Applications. in Oncology
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2 Kewal K. Jain Applications of Biotechnology in Oncology
3 Applications of Biotechnology in Oncology
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5 Applications of Biotechnology in Oncology Kewal K. Jain, MD, FRACS, FFPM Jain PharmaBiotech, Basel, Switzerland
6 Kewal K. Jain Jain PharmaBiotech Basel, Switzerland ISBN ISBN (ebook) DOI / Springer New York Heidelberg Dordrecht London Library of Congress Control Number: Springer Science+Business Media New York 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is a brand of Springer Springer is part of Springer Science+Business Media (
7 Preface This book puts together excerpts from various writings by the author on biotechnology topics as they relate to cancer. It is meant for oncologists, scientists involved in research on cancer biology, and physicians in various specialties who deal with cancer. It will be useful for those working in life sciences and pharmaceutical industries, particularly those involved in the discovery of anticancer agents and drug delivery in cancer. Basics of various omics technologies and their application in oncology are described as oncogenomics and oncoproteomics. Because the book is organized according to technologies, only examples of application in cancers of various organs/systems are described in various chapters. This may involve some repetition of overlapping technologies for genomics, proteomics, biomarkers, and molecular diagnostics. Molecular diagnostics have important applications in the investigation and treatment of cancer. Biomarkers also provide important information relevant to diagnosis, prognosis, and monitoring of treatment. Sequencing is making important contributions to molecular diagnostics. Next generation sequencing has helped to advance our understanding of pathophysiology of cancer, improve molecular diagnosis of cancer, and facilitate anticancer therapeutics. Nanobiotechnology is making important contributions to cancer diagnosis, drug delivery, and therapy, justifying the use of nanooncology as a chapter heading. Many of the drugs developed for cancer failed because of lack of penetration to the site of action in the brain. Routes of drug delivery and applications to various types of cancer are described. Various methods of improving systemic administration of drugs for targeted delivery to cancer are described, including the use of nanobiotechnology. Cell and gene therapies, including antisense and RNA interference as well as vaccines, have emerged as effective methods for the treatment of cancer. Modern cancer therapies have many biotechnology-based products. Nanobiotechnology is probably the most important biotechnology in relation to the refinement of drug delivery, refinement of molecular diagnostics, and its integration with therapeutics. v
8 vi Preface Finally, a chapter on personalized oncology is important for the era of personalized medicine. This concept is the best way of integrating new technologies to select the appropriate strategy for the treatment of an individual patient. Knowledge in biotechnology and oncology has grown tremendously and both fields require massive encyclopedias for coverage. As a handy volume integrating both of these fields, only coverage of selected highlights is possible. The bibliography includes a total of ~1,000 selected references from recent literature on this topic, which are appended to each chapter according to their relevance. The text is supplemented by 53 tables and 10 figures. The author wishes to acknowledge the help, guidance, and encouragement received during the preparation of this work from David Casey, Editor for this project at Springer, and Patrick J. Marton, Managing Editor, Springer Protocols. Basel, Switzerland Kewal K. Jain
9 About This Book This book contains excerpts from various biotechnology books and reports authored by Prof. K.K. Jain that are relevant to cancer. The most important contributions of biotechnology are to the molecular diagnosis of cancer and drug delivery in cancer for personalized management of patients. vii
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11 Author s Biography Professor K.K. Jain is a neurologist/neurosurgeon by training and since his retirement from neurosurgery has been working in the biotechnology/biopharmaceuticals industry as a consultant at Jain PharmaBiotech. He received graduate training in Europe as well as North America and has held academic positions in several other countries. Currently, he is a Fellow of the Royal Australasian College of Surgeons and a Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of UK. Prof. Jain s 448 publications include 24 books (5 as editor + 19 as author) and 50 special reports, which have covered important areas in biotechnology, oncology, cell/gene therapy, and biopharmaceuticals. His Textbook of Gene Therapy was translated into Chinese language in The Textbook of Hyperbaric Medicine (5th Ed 2009), which contains a chapter on cancer, has been a standard reference on the subject for the past two decades. Prof. Jain is editing 2nd edition of Drug Delivery Systems (Humana/Springer 2014). His recent books include Textbook of Personalized Medicine (Springer 2009; Japanese edition 2012), Handbook of Biomarkers (Springer 2010), Handbook of Neuroprotection (Springer 2011), and Handbook of Nanomedicine, 2nd Ed (Springer/Humana 2012). ix
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13 Contents 1 Molecular Biology of Cancer Introduction The Genesis of Cancer DNA Damage and Repair Telomeres and Cancer Role of Epigenetics in Cancer Metabolic Changes in Cancer Hallmarks of Cancer Self-Sufficiency of Tumor Proliferation Apoptosis Tumor Angiogenesis Acquisition of a Potential for Unlimited Replication Invasion and Metastases Ion Channels and Cancer Cancer Microenvironment Epidemiology of Cancer Current Management of Cancer Chemotherapy Radiotherapy Surgery Role of Omics in Oncology Historical Landmarks in Cancer Detection and Treatment References Oncogenomics Introduction Cancer Genes Oncogenes Tumor Suppressor Genes Role of Bub 1 Gene in Cell Division xi
14 xii Contents Anticancer Treatments Based on RNA Regulation of Genes Interaction of Cancer Genes Cancer Genome Anatomy Project Human Tumor Gene Index Gene Expression Profiling in Cancer References Sequencing in Cancer Introduction Sequencing Technologies for Tumor DNA Amplicon Sequencing in Cancer Exosome Sequencing Gaining Insights into Mutational Processes Multiplexed Cancer Gene Mutation Analysis NGS-Based Molecular Profiling of Cancer in FFPE Specimens Paired-End Sequencing RNA-Seq to Study Cancer Transcriptome Sequencing Cancer Cell Lines Sequencing for Studying Chromothripsis in Cancer Sequencing of Complex Human Cancer Genomes Sequencing Single Cells to Study Evolution of Cancer Sequencing for Assessing Resistance to Anticancer Therapy Cancer Genome Atlas Sequencing of Tumors of Various Organs/Systems Sequencing of Brain Tumors Sequencing of Breast Cancer Sequencing of Colorectal Cancer Sequencing of Head and Neck Cancer Sequencing of Hematological Malignancies Sequencing of Hepatocellular Carcinoma Sequencing of Melanoma Sequencing of Ovarian Cancer Sequencing of Prostate Cancer References Oncoproteomics Introduction Proteomic Technologies for the Study of Cancer Application of CellCarta Technology for Oncology Accentuation of Differentially Expressed Proteins Using Phage Technology Cancer Tissue Proteomics... 66
15 Contents xiii Desorption Electrospray Ionization for Cancer Diagnosis Id Proteins as Targets for Cancer Therapy Identification of Oncogenic Tyrosine Kinases Using Phosphoproteomics Laser Capture Microdissection Technology and Cancer Proteomics Mass Spectrometry for Identification of Oncogenic Chimeric Proteins Proteomic Analysis of Cancer Cell Mitochondria ProteinChip System Proteomic Study of p Role of Proteomics in the Study of Cancer Stem Cell Biology Single-Cell Protein Expression Analysis by Microfluidic Techniques Integration of Cancer Genomics and Proteomics Use of Proteomics in Cancers of Various Organ Systems Proteomics of Brain Tumors Proteomics of Breast Cancer Proteomics of Colorectal Cancer Proteomics of Esophageal Cancer Proteomics of Hepatic Cancer Proteomics of Leukemia Proteomics of Lung Cancer Proteomics of Pancreatic Cancer Proteomics of Prostate Cancer Proteomics and Tumor Immunology Proteomics and Study of Tumor Invasiveness Role of Proteomics in Studying Drug Resistance in Cancer Future Prospects of Oncoproteomics References Biomarkers of Cancer Introduction The Ideal Biomarker for Cancer Single vs. Multiple Biomarkers of Cancer Types of Cancer Biomarkers Biomarkers of Epigenetic Gene Silencing in Cancer Circulating Tumor Cells as Cancer Biomarkers Circulating Nucleic Acids as Potential Biomarkers of Cancer HER3 as Biomarker of Cancer Immunological Biomarkers of Cancer... 92
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