Small Molecules in Oncology

Small Molecules in Oncology

by Uwe M. Martens (Editor)

Paperback(2010)

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Overview

Written by acknowledged experts, this text provides a broad overview of the small molecules currently used for the treatment of malignant diseases, and discusses interesting novel compounds that are in the process of clinical development to combat cancer.

Product Details

ISBN-13: 9783642261459
Publisher: Springer Berlin Heidelberg
Publication date: 04/06/2012
Series: Recent Results in Cancer Research , #184
Edition description: 2010
Pages: 238
Product dimensions: 6.10(w) x 9.25(h) x 0.03(d)

About the Author

Uwe Martens, Prof. Dr. med., is chair of the Cancer Center Heilbronn-Franken and head of the Department of Hematology and Oncology at the SLK Clinic Heilbronn, which is an academic teaching hospital of the University of Heidelberg. He graduated in Medicine from the University of Freiburg and continued his medical and scientific training at the Medical University Center in Freiburg and at the BC Cancer Research Center in Vancouver. His scientific focus is the development of personalized cancer therapy and immunotherapy. He is a co-founder of the MOLIT Institute for Personalized Medicine at the science and technology park in Heilbronn, which aims to rapidly translate precision medicine into standard care.

Table of Contents

Part I Protein Kinase Inhibitors

1 Imatinib Mesylate Cornelius F. Waller 3

1.1 Introduction 3

1.2 Chemical Structure 5

1.3 Clinical Pharmacology 6

1.4 Drug Targets 6

1.5 Preclinical Studies 6

1.6 Clinical Data in CML 8

1.6.1 Phase I Trials 8

1.6.2 Phase II Studies 8

1.6.3 Phase III Study (IRIS-Trial) 9

1.6.4 Side Effects/Toxicity 10

1.7 Disease Progression and Imatinib Resistance 11

1.8 Treatment Recommendations for the Use of Imatinib in Chronic Phase CML 34

1.9 Imatinib in Combination with Other Drugs 15

1.10 Imatinib - Other Targets 15

1.11 Conclusion and Future Perspectives 16

References 17

2 Erlotinib M. Steins M. Thomas M. Geiser 21

2.1 Introduction 21

2.2 Mechanism of Action 22

2.3 Non-Small Cell Lung Cancer 22

2.4 Pancreatic Adenocarcinoma 24

2.5 Hepatocellular Carcinoma 27

2.6 Other Tumour Entities 28

References 28

3 Axirinib (AG-013736) Reman Joseph Kelly Olivier Rixe 33

3.1 Introduction 33

3.2 Structure of Molecule 34

3.3 Preclinical Data 34

3.3.1 Bioavailability in Humans 36

3.4 Phase II Studies 36

3.4.1 Axirinib in Renal Cell Carcinoma 36

3.4.2 Axirinib in Pancreatic Cancer 37

3.4.3 Axirinib in Metastatic Breast Cancer 38

3.4.4 Axirinib in Thyroid Cancer 38

3.4.5 Axirinib in Other Solid Tumors 39

3.5 Phase III Studies 39

3.6 Toxicity 40

3.7 Drag Interactions 41

3.8 Future 42

References 42

4 Lapatinib Tanja Schneider-Merck Martin Trepel 45

4.1 Introduction 45

4.1.1 The Epidermal Growth Factor Receptor Family of Tyrosine Kinases 45

4.1.2 Human Epidermal Growth Factor Receptors and Breast Cancer 47

4.2 Structure and Mechanism of Action 47

4.3 Clinical Data 49

4.3.1 Pharmacology49

4.3.2 Results from Clinical Trials 49

4.4 Conclusion and Future Perspectives 54

References 55

5 Sorafenib Jens Hasskarl 61

5.1 Introduction 61

5.2 Structure and Mechanism of Action 62

5.3 Clinical Data 64

5.3.1 Phase 1 64

5.3.2 Sorafenib in the Treatment of Renal Cell Cancer (RCC) 64

5.3.3 Sorafenib in the Treatment of Lung Cancer 66

5.3.4 Sorafenib in the Treatment of Hepatocellular Cancer (HCC) 66

5.3.5 Sorafenib in the Treatment of Breast Cancer 66

5.3.6 Sorafenib in the Treatment of Malignant Melanoma 66

5.3.7 Sorafenib in the Treatment of Prostate Cancer 67

5.3.8 Sorafenib in the Treatment of Head and Neck Cancer 67

5.3.9 Sorafenib in the Treatment of Ovarian Cancer 67

5.3.10 Sorafenib in the Treatment of Brain Tumors 67

5.3.11 Sorafenib in the Treatment of Thyroid Cancer 67

5.3.12 Sorafenib in the Treatment of Hematologic Diseases 67

5.4 Conclusion and Future Perspectives 68

References 68

6 Sunitinib Daniel Y. C. Heng Christian Kollmannsberger 71

6.1 Introduction 71

6.2 Sunitinib 71

6.3 Renal Cell Carcinoma 72

6.3.1 Targets for Renal Cell Carcinoma 72

6.3.2 Phase II/III Studies in Metastatic RCC 74

6.4 Gastrointestinal Stromal Tumors 75

6.4.1 Targets for Gastrointestinal Stromal Tumors 75

6.4.2 GIST Clinical Trials 75

6.4.3 Side Effects 76

6.4.4 Drug Interactions 78

6.4.5 Activity in Other Tumor Sites and Ongoing Research 78

6.5 Conclusion 79

References 79

7 Dasatinib Markus Lindauer Andreas Hocbhaus 83

7.1 Introduction 83

7.2 Structure and Mechanism of Action 85

7.2.1 Inhibition of ABL 86

7.2.2 Inhibition of SRC 87

7.2.3 Inhibition of c-KJT 87

7.2.4 Inhibition of Platelet-Derived Growth Factor Receptor (PDGFR)-α and β Tyrosine Kinases 88

7.2.5 Inhibition of Ephrin Receptor Tyrosine Kinases 88

7.2.6 Additional Effects 88

7.3 Clinical Data 88

7.3.1 Phannacokinetic Profile 88

7.3.2 Clinical Studies with Dasatinib in CML and Other Diseases 89

7.3.3 CML and Ph+ ALL-Overview 89

7.3.4 Dasatinib and Other Diseases 95

7.3.5 Safety and Tolerability 96

7.4 Conclusion and Further Perspectives 98

References 99

8 Nilotinib Alfonso Quintás-Cardama Theo Daniel Kim Vince Cataldo Philipp le Coutre 103

8.1 Background 103

8.2 Preclinical and Pharmacokinetic Data 104

8.2.1 Pharmacological Design 104

8.2.2 Drug Targets 104

8.2.3 Preclinical Activity 104

8.2.4 Pharmacokinetics and Metabolism 105

8.3 Clinical Efficacy 105

8.3.1 Nilotinib Phase I Study 106

8.3.2 Nilotinib After Imatinib Failure 106

8.3.3 Nilotinib First-Line Therapy 108

8.3.4 Nilotinib After Dasatinib Failure 108

8.3.5 Toxicity 109

8.3.6 Resistance to Nilotinib 112

8.4 Outlook 113

8.5 Conclusion 114

References 114

9 Bosutinib Gunhild Keller Philippe Schafhausen Tim H. Brümmendorf 119

9.1 Chemical Structure 119

9.2 Mechanism of Action 119

9.2.1 SRC Kinase Inhibition 120

9.2.2 Abl and bcr-abl Inhibition 120

9.3 Bosutinib in Chronic Myeloid Leukaemia (CML) 121

9.3.1 Preclinical Data 121

9.3.2 Clinical Trials 121

9.4 Bosutinib in Solid Tumours 124

9.4.1 Preclinical Data 124

9.4.2 Clinical Trials 125

9.5 Conclusion and Future Directions 125

References 126

Part II Epigenetic Modifiers

10 Decitabine Michael Daskalakis Nadja Blagitko-Dorfs Björn Hackanson 131

10.1 Introduction 131

10.2 Structure and Mechanism of Action 132

10.3 Studies of Single-Agent Decitabine in MDS and Acute Leukemias 133

10.4 Combination Treatment in AML, MDS, and Other Diseases 135

10.5 Decitabine as a Preparative Agent in Allogeneic Stem Cell Transplantation 140

10.6 Immunomodulation with Decitabine 142

10.7 Decitabine Treatment in Other Diseases 143

10.7.1 Activity of Decitabine in Patients with Acute Lymphoblastic Leukemia 143

10.7.2 Activity of Decitabine in Patients with Chronic Myeloid Leukemia l44

10.7.3 Activity of Decitabine in Patients with Idiopathic Myelofibrosis (IMF) 145

10.7.4 Clinical Effects of Decitabine in Severe β-Thalassemia and Sickle Cell Disease 145

10.7.5 Efficacy of Decitabine in Patients with Solid Tumors 146

10.8 Conclusion and Future Perspectives 148

References 149

11 5-Azacytidine/Azacitidine Antonia Müller Mareike Florek 149

11.1 Introduction: 5-Azacytidine - Novel or Almost Historic? 159

11.2 Agent 160

11.2.1 Chemical Structure 160

11.2.2 Mode of Action 160

11.3 Pharmacology 161

11.3.1 Route of Administration and Dosage 161

11.3.2 Bioavailability, Half-Life, Elimination, Drug-Drug Interactions 162

11.3.3 Safety, Side Effects, and Contraindications 162

11.4 Clinical Use of 5-Azacytidine 164

11.4.1 Early Studies 164

11.4.2 5-Azacytidine in Myelodysplastic Syndromes (MDS) 164

11.4.3 New Therapeutic Approaches 166

11.5 Future Perspective, Experimental Studies, and Conclusion 166

References 167

Part III Cell Cycle Inhibitors

12 Bortezomib Hermann Einsele 173

12.1 Mode of Action 173

12.2 Antitumor Effects 175

12.3 Clinical Application of Proteasome Inhibitors 176

12.4 Bortezomib 177

12.5 Bortezomib-Based Combination Therapy for Multiple Myeloma 178

12.6 Treatment Options for Patients Eligible for Transplant 179

12.7 Next Generation Proteasome Inhibitors 179

References 180

13 Temsirolimus Christian Stock Massimo Zaccagnini Michael Schulze Dogu Teber Jens J. Rassweiler 189

13.1 Introduction 189

13.2 Development 190

13.3 Structure and mechanism of action 190

13.4 Clinical Data 192

13.5 Safety and Efficacy 192

13.6 Side Effects 193

13.7 Conclusion and Future Perspectives 194

References 195

14 Danusertib (formerly PHA-739358) - A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor Artur Gontarewicz Tim H. Brümmendorf 199

14.1 Introduction 199

14.2 Structure, Localization, and Functions 200

14.3 Aurora Kinases and Cancer 201

14.4 Inhibitors 202

14.5 Danusertib (formerly PHA-739358) 204

14.6 Conclusion 208

References 209

15 BI_2536 - Targeting the Mitotic Kinase Polo-Like Kinase 1 (Plkl) R. Wäsch J. Hasskarl D. Schnerch M. Lübbert 215

15.1 Introduction 215

15.2 Structure and Mechanism of Action 217

15.3 Clinical Data 217

15.4 Conclusion and Future Perspectives 218

References 218

Part IV Other Novel Agents

16 Imetelstat (GRN163L) - Telomerase-Based Cancer Therapy Alexander Röth Calvin B Harley Gabriela M Baerlocher 221

16.1 Introduction 221

16.2 Telomerase-Based Approaches of Cancer Treatment 224

16.3 Telomerase Inhibition 224

16.4 Structure of Imetelstat and Mechanism of Action 224

16.5 Preclinical and Clinical Data of Imetelstat 225

16.6 Conclusion and Future Prospects 229

References 229

17 GDC-0449 - Targeting the Hedgehog Signaling Pathway Christine Dierks 235

17.1 Introduction 235

17.2 Structure and Mechanism of Action 236

17.3 Clinical Datak 236

17.4 Conclusion and Future Perspectives 237

References 237

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