Volume II:Cancer Treatment and Therapy,edited by Sonia Jakowlew, 2007

Transforming Growth Factor-� inCancer Therapy, Volume 1: Basicand Clinical Biology, edited bySonia Jakowlew, 2007

Microtubule Targets in CancerTherapy, edited by Antonio T.Fojo, 2007

Cytokines in the Genesis andTreatment of Cancer, edited byMichael A. Caligiuri, Michael T.Lotze, and Frances R. Balkwill,2007

Regional Cancer Therapy, edited byPeter M. Schlag and Ulrike Stein,2007

Gene Therapy for Cancer, edited byKelly K. Hunt, Stephan A.Vorburger, and Stephen G.Swisher, 2007

Deoxynucleoside Analogs in CancerTherapy, edited by Godefridus J.Peters, 2006

Cancer Drug Resistance, edited byBeverly A. Teicher, 2006

Histone Deacetylases: TranscriptionalRegulation and Other CellularFunctions, edited by Eric Verdin,2006

Immunotherapy of Cancer, edited byMary L. Disis, 2006

Biomarkers in Breast Cancer:Molecular Diagnostics forPredicting and MonitoringTherapeutic Effect, edited byGiampietro Gasparini and DanielF. Hayes, 2006

Protein Tyrosine Kinases: FromInhibitors to Useful Drugs, editedby Doriana Fabbro and FrankMcCormick, 2005

Bone Metastasis: Experimental andClinical Therapeutics, edited byGurmit Singh and Shafaat A.Rabbani, 2005

The Oncogenomics Handbook, editedby William J. LaRochelle andRichard A. Shimkets, 2005

Camptothecins in Cancer Therapy,edited by Thomas G. Burke and ValR. Adams, 2005

Cancer

Proteomics

From Bench to Bedside

Edited by

Sayed S. Daoud

Department of Pharmaceutical SciencesWashington State UniversityPullman, WA

© 2008 Humana Press Inc.999 Riverview Drive, Suite 208Totowa, New Jersey 07512www.humanapress.com

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Due diligence has been taken by the publishers, editors, and authors of this book to assurethe accuracy of the information published and to describe generally accepted practices. Thecontributors herein have carefully checked to ensure that the drug selections and dosages setforth in this text are accurate and in accord with the standards accepted at the time of publication.Notwithstanding, as new research, changes in government regulations, and knowledge fromclinical experience relating to drug therapy and drug reactions constantly occurs, the reader isadvised to check the product information provided by the manufacturer of each drug for anychange in dosages or for additional warnings and contraindications. This is of utmost importancewhen the recommended drug herein is a new or infrequently used drug. It is the responsibility ofthe treating physician to determine dosages and treatment strategies for individual patients. Furtherit is the responsibility of the health care provider to ascertain the Food and Drug Administrationstatus of each drug or device used in their clinical practice. The publisher, editors, and authorsare not responsible for errors or omissions or for any consequences from the application of theinformation presented in this book and make no warranty, express or implied, with respect tothe contents in this publication.

Production Editor: Rhukea HussainCover design by Karen SchulzCover Illustration: “The Power of Mass Spectrometry in Target Identification” Derived fromFig. 4 of Chapter 2 by Kyunghee Lee, et al., and Fig. 3A of Chapter 5 by Christina M. Annunziata,et al.This publication is printed on acid-free paper. ∞ANSI Z39.48-1984 (American National Standards Institute)Permanence of Paper for Printed Library Materials

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Preface

Over the past 20 years or so, there have been tremendous advancesin our understanding of how normal cells transform to cancer and theimportance of signaling pathways in cancer initiation and progression.This progress in scientific knowledge has resulted in the devel-opment of many drugs that target specific pathways with muchwider therapeutic windows. In addition, technologic advances and theuse of high-throughput approaches, particularly in the last 5 years,are beginning to impact the diagnosis and treatment of cancer.Microarray chips, for example, allow for global analysis of genesignatures in tumor and normal tissues; while proteomic approaches(functional—expression) allow for the evaluation of protein abundanceand posttranslational modifications that are important in cancer devel-opment and progression. Thus genomics and proteomics approachesprovide major opportunities in tumor diagnosis, in rational drugdiscovery and individualization of therapy for cancer patients. In spiteof these advances in our knowledge and technical capabilities, therehas not been a substantial decrease in overall death rate due to cancer.This is because too many cancers are diagnosed in late stage in thecourse of the disease. Therefore, we need an approach that will allowfor early detection and proper diagnosis of the disease so it can betreated properly. For example, there is a need for proper use of humanserum and other body fluids such as urine and sputum in early detectionof cancer. Analyses of body fluids proteins by advanced proteomicprofiling strategies allow for great opportunity for improved diagnosticand screening tests for early cancer. Furthermore, most pharmaco-logical targets are proteins or DNA, not RNA. Any pharmacologist,given a chance, would choose information on protein expression overthat RNA expression, so that is where we chose to start.

This book provides the reader with broad perspectives and breadth ofknowledge on current topics related to the use of proteomic strategiesin cancer therapy as well as anticipated challenges that may arise fromits application in daily practice. The book is divided into four parts.The first part begins with the current technologies used in proteomicsthat allow for protein profiling and for the identification of druggabletargets in human samples. Mass spectrometry-based protein charac-terization and protein microarrays hold great promise of predicting

v

vi Preface

response to specific drugs in cancer therapy. The second part deals withthe use proteomics in cell signaling. At present, the pharmaceutical andbiotechnology industries have many potentially useful small moleculeinhibitors of many pathways important in cancer that have yet to betaken to clinical trials. Understanding protein–protein interaction andposttranslational modifications through proteomics will likely makeit much more feasible to do effective clinical trials of these smallmolecules alone and in combinations to overcome drug resistance andimprove patient care. The third part of the book moves from signalingto actual clinical applications of proteomics in cancer therapy. Casestudies in many tumor types are provided to show the feasibilityof generating the critical information needed for individualization oftherapy in cancer patients. The final part of the book provides in-depthinformation on annotating the human proteome and the role of Foodand Drug Administration (FDA) in regulating the use of proteomicsin cancer therapy. To functionally annotate the human proteome, theSwiss Institute for Bioinformatics (SIB) and the European Bioinfor-matics Institute (EBI) initiated a major effort to distribute to thescientific community highly integrated information on human proteinsequences. This initiative, which is called the Human ProteomicsInitiative (HPI), aims to provide for each known human protein awealth of information including the description of its function, domainand protein family classification, subcellular location, posttranslationalmodifications, variants and similarities to other proteins. Integration ofbioinformatics into clinical application of proteomics in cancer therapyis outlined as well as regulations and policy of commercial applicationof proteomics in patient care.

The chapters in this book collectively provide the current status ofproteomics in cancer therapy. While the editor regularly expresses thesentiment that “proteomics holds great promise in individualizationof medicine in cancer patients”, the examples provided herein aretestament to the fact that this promise has many challenges. Proteomicstechnologies must be improved for more global analysis of proteincontent of cells, tissues and body fluids, as well as the posttranslationalmodifications. Clinical proteomics studies require a large team effort.This team includes basic scientists, translational scientists, cliniciansand computer scientists, and this has many challenges in our academicworld. Finally, with the large volume of data generated, advancesin informatics and data mining will be necessary to realize the fullpotential of proteomics in cancer detection, prognosis, diagnosis andtherapy.

Preface vii

I wish to thank all the contributors to this volume for their effort,and I am grateful to them for taking the time and having the patienceto disseminate the detailed information required in order that otherscan succeed in the application of this technology in their practice.I would also like to thank Beverly A. Teicher, the series editor, for hersupport and guidance, and Gina Impallomeni for editorial assistanceand Rhukea Hussain in organization and development of this volume.

Lastly, special thanks to the anchors of my life, my wife Mariamand our children Eihab, Hany, and Sarah for their encouragement andpleasurable distraction. In the memory of my parents who believed inthe power of learning and gave too much, I dedicate this book.

Sayed S. Daoud

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Part I: Proteomics Technologies

1 Current and Emerging Mass SpectrometryInstrumentation and Methodsfor Proteomic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 3Belinda Willard, Suma Kaveti,and Michael T. Kinter

Part II: Cell Signaling Proteomics

2 Integration of Genomics and Proteomics in Dissectingp53 Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Kyunghee Lee, Tao Wang, Abdur Rehman,Yuhua Wang, and Sayed S. Daoud

3 Proteomic Profiling of Tyrosine Kinasesas Pharmacological Endpoints for TargetedCancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Moulay A. Alaoui-Jamali and Devanand Pinto

Part III: Tumor Proteomics

4 Oncoproteomics for Personalized Managementof Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81K. K. Jain

5 Application of Serum and Tissue Proteomicsto Understand and Detect Solid Tumors . . . . . . . . . . 101Christina M. Annunziata, Dana M. Roque,Nilofer Azad, and Elise C. Kohn

6 Insight on Renal Cell Carcinoma Proteome . . . . . . . . . . 121Cecilia Sarto, Vanessa Proserpio, Fulvio Magni,and Paolo Mocarelli

7 Proteomics in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . 139M. A. Reymond, M. Beshay, and H. Lippert

ix

x Contents

8 Proteomic Strategies of Therapeutic Individualizationand Target Discovery in AcuteMyeloid Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161Bjørn Tore Gjertsen and Gry Sjøholt

9 New Tumor Biomarkers: Practical ConsiderationsPrior to Clinical Application . . . . . . . . . . . . . . . . . . . . . . 189Nils Brünner, Mads Holten-Andersen, Fred Sweep,John Foekens, Manfred Schmitt, Michael J. Duffy,on behalf of the EORTC PathoBiology Group

Part IV: Bioinformatics and Regulatory

Aspects of Proteomics

10 Annotating the Human Proteome: From Establishinga Parts List to a Tool for Target Identification . . . . . 211Rolf Apweiler and Michael Mueller

11 Regulatory Issues in the Co-Development of OncologyDrugs and Proteomic Tests: An Overview . . . . . . . . 237Dave Li, Joseph Hackett, Maria Chan,Gene Pennello, and Steve Gutman

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

Contributors

Moulay Alaoui-Jamali • McGill University, Montreal, CanadaChristina M. Annunziata • National Cancer Institute,

Bethesda, MDRolf Apweiler • European Bioinformatics Institute-EMBL,

Cambridge, EnglandNilofer Azad • National Cancer Institute, Bethesda, MDM. Beshay • University of Magdeburg, GermanyNils Brünner • Copenhagen University Hospital, Copenhagen,

DenmarkMaria Chan • Food and Drug Administration, Rockville, MDSayed S. Daoud • Washington State University, Pullman, WAMichael J. Duffy • Nuclear Medicine Department, St. Vincent’s

University Hospital, National University of Ireland, IrelandJohn Foekens • Erasmus MedicalCenter Rotterdam, Rotterdam, The

NetherlandsBjørn Tore Gjertsen • University of Bergen, Bergen, NorwaySteve Gutman • Food and Drug Administration, Rockville, MDJoseph Hackett • Food and Drug Administration, Rockville, MDMads Holten-Andersen • Copenhagen University Hospital,

Copenhagen, DenmarkK. K. Jain • PharmaBiotech, Basel, SwitzerlandSuma Kaveti • Lerner Research Institute, Cleveland, OHMichael T. Kinter • Lerner Research Institute, Cleveland, OHElise C. Kohn • National Cancer Institute, Bethesda, MDKyunghee Lee • Washington State University, Pullman, WADave Li • Food and Drug Administration, Rockville, MDH. Lippert • University of Magdeburg, GermanyFulvio Magni • Desio Hospital-University of Milano Bicocca,

Milano, ItalyPaolo Mocarelli • Desio Hospital-University of Milano Bicocca,

Milano, ItalyMichael Mueller • European Bioinformatics Institute-EMBL,

Cambridge, EnglandGene Pennello • Food and Drug Administration, Rockville, MDDevanand Pinto • Dalhousie University, Halifax, Canada

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xii Contributors

Vanessa Proserpio • Desio Hospital-University of Milano Bicocca,Milano, Italy

Abdur Rehman • Washington State University, Pullman, WAM. A. Reymond • University of Magdeburg, GermanyDana M. Roque • National Cancer Institute, Bethesda, MDCecilia Sarto • Desio Hospital-University of Milano Bicocca,

Milano, ItalyManfred Schmitt • Department of Obstetrics and Gynecology,

Technical University of Munich, Munich, GermanyGry Sjøholt • University of Bergen, Bergen, NorwayFred Sweep • University Medical Center Nijmegen, Nijmegen, The

NetherlandsTao Wang • Washington State University, Pullman, WAYuhua Wang • Washington State University, Pullman, WABelinda Willard • Lerner Research Institute, Cleveland, OH