Recent Results in Cancer Research

Transcription

1 Recent Results in Cancer Research 184 Managing Editors P. M. Schlag, Berlin H.-J. Senn, St. Gallen Associate Editors P. Kleihues, Zürich F. Stiefel, Lausanne B. Groner, Frankfurt A. Wallgren, Göteborg Founding Editor P. Rentchnik, Geneva

2 Uwe M. Martens (Ed.) Small Molecules in Oncology 1 3

3 Editor Prof. Dr. Uwe M. Martens SLK-Kliniken Heilbronn GmbH Medizinische Klinik III Am Gesundbrunnen Heilbronn Germany ISBN: e-isbn: DOI: / Springer Heidelberg Dordrecht London New York Library of Congress Control Number: Springer-Verlag Berlin Heidelberg 2010 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, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. 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: estudiocalamar Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (

4 Contents Part I Protein Kinase Inhibitors 1 Imatinib Mesylate Cornelius F. Waller 1.1 Introduction Chemical Structure Clinical Pharmacology Drug Targets Preclinical Studies Clinical Data in CML Phase I Trials Phase II Studies Phase III Study (IRIS-Trial) Side Effects/Toxicity Disease Progression and Imatinib Resistance Treatment Recommendations for the Use of Imatinib in Chronic Phase CML Imatinib in Combination with Other Drugs Imatinib Other Targets Conclusion and Future Perspectives References Erlotinib M. Steins, M. Thomas, and M. Geißler 2.1 Introduction Mechanism of Action Non-Small Cell Lung Cancer Pancreatic Adenocarcinoma Hepatocellular Carcinoma Other Tumour Entities References v

5 vi Contents 3 Axitinib (AG ) Ronan Joseph Kelly and Olivier Rixe 3.1 Introduction Structure of Molecule Preclinical Data Bioavailability in Humans Phase II Studies Axitinib in Renal Cell Carcinoma Axitinib in Pancreatic Cancer Axitinib in Metastatic Breast Cancer Axitinib in Thyroid Cancer Axitinib in Other Solid Tumors Phase III Studies Toxicity Drug Interactions Future References Lapatinib Tanja Schneider-Merck and Martin Trepel 4.1 Introduction The Epidermal Growth Factor Receptor Family of Tyrosine Kinases Human Epidermal Growth Factor Receptors and Breast Cancer Structure and Mechanism of Action Clinical Data Pharmacology Results from Clinical Trials Conclusion and Future Perspectives References Sorafenib Jens Hasskarl 5.1 Introduction Structure and Mechanism of Action Clinical Data Phase I Sorafenib in the Treatment of Renal Cell Cancer (RCC) Sorafenib in the Treatment of Lung Cancer Sorafenib in the Treatment of Hepatocellular Cancer (HCC) Sorafenib in the Treatment of Breast Cancer Sorafenib in the Treatment of Malignant Melanoma Sorafenib in the Treatment of Prostate Cancer

6 Contents vii Sorafenib in the Treatment of Head and Neck Cancer Sorafenib in the Treatment of Ovarian Cancer Sorafenib in the Treatment of Brain Tumors Sorafenib in the Treatment of Thyroid Cancer Sorafenib in the Treatment of Hematologic Diseases Conclusion and Future Perspectives References Sunitinib Daniel Y. C. Heng and Christian Kollmannsberger 6.1 Introduction Sunitinib Renal Cell Carcinoma Targets for Renal Cell Carcinoma Phase II/III Studies in Metastatic RCC Gastrointestinal Stromal Tumors Targets for Gastrointestinal Stromal Tumors GIST Clinical Trials Side Effects Drug Interactions Activity in Other Tumor Sites and Ongoing Research Conclusion References Dasatinib Markus Lindauer and Andreas Hochhaus 7.1 Introduction Structure and Mechanism of Action Inhibition of ABL Inhibition of SRC Inhibition of c-kit Inhibition of Platelet-Derived Growth Factor Receptor (PDGFR)-α and β Tyrosine Kinases Inhibition of Ephrin Receptor Tyrosine Kinases Additional Effects Clinical Data Pharmacokinetic Profile Clinical Studies with Dasatinib in CML and Other Diseases CML and Ph + ALL Overview Dasatinib and Other Diseases Safety and Tolerability Conclusion and Further Perspectives References

7 viii Contents 8 Nilotinib Alfonso Quintás-Cardama, Theo Daniel Kim, Vince Cataldo, and Philipp le Coutre 8.1 Background Preclinical and Pharmacokinetic Data Pharmacological Design Drug Targets Preclinical Activity Pharmacokinetics and Metabolism Clinical Efficacy Nilotinib Phase I Study Nilotinib After Imatinib Failure Nilotinib First-Line Therapy Nilotinib After Dasatinib Failure Toxicity Resistance to Nilotinib Outlook Conclusion References Bosutinib Gunhild Keller, Philippe Schafhausen, and Tim H. Brümmendorf 9.1 Chemical Structure Mechanism of Action SRC Kinase Inhibition Abl and bcr-abl Inhibition Bosutinib in Chronic Myeloid Leukaemia (CML) Preclinical Data Clinical Trials Bosutinib in Solid Tumours Preclinical Data Clinical Trials Conclusion and Future Directions References Part II Epigenetic Modifiers 10 Decitabine Michael Daskalakis, Nadja Blagitko-Dorfs, and Björn Hackanson 10.1 Introduction Structure and Mechanism of Action Studies of Single-Agent Decitabine in MDS and Acute Leukemias Combination Treatment in AML, MDS, and Other Diseases

8 Contents ix 10.5 Decitabine as a Preparative Agent in Allogeneic Stem Cell Transplantation Immunomodulation with Decitabine Decitabine Treatment in Other Diseases Activity of Decitabine in Patients with Acute Lymphoblastic Leukemia Activity of Decitabine in Patients with Chronic Myeloid Leukemia Activity of Decitabine in Patients with Idiopathic Myelofibrosis (IMF) Clinical Effects of Decitabine in Severe β-thalassemia and Sickle Cell Disease Efficacy of Decitabine in Patients with Solid Tumors Conclusion and Future Perspectives References Azacytidine/Azacitidine Antonia Müller and Mareike Florek 11.1 Introduction: 5-Azacytidine Novel or Almost Historic? Agent Chemical Structure Mode of Action Pharmacology Route of Administration and Dosage Bioavailability, Half-Life, Elimination, Drug Drug Interactions Safety, Side Effects, and Contraindications Clinical Use of 5-Azacytidine Early Studies Azacytidine in Myelodysplastic Syndromes (MDS) New Therapeutic Approaches Future Perspective, Experimental Studies, and Conclusion References Part III Cell Cycle Inhibitors 12 Bortezomib Hermann Einsele 12.1 Mode of Action Antitumor Effects Clinical Application of Proteasome Inhibitors Bortezomib Bortezomib-Based Combination Therapy for Multiple Myeloma

9 x Contents 12.6 Treatment Options for Patients Eligible for Transplant Next Generation Proteasome Inhibitors References Temsirolimus Christian Stock, Massimo Zaccagnini, Michael Schulze, Dogu Teber, and Jens J. Rassweiler 13.1 Introduction Development Structure and mechanism of action Clinical Data Safety and Efficacy Side Effects Conclusion and Future Perspectives References Danusertib (formerly PHA ) A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor Artur Gontarewicz and Tim H. Brümmendorf 14.1 Introduction Structure, Localization, and Functions Aurora Kinases and Cancer Inhibitors Danusertib (formerly PHA ) Conclusion References BI_ Targeting the Mitotic Kinase Polo-Like Kinase 1 (Plk1) R. Wäsch, J. Hasskarl, D. Schnerch, and M. Lübbert 15.1 Introduction Structure and Mechanism of Action Clinical Data Conclusion and Future Perspectives References Part IV Other Novel Agents 16 Imetelstat (GRN163L) - Telomerase-Based Cancer Therapy Alexander Röth, Calvin B. Harley, and Gabriela M. Baerlocher 16.1 Introduction Telomerase-Based Approaches of Cancer Treatment Telomerase Inhibition Structure of Imetelstat and Mechanism of Action

10 Contents xi 16.5 Preclinical and Clinical Data of Imetelstat Conclusion and Future Prospects References GDC Targeting the Hedgehog Signaling Pathway Christine Dierks 17.1 Introduction Structure and Mechanism of Action Clinical Data Conclusion and Future Perspectives References

11 Contributors Gabriela M. Baerlocher Department of Hematology University Hospital Bern, Freiburgstraße 3010 Bern, Switzerland Nadja Blagitko-Dorfs Tim H. Brümmendorf University Hospital Aachen Pauwelsstraße Aachen, Germany University Cancer Center Hamburg (UCCH) University Hospital Eppendorf Martinistraße Hamburg, Germany Vince Cataldo Division of Cancer Medicine, M.D. Anderson Cancer Center 1515 Holcombe Boulevard Houston, TX 77030, USA Philipp le Coutre Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Medizinische Klinik m.s. Hämatologie und Onkologie Augustenburger Platz Berlin, Germany Philipp.lecoutre@charite.de Michael Daskalakis michael.daskalakis@uniklinik-freiburg.de Christine Dierks christine.dierks@uniklinik-freiburg.de Hermann Einsele Department of Internal Medicine II University Hospital Würzburg Josef-Schneider Straße Würzburg, Germany Einsele_h@klinik.uni-wuerzburg.de xiii

12 xiv Contributors Mareike Florek Stanford University, School of Medicine Division of Blood and Marrow Transplantation, 269 West Campus Drive CCSR, Stanford, CA 94305, USA Michael Geißler Städtische Kliniken Esslingen Department of Oncology Gastroenterology and Internal Medicine Hirschlandstraße Esslingen, Germany Artur Gontarewicz Department of Oncology and Hematology University Hospital Hamburg-Eppendorf Martinistraße Hamburg, Germany Björn Hackanson Calvin B. Harley Geron Corporation, Menlo Park, CA, USA Jens Hasskarl Daniel Y.C. Heng BC Cancer Agency 600 West 10th Avenue Vancouver, British Columbia, V5Z 4E6 Canada Andreas Hochhaus III. Medizinische Klinik Hämatologie und Internistische Onkologie Universitätsmedizin Mannheim Universität Heidelberg Theodor-Kutzer-Ufer Mannheim, Germany Universitätsklinikum Jena Klinik für Innere Medizin II Abteilung Hämatologie und Internistische Onkologie, Erlanger Allee Jena, Germany hochhaus@uni-hd.de Andreas.Hochhaus@med3.ma.uni-heidel berg.de Gunhild Keller Klinik für Onkologie und Hämatologie mit der Sektion Pneumologie Universitäres Cancer Center Hamburg (UCCH) Universitäts-Klinikum Hamburg-Eppendorf Martinistraße Hamburg, Germany Ronan Joseph Kelly Thoracic Oncology Department Medical Oncology Branch National Cancer Institute Bethesda, MD 20892, USA kellyro@mail.nih.gov Theo Daniel Kim Charité Universitätsmedizin Berlin Campus Virchow-Klinikum Medizinische Klinik m.s. Hämatologie und Onkologie Augustenburger Platz 1 Berlin 13353, Germany

13 Contributors xv Christian Kollmannsberger BC Cancer Agency 600 West 10th Avenue Vancouver, British Columbia, V5Z 4E6 Canada Markus Lindauer SLK-Kliniken Heilbronn GmbH Medizinische Klinik III Am Gesundbrunnen Heilbronn Germany Michael Lübbert Antonia Müller Stanford University, School of Medicine Division of Blood and Marrow Transplantation 269 West Campus Drive CCSR, Stanford, CA 94305, USA Alfonso Quintás-Cardama Department of Leukemia Division of Cancer Medicine M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Houston TX 77030, USA Jens J. Rassweiler Department of Urology SLK-Kliniken Heilbronn GmbH Medizinische Klinik III Am Gesundbrunnen Heilbronn Germany Olivier Rixe Medical Oncology Branch National Cancer Institute Bethesda, MD USA Alexander Röth Department of Hematology University Hospital Essen University of Duisburg-Essen Hufelandstraße Essen, Germany Philippe Schafhausen Klinik für Onkologie und Hämatologie mit der Sektion Pneumologie Universitäres Cancer Center Hamburg (UCCH) Universitäts-Klinikum Hamburg-Eppendorf Martinistraße Hamburg, Germany Tanja Schneider-Merck Department of Oncology and Hematology University Medical Center Hamburg-Eppendorf Martinistraße Hamburg, Germany

14 xvi Contributors Schnerch D. Michael Schulze Department of Urology SLK-Kliniken Heilbronn GmbH Am Gesundbrunnen Heilbronn Germany Martin Steins Clinic for Thoracic Diseases University of Heidelberg Amalienstraße Heidelberg, Germany martin.steins@thoraxklinik-heidelberg.de Christian Stock Department of Urology SLK-Kliniken Heilbronn GmbH Am Gesundbrunnen Heilbronn Germany Dogu Teber Department of Urology SLK-Kliniken Heilbronn GmbH Am Gesundbrunnen Heilbronn Germany Martin Trepel University Medical Center Hamburg-Eppendorf Department of Oncology and Hematology Martinistraße Hamburg, Germany m.trepel@uke.de Cornelius F. Waller cornelius.waller@uniklinik-freiburg.de Ralph Wäsch ralph.waesch@uniklinik-freiburg.de Massimo Zaccagnini Department of Urology U. Bracci Policlinico Umberto I University of Rome La Sapienza Italy Michael Thomas Clinic for Thoracic Diseases University of Heidelberg Amalienstraße Heidelberg, Germany Michael.thomas@thoraxklinik-heidelberg.de