Successes and Limitations of Targeted Cancer Therapy , livre ebook

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The treatment of patients with advanced malignancies has undergone remarkable change in the last few years. While in the past decisions about systemic therapy were largely based on the performance status of a patient, oncologists today also take into account the pathological and molecular characteristics of the patient’s tumor. Targeting specific molecular pathways important for tumorigenesis has become the preferred way of treatment for many types of malignancies. With these advances come new challenges including the optimization of therapy, recognizing and dealing with side effects and, importantly, the development of resistance. This book provides an up-to-date overview of the advances and limitations of targeted therapy for several tumor entities including breast cancer, colon cancer, gastrointestinal stromal tumors, lung cancer, melanoma, ovarian cancer and renal cell carcinoma. Written by over a dozen internationally renowned scientists, the book is suitable for advanced students, postdoctoral researchers, scientists and clinicians who wish to update their knowledge of the latest approaches to targeted cancer therapies.

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Publié par	S. Karger AG
Date de parution	19 février 2014
Nombre de lectures	0
EAN13	9783318025422
Langue	English
Poids de l'ouvrage	2 Mo

Informations légales : prix de location à la page 0,0480€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

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Successes and Limitations of Targeted Cancer Therapy
Progress in Tumor Research
Vol. 41
Series Editors
Rolf A. Stahel Zurich
Solange Peters Lausanne
Successes and Limitations of Targeted Cancer Therapy
Volume Editors
Solange Peters Lausanne
Rolf A. Stahel Zurich
12 figures, 6 in color, and 19 tables, 2014
Progress in Tumor Research
Formerly published as ‘Progress in Experimental Tumor Research’
_______________________ Dr. Solange Peters Medical Oncology Unit Department of Oncology Centre Hospitalier Universitaire Vaudois (CHUV) 1011 Lausanne Switzerland
_______________________ Prof. Dr. Rolf A. Stahel Clinic of Oncology University Hospital Zurich 8091 Zurich Switzerland

Library of Congress Cataloging-in-Publication Data
Successes and limitations of targeted cancer therapy / volume editors, Solange Peters, Rolf A. Stahel.
p. ; cm. –– (Progress in tumor research, ISSN 2296-1895 ; vol. 41)
Includes bibliographical references and index.
ISBN 978-3-318-02541-5 (hard cover: alk. paper) –– ISBN 978-3-318-02542-2 (electronic version)
I. Peters, Solange, editor of compilation. II. Stahel, Rolf A., editor of compilation. III. Series: Progress in tumor research ; v. 41. 2296-1895
[DNLM: 1. Molecular Targeted Therapy––methods. 2. Neoplasms––drug therapy. 3. Antineoplastic Agents––therapeutic use. W1 PR668T v.41 2014 / QZ 267]
RC270.8
616.99’406––dc23
2013045767
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents ® .
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2014 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland)
www.karger.com
Printed in Germany on acid-free and non-aging paper (ISO 9706) by Kraft Druck, Ettlingen
ISSN 2296-1895
e-ISSN 2296-1887
ISBN 978-3-318-02541-5
e-ISBN 978-3-318-02542-2
Contents
Targeting Oncogenic Drivers
Zhao, Y.; Adjei, A.A. (Buffalo, N.Y.)
Successes and Limitations of Targeted Cancer Therapy in Breast Cancer
Curigliano, G.; Criscitiello, C. (Milan)
Successes and Limitations of Targeted Cancer Therapy in Colon Cancer
Köhne, C.-H. (Oldenburg)
Successes and Limitations of Targeted Cancer Therapy in Gastrointestinal Stromal Tumors
Casali, P.G. (Milan)
Successes and Limitations of Targeted Cancer Therapy in Lung Cancer
Suda, K. (Osaka-Sayama/Fukuoka); Mitsudomi, T. (Osaka-Sayama)
Successes and Limitations of Targeted Cancer Therapy in Melanoma
Romano, E.; Michielin, O. (Lausanne)
Successes and Limitations of Targeted Cancer Therapy in Ovarian Cancer
Damia, G. (Milan); Sessa, C. (Bellinzona)
Successes and Limitations of Targeted Therapies in Renal Cell Carcinoma
Pracht, M.; Berthold, D. (Lausanne)
Author Index
Subject Index
Peters S, Stahel RA (eds): Successes and Limitations of Targeted Cancer Therapy. Prog Tumor Res. Basel, Karger, 2014, vol 41, pp 1-14 (DOI: 10.1159/000355895)
______________________
Targeting Oncogenic Drivers
Yujie Zhao Alex A. Adjei
Department of Medicine, Roswell Park Cancer Institute, Buffalo, N.Y., USA
______________________
Abstract
Cancer is a genetic disease caused by a series of somatic and/or germline mutations. The roles of oncogenes and tumor suppressors in cancer molecular origin have been well established. Targeting oncogene products has become an attractive therapeutic strategy with great clinical success, whereas tumor suppressors are considered ‘undruggable’ because current technology is not able to restore tumor suppressor function in metastatic disease. Although systematic approaches to discover genetic alterations have become available to individual patients, differentiating driver from passenger mutations and identifying and validating drug targets remain challenging. Protein tyrosine kinases play crucial roles in virtually all cellular processes and possess structural features that render them ‘druggable’. Monoclonal antibodies and small-molecule inhibitors represent two major classes of targeted therapeutic agents, each possessing its own strength and weakness. Although initial successes have been achieved, targeted therapy faces many challenges that need to be addressed and hurdles to overcome.
© 2014 S. Karger AG, Basel
Cancer is the most common human genetic disease, developing after a series of gene alterations that lead to uncontrolled growth of cells. While a small number of hereditary cancer syndromes are directly caused by germline mutations, the vast majority of human cancers are driven by sequentially accumulated somatic genetic and epigenetic changes. These genetic alterations ultimately lead to acquisition of the hallmarks of malignancy comprising resistance to cell death, sustained proliferative signaling, activation of invasion and metastasis mechanisms, angiogenesis induction and replicative immortality [ 1 ] . Additionally, inheritable genetic variations also contribute to cancer development by influencing the susceptibility to malignancy transformation [ 2 , 3 ].
Genetic alterations may promote cancer development through either constitutive activation of proto-oncogenes or loss of function of tumor suppressor genes [ 4 , 5 ]. Proto-oncogenes are normal cellular genes that encode proteins involved in cell proliferation and cell-death protection. When deregulation occurs, either through changes in the protein-coding segment or by alteration of their expression levels, proto-oncogenes are converted to oncogenes, which promote cancer development. The first oncogene isolated was from a cancer-inducing retrovirus, the Rous sarcoma virus, which transmits sarcomas to infected chicks through incorporation of the v-src oncogene to host genomes [ 6 ] . Since the discovery of v- src , numerous other proto-oncogenes have been identified. They can be converted to oncogenes through various genetic alterations such as point mutations, deletions, duplication/amplification and chromosome translocations, as well as epigenetic alterations. Following the understanding of oncogenes, a second group of genes in tumor development, the tumor suppressor genes, also entered the center stage of research in the molecular origin of cancer. In contrast to oncogenes, tumor suppressor genes encode proteins that prevent tumor development or progression [ 4 ] . This is usually accomplished through maintaining genome integrity and constraining cell proliferation by regulating the cell cycle, promoting apoptosis and facilitating DNA repair. The first gene recognized as a tumor suppressor gene was a gene involved in cell cycle control, the retinoblastoma ( RB ) gene [ 7 - 9 ] . Loss of RB was found to be the cause of hereditary as well as sporadic retinoblastoma. Since in general one copy of a tumor suppressor gene is sufficient to control cell proliferation, both alleles of a tumor suppressor gene have to be lost or inactivated in order to promote tumor development. This may occur through alterations such as point mutations, deletions, chromosome deletions and translocations, and epigenetic silencing [ 10 , 11 ] . In addition to oncogenes and tumor suppressors, genetic materials acquired from viruses, including human papilloma virus, Epstein-Barr virus, hepatitis B virus, human T lymphotropic virus 1 and human herpes virus 8, can also promote tumor development. This usually occurs through mechanisms such as inactivation of cellular tumor suppressors or alteration of the transcription of the neighboring genes after integration into the host genome, although viral genes may function as oncogenes themselves as well [ 12 , 13 ] . The understanding of the molecular origin of cancer development has led to investigations of new therapeutic agents [ 14 ] . While strategies to restore tumor suppressor gene functions have been hindered by technical hurdles of ineffective gene delivery, numerous new therapeutics targeting oncoproteins have been evaluated in clinical studies with many approved for clinical use.
Identification of Cancer Therapy Targets
One of the most exciting developments in biomedical research over the past decade has been the