Small Molecules in Oncology

by Martens, Uwe M.

• ISBN13: 9783642012211
• ISBN10: 3642012213
• Edition: 1st
• Format: Hardcover
• Copyright: 2009-11-01
• Publisher: Springer Verlag

Summary

Extensive research into the molecular mechanisms of cancer disease has heralded a new age of targeted therapy. In malignant cells, key proteins that are crucial to tumor growth and survival are now being targeted directly with rationally designed inhibitors. Apart from monoclonal antibodies, small molecule therapeutics such as oncogenic protein kinase inhibitors are attracting a vast amount of investigational attention. This textbook, written by acknowledged experts, 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.

Table of Contents

Protein Kinase Inhibitors
Imatinib Mesylate	p. 3
Introduction	p. 3
Chemical Structure	p. 5
Clinical Pharmacology	p. 6
Drug Targets	p. 6
Preclinical Studies	p. 6
Clinical Data in CML	p. 8
Phase I Trials	p. 8
Phase II Studies	p. 8
Phase III Study (IRIS-Trial)	p. 9
Side Effects/Toxicity	p. 10
Disease Progression and Imatinib Resistance	p. 11
Treatment Recommendations for the Use of Imatinib in Chronic Phase CML	p. 34
Imatinib in Combination with Other Drugs	p. 15
Imatinib - Other Targets	p. 15
Conclusion and Future Perspectives	p. 16
References	p. 17
Erlotinib	p. 21
Introduction	p. 21
Mechanism of Action	p. 22
Non-Small Cell Lung Cancer	p. 22
Pancreatic Adenocarcinoma	p. 24
Hepatocellular Carcinoma	p. 27
Other Tumour Entities	p. 28
References	p. 28
Axirinib (AG-013736)	p. 33
Introduction	p. 33
Structure of Molecule	p. 34
Preclinical Data	p. 34
Bioavailability in Humans	p. 36
Phase II Studies	p. 36
Axirinib in Renal Cell Carcinoma	p. 36
Axirinib in Pancreatic Cancer	p. 37
Axirinib in Metastatic Breast Cancer	p. 38
Axirinib in Thyroid Cancer	p. 38
Axirinib in Other Solid Tumors	p. 39
Phase III Studies	p. 39
Toxicity	p. 40
Drag Interactions	p. 41
Future	p. 42
References	p. 42
Lapatinib	p. 45
Introduction	p. 45
The Epidermal Growth Factor Receptor Family of Tyrosine Kinases	p. 45
Human Epidermal Growth Factor Receptors and Breast Cancer	p. 47
Structure and Mechanism of Action	p. 47
Clinical Data	p. 49
Pharmacology	p. 49
Results from Clinical Trials	p. 49
Conclusion and Future Perspectives	p. 54
References	p. 55
Sorafenib	p. 61
Introduction	p. 61
Structure and Mechanism of Action	p. 62
Clinical Data	p. 64
Phase 1	p. 64
Sorafenib in the Treatment of Renal Cell Cancer (RCC)	p. 64
Sorafenib in the Treatment of Lung Cancer	p. 66
Sorafenib in the Treatment of Hepatocellular Cancer (HCC)	p. 66
Sorafenib in the Treatment of Breast Cancer	p. 66
Sorafenib in the Treatment of Malignant Melanoma	p. 66
Sorafenib in the Treatment of Prostate Cancer	p. 67
Sorafenib in the Treatment of Head and Neck Cancer	p. 67
Sorafenib in the Treatment of Ovarian Cancer	p. 67
Sorafenib in the Treatment of Brain Tumors	p. 67
Sorafenib in the Treatment of Thyroid Cancer	p. 67
Sorafenib in the Treatment of Hematologic Diseases	p. 67
Conclusion and Future Perspectives	p. 68
References	p. 68
Sunitinib	p. 71
Introduction	p. 71
Sunitinib	p. 71
Renal Cell Carcinoma	p. 72
Targets for Renal Cell Carcinoma	p. 72
Phase II/III Studies in Metastatic RCC	p. 74
Gastrointestinal Stromal Tumors	p. 75
Targets for Gastrointestinal Stromal Tumors	p. 75
GIST Clinical Trials	p. 75
Side Effects	p. 76
Drug Interactions	p. 78
Activity in Other Tumor Sites and Ongoing Research	p. 78
Conclusion	p. 79
References	p. 79
Dasatinib	p. 83
Introduction	p. 83
Structure and Mechanism of Action	p. 85
Inhibition of ABL	p. 86
Inhibition of SRC	p. 87
Inhibition of c-KJT	p. 87
Inhibition of Platelet-Derived Growth Factor Receptor (PDGFR)-¿ and ß Tyrosine Kinases	p. 88
Inhibition of Ephrin Receptor Tyrosine Kinases	p. 88
Additional Effects	p. 88
Clinical Data	p. 88
Phannacokinetic Profile	p. 88
Clinical Studies with Dasatinib in CML and Other Diseases	p. 89
CML and Ph+ ALL-Overview	p. 89
Dasatinib and Other Diseases	p. 95
Safety and Tolerability	p. 96
Conclusion and Further Perspectives	p. 98
References	p. 99
Nilotinib	p. 103
Background	p. 103
Preclinical and Pharmacokinetic Data	p. 104
Pharmacological Design	p. 104
Drug Targets	p. 104
Preclinical Activity	p. 104
Pharmacokinetics and Metabolism	p. 105
Clinical Efficacy	p. 105
Nilotinib Phase I Study	p. 106
Nilotinib After Imatinib Failure	p. 106
Nilotinib First-Line Therapy	p. 108
Nilotinib After Dasatinib Failure	p. 108
Toxicity	p. 109
Resistance to Nilotinib	p. 112
Outlook	p. 113
Conclusion	p. 114
References	p. 114
Bosutinib	p. 119
Chemical Structure	p. 119
Mechanism of Action	p. 119
SRC Kinase Inhibition	p. 120
Abl and bcr-abl Inhibition	p. 120
Bosutinib in Chronic Myeloid Leukaemia (CML)	p. 121
Preclinical Data	p. 121
Clinical Trials	p. 121
Bosutinib in Solid Tumours	p. 124
Preclinical Data	p. 124
Clinical Trials	p. 125
Conclusion and Future Directions	p. 125
References	p. 126
Epigenetic Modifiers
Decitabine	p. 131
Introduction	p. 131
Structure and Mechanism of Action	p. 132
Studies of Single-Agent Decitabine in MDS and Acute Leukemias	p. 133
Combination Treatment in AML, MDS, and Other Diseases	p. 135
Decitabine as a Preparative Agent in Allogeneic Stem Cell Transplantation	p. 140
Immunomodulation with Decitabine	p. 142
Decitabine Treatment in Other Diseases	p. 143
Activity of Decitabine in Patients with Acute Lymphoblastic Leukemia	p. 143
Activity of Decitabine in Patients with Chronic Myeloid Leukemia	p. l44
Activity of Decitabine in Patients with Idiopathic Myelofibrosis (IMF)	p. 145
Clinical Effects of Decitabine in Severe ß-Thalassemia and Sickle Cell Disease	p. 145
Efficacy of Decitabine in Patients with Solid Tumors	p. 146
Conclusion and Future Perspectives	p. 148
References	p. 149
5-Azacytidine/Azacitidine	p. 149
Introduction: 5-Azacytidine - Novel or Almost Historic?	p. 159
Agent	p. 160
Chemical Structure	p. 160
Mode of Action	p. 160
Pharmacology	p. 161
Route of Administration and Dosage	p. 161
Bioavailability, Half-Life, Elimination, Drug-Drug Interactions	p. 162
Safety, Side Effects, and Contraindications	p. 162
Clinical Use of 5-Azacytidine	p. 164
Early Studies	p. 164
5-Azacytidine in Myelodysplastic Syndromes (MDS)	p. 164
New Therapeutic Approaches	p. 166
Future Perspective, Experimental Studies, and Conclusion	p. 166
References	p. 167
Cell Cycle Inhibitors
Bortezomib	p. 173
Mode of Action	p. 173
Antitumor Effects	p. 175
Clinical Application of Proteasome Inhibitors	p. 176
Bortezomib	p. 177
Bortezomib-Based Combination Therapy for Multiple Myeloma	p. 178
Treatment Options for Patients Eligible for Transplant	p. 179
Next Generation Proteasome Inhibitors	p. 179
References	p. 180
Temsirolimus	p. 189
Introduction	p. 189
Development	p. 190
Structure and mechanism of action	p. 190
Clinical Data	p. 192
Safety and Efficacy	p. 192
Side Effects	p. 193
Conclusion and Future Perspectives	p. 194
References	p. 195
Danusertib (formerly PHA-739358) - A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor	p. 199
Introduction	p. 199
Structure, Localization, and Functions	p. 200
Aurora Kinases and Cancer	p. 201
Inhibitors	p. 202
Danusertib (formerly PHA-739358)	p. 204
Conclusion	p. 208
References	p. 209
BI_2536 - Targeting the Mitotic Kinase Polo-Like Kinase 1 (Plkl)	p. 215
Introduction	p. 215
Structure and Mechanism of Action	p. 217
Clinical Data	p. 217
Conclusion and Future Perspectives	p. 218
References	p. 218
Other Novel Agents
Imetelstat (GRN163L) - Telomerase-Based Cancer Therapy	p. 221
Introduction	p. 221
Telomerase-Based Approaches of Cancer Treatment	p. 224
Telomerase Inhibition	p. 224
Structure of Imetelstat and Mechanism of Action	p. 224
Preclinical and Clinical Data of Imetelstat	p. 225
Conclusion and Future Prospects	p. 229
References	p. 229
GDC-0449 - Targeting the Hedgehog Signaling Pathway	p. 235
Introduction	p. 235
Structure and Mechanism of Action	p. 236
Clinical Datak	p. 236
Conclusion and Future Perspectives	p. 237
References	p. 237
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