Milestones in Drug Therapy

Transcription

1 Milestones in Drug Therapy Series Editors Michael J. Parnham, Director of Science & Technology, MediMlijeko d.o.o., Zagreb, Croatia Jacques Bruinvels, Bilthoven, The Netherlands Advisory Board J.C. Buckingham, Imperial College School of Medicine, London, UK R.J. Flower, The William Harvey Research Institute, London, UK A.G. Herman, Universiteit Antwerpen, Antwerp, Belgium P. Skolnick, National Institute on Drug Abuse, Bethesda, MD, USA For further volumes:

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3 Maria Sibilia Christoph C. Zielinski l l Rupert Bartsch Thomas W. Grunt l Editors Drugs for HER-2-positive Breast Cancer

4 Volume Editors Prof. Dr. Maria Sibilia Comprehensive Cancer Center Institute of Cancer Research Department of Medicine I Medical University of Vienna Borschkegasse 8a 1090 Vienna Austria [email protected] Dr. Rupert Bartsch Comprehensive Cancer Center Department of Medicine I Clinical Division of Oncology Medical University of Vienna Waehringer Guertel Vienna Austria [email protected] Prof. Dr. Christoph C. Zielinski Comprehensive Cancer Center Department of Medicine I Medical University of Vienna General Hospital Waehringer Guertel Vienna Austria [email protected] Assoc. Prof. Dr. Thomas W. Grunt, PH.D. Comprehensive Cancer Center Department of Medicine I Clinical Division of Oncology Medical University of Vienna Waehringer Guertel Vienna Austria [email protected] Series Editors Prof. Dr. Michael J. Parnham Director of Science & Technology MediMlijeko d.o.o. Pozarinje 7 HR Zagreb Croatia Prof. Dr. Jacques Bruinvels Sweelincklaan 75 NL-3723 JC Bilthoven The Netherlands ISBN e-isbn DOI / # Springer Basel AG 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. The use of general descriptive names, registered names, trademarks, 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. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: deblik, Berlin Printed on acid-free paper Springer Basel AG is part of Springer Science þ Business Media (

5 Preface Drugs for HER-2-positive Breast Cancer: A Major Approval for Translational Cancer Research Research over the last 2 3 decades in the fields of cell and molecular biology as well as biomedicine has tremendously improved our understanding of the mechanisms of malignant transformation and progression. A lot of knowledge gained from these findings could already be transferred to clinical application and has led to a number of major advances in the early diagnosis and treatment of cancer. This applies especially to breast cancer. Development of molecular-targeted drugs nowadays is characterized by several key features. In the first step, promising molecular targets have to be identified. The ideal cancer drug target albeit not often found should represent a molecule that is absolutely required for the proliferation and survival of the transformed cell. In other words, it should be a molecule to which the tumour cell is addicted (the Achilles heel ). Consequently, the choice of drug targets is based on and driven by a profound knowledge about the cellular and molecular biology of the crucial regulatory processes that are significantly aberrant in malignant cells. In the second step, promising chemical lead structures are identified or a panel of antibodies is produced. Therefore, whereas classical cytotoxic drugs were previously identified by more or less random screening of large libraries of (natural and synthetic) compounds, novel molecular-targeted drugs are usually identified by a more rational approach that takes into account several aspects such as the physical chemical properties of the aimed target domain and the therapeutic compound. These agents are then screened for optimal therapeutic indexes (maximal treatment effects with concurrent minimal side effects). Tamoxifen was the first molecular-targeted drug ever in use in clinical oncology. It has been and is still being used for the management of oestrogen receptor-positive breast tumours. This drug originally developed as an oral contraceptive was not successful for that indication. However, by chance it was found that tamoxifen potently blocks the growth of oestrogen receptor-positive breast cancer cells [1]. In contrast to tamoxifen, development of the anti-erbb2 antibody trastuzumab v

6 vi Preface against ErbB2-positive metastatic breast cancer was hypothesis-driven according to the above-mentioned criteria. Thus, trastuzumab became the first clinically available oncogene-targeted therapeutic agent for the treatment of solid tumours (see chapter by Bartsch and Steger). The first kinase inhibitor for application against malignant diseases was imatinib. It inhibits the ABL kinase, which is rearranged and hyperactive in chronic myelogenous leukaemia. Notably, recent encouraging data indicate that the reversible dual-specific EGFR/ErbB2 kinase inhibitor lapatinib is still effective in ErbB2-positive breast cancer patients who have already developed resistance to trastuzumab. In conclusion, breast cancer belongs to that type of solid tumours, in which molecular-targeted therapies were most efficient and yielded most clinical benefits so far (e.g. tamoxifen, trastuzumab, lapatinib). Unfortunately, however, despite these improvements, breast cancer is still a major life-threatening disease for women in industrialized as well as developing countries, and there are several significant detriments when using ErbB-targeted therapies against mammary cancer. First, only a proportion of ErbB2-positive breast cancers are actually sensitive to trastuzumab (a priori, primary resistance). Moreover, almost all ErbB2-positive, trastuzumab-sensitive breast cancers become resistant within 1 year of trastuzumab treatment (acquired, secondary resistance) (see chapters by Morgillo et al., Bianchi and Gianni, von Minckwitz and Pirvulescu). In recent years, it has become increasingly evident that signalling pathways are by no means linear cascades of signal processing; they rather represent intensely interwoven regulatory networks that communicate with each other via several relay proteins that function as signalling hubs (see chapter by Köstler and Yarden). Thus, even if a highly specific drug such as trastuzumab potently silences its intended target ErbB2, the cell still might be capable of avoiding the growth-inhibitory pressure by rerouting the signal to other growth-promoting cascades leading to resistance after a certain treatment period. Therefore, targeted cancer treatment should seek to specifically neutralise the hub proteins, which control a number of signal pathways that are crucial for cancer cell growth and survival (the Achilles heel of cancer). Another possibility is to use kinase inhibitors with broader specificity in order to neutralize more than one signalling protein. Novel treatment strategies usually apply more than one targeted inhibitor or antibody, or they combine target-specific blockers with classical cytotoxic drugs. Moreover, therapeutic efficiency may be further increased by using inhibitors that bind covalently instead of reversibly by hydrogen bonds to their respective substrates and thus permanently neutralise the target. Such second-generation, irreversible, multi-specific kinase inhibitors are currently in clinical development (see chapter by Solca et al.). In summary, the recent developments in targeted therapy for breast cancer and of other neoplastic diseases have already considerably improved cancer treatment. Moreover, this era is characterized by an intense, fast and bi-directional flow of knowledge between basic science and clinical application. This type of research is growing very rapidly and has created an entirely new field of research known as translational research, which is located right at the interface between basic science and clinical medicine. Milestone achievements during the last decade

7 Preface vii suggest that we are currently just at the beginning of a revolutionary and exciting era of cancer research, which almost certainly will tremendously improve future options for diagnosis, classification, individualisation and treatment of cancer. Vienna, Austria Maria Sibilia Christoph C. Zielinski Rupert Bartsch Thomas W. Grunt Reference 1. Jordan CV (1988) The development of tamoxifen for breast cancer therapy: a tribute lto the late Arthur L. Walpole. Breast Cancer Res Treat 11:

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9 Contents The EGFR/ErbB Family in Breast Cancer: From Signalling to Therapy... 1 Wolfgang J. Köstler and Yosef Yarden Trastuzumab as Adjuvant Treatment for Early Stage HER-2-positive Breast Cancer Rupert Bartsch and Guenther G. Steger Trastuzumab Resistance in Breast Cancer Floriana Morgillo, Michele Orditura, Teresa Troiani, Erika Martinelli, Ferdinando De Vita, and Fortunato Ciardiello Treatment with Trastuzumab Beyond Progression Gunter von Minckwitz and Cristina Pirvulescu Pertuzumab a HER-2 Dimerisation Inhibitor for the Treatment of Breast and Other Cancers Giulia Bianchi and Luca Gianni Beyond Trastuzumab: Second-Generation Targeted Therapies for HER-2-positive Breast Cancer Flavio F. Solca, Guenther R. Adolf, Hilary Jones, and Martina M. Uttenreuther-Fischer Index ix