Small Molecules in Oncology (eBook)

Recent Results in Cancer Research 1
Protein Kinase Inhibitors 15
Imatinib Mesylate 16
Introduction 16
Chemical Structure 18
Clinical Pharmacology 19
Drug Targets 19
Preclinical Studies 19
Clinical Data in CML 21
Phase I Trials 21
Phase II Studies 21
Phase III Study (IRIS-Trial) 22
Side Effects/Toxicity 23
Disease Progression and Imatinib Resistance 24
Treatment Recommendations for the Use of Imatinib in Chronic Phase CML 27
Imatinib in Combination with Other Drugs 28
Imatinib – Other Targets 28
Conclusion and Future Perspectives 29
References 30
Erlotinib 34
Introduction 34
Mechanism of Action 35
Non-Small Cell Lung Cancer 35
Pancreatic Adenocarcinoma 37
Hepatocellular Carcinoma 40
Other Tumour Entities 41
References 41
Axitinib (AG-013736) 45
Introduction 45
Structure of Molecule 46
Preclinical Data 46
Bioavailability in Humans 48
Phase II Studies 48
3.4.1Axitinib in Renal Cell Carcinoma 48
Axitinib in Pancreatic Cancer 49
Axitinib in Metastatic Breast Cancer 50
Axitinib in Thyroid Cancer 50
Axitinib in Other Solid Tumors 51
Phase III Studies 51
Toxicity 52
Drug Interactions 53
Future 54
References 54
Lapatinib 57
4.1.Introduction 57
4.1.1.The Epidermal Growth Factor Receptor Family of Tyrosine Kinases 57
4.1.2.Human Epidermal Growth Factor Receptors and Breast Cancer 59
4.2.Structure and Mechanism of Action 59
4.3.Clinical Data 61
4.3.1.Pharmacology 61
4.3.2.Results from Clinical Trials 61
4.3.2.1.Efficacy 61
4.3.2.2.Tolerability 66
4.4.Conclusion and Future Perspectives 66
References 67
Sorafenib 72
5.1.Introduction 72
5.2.Structure and Mechanism of Action 73
5.3.Clinical Data 75
5.3.1.Phase I 75
5.3.2.Sorafenib in the Treatment of Renal Cell Cancer (RCC) 75
5.3.3.Sorafenib in the Treatment of Lung Cancer 77
5.3.4.Sorafenib in the Treatment of Hepatocellular Cancer (HCC) 77
5.3.5.Sorafenib in the Treatment of Breast Cancer 77
5.3.6.Sorafenib in the Treatment of Malignant Melanoma 77
5.3.7.Sorafenib in the Treatment of Prostate Cancer 78
5.3.8.Sorafenib in the Treatment of Head and Neck Cancer 78
5.3.9.Sorafenib in the Treatment of Ovarian Cancer 78
5.3.10.Sorafenib in the Treatment of Brain Tumors 78
5.3.11.Sorafenib in the Treatment of Thyroid Cancer 78
5.3.12.Sorafenib in the Treatment of Hematologic Diseases 78
5.4.Conclusion and Future Perspectives 79
References 79
Sunitinib 82
Introduction 82
Sunitinib 82
Renal Cell Carcinoma 83
6.3.1Targets for Renal Cell Carcinoma 83
Phase II/III Studies in Metastatic RCC 85
Gastrointestinal Stromal Tumors 86
Targets for Gastrointestinal Stromal Tumors 86
GIST Clinical Trials 86
Side Effects 87
Drug Interactions 89
Activity in Other Tumor Sites and Ongoing Research 89
Conclusion 90
References 90
Dasatinib 94
Introduction 94
Structure and Mechanism of Action 96
Inhibition of ABL 97
Inhibition of SRC 98
Inhibition of c-KIT 98
Inhibition of Platelet-Derived Growth Factor Receptor (PDGFR)-.a. and .b. Tyrosine Kinases 99
Inhibition of Ephrin Receptor Tyrosine Kinases 99
Additional Effects 99
Clinical Data 99
Pharmacokinetic Profile 99
Clinical Studies with Dasatinib in CML and Other Diseases 100
CML and Ph.+. ALL – Overview 100
Phase I Dose Escalation Study 100
Phase II: Chronic Phase CML (START C) 101
Accelerated Phase CML (START A) 101
Myeloid Blast Phase CML (START B) and Lymphatic Blast Phase CML (START L) 101
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (ALL) 103
Central Nervous System Disease of Ph.+. Blast Phase CML or Ph.+. ALL 103
Randomized Comparison of Dasatinib vs. High-Dose Imatinib (START R) 103
Dasatinib in Previously Untreated Chronic Myelogenous Leukemia Patients 104
Dose Optimization Trial in Chronic Phase CML 104
Dose Optimization Phase III Trial in Advanced Phase CML 105
Dasatinib and Other Diseases 106
Phase I Study in GIST 106
Phase I Study in Solid Tumors 106
Phase II Study of Dasatinib in Philadelphia Chromosome Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocy 106
Phase II Study with Dasatinib in Patients with Hormone Refractory Progressive Prostate Cancer 107
Safety and Tolerability 107
Hematological Toxicity 107
Fluid Retention 107
Bleeding 109
QT-Prolongation 109
Conclusion and Further Perspectives 109
References 110
Nilotinib 114
Background 114
Preclinical and Pharmacokinetic Data 115
Pharmacological Design 115
Drug Targets 115
Preclinical Activity 115
Pharmacokinetics and Metabolism 116
Clinical Efficacy 116
Nilotinib Phase I Study 117
Nilotinib After Imatinib Failure 117
Nilotinib First-Line Therapy 119
Nilotinib After Dasatinib Failure 119
Toxicity 120
Resistance to Nilotinib 123
Outlook 124
Conclusion 125
References 125
Bosutinib 129
Chemical Structure 129
Mechanism of Action 129
SRC Kinase Inhibition 130
Abl and bcr-abl Inhibition 130
Bosutinib in Chronic Myeloid Leukaemia (CML) 131
Preclinical Data 131
Clinical Trials 131
CML Chronic Phase (CP CML) 131
Accelerated Phase (AP CML), Blast Phase (BP CML) and Ph.+. ALL 132
Bosutinib in Solid Tumours 134
Preclinical Data 134
Breast Cancer 134
Colorectal Cancer 134
Non-Small Cell Lung Cell Cancer (NSCLC) 134
Clinical Trials 135
Conclusion and Future Directions 135
References 136
Epigenetic Modifiers 138
Decitabine 139
Introduction 139
Structure and Mechanism of Action 140
Studies of Single-Agent Decitabine in MDS and Acute Leukemias 141
Combination Treatment in AML, MDS, and Other Diseases 143
Decitabine as a Preparative Agent in Allogeneic Stem Cell Transplantation 148
Immunomodulation with Decitabine 150
Decitabine Treatment in Other Diseases 151
Activity of Decitabine in Patients with Acute Lymphoblastic Leukemia 151
Activity of Decitabine in Patients with Chronic Myeloid Leukemia 152
Activity of Decitabine in Patients with Idiopathic Myelofibrosis (IMF) 153
Clinical Effects of Decitabine in Severe .b.-Thalassemia and Sickle Cell Disease 153
Efficacy of Decitabine in Patients with Solid Tumors 154
Conclusion and Future Perspectives 156
References 157
5-Azacytidine/Azacitidine 166
Introduction...: 5-Azacytidine – Novel or Almost Historic? 166
Agent 167
Chemical Structure 167
Mode of Action 167
Pharmacology 168
Route of Administration and Dosage 168
Bioavailability, Half-Life, Elimination, Drug–Drug Interactions 169
Safety, Side Effects, and Contraindications 169
Hematologic Toxicity/Myelosuppression 169
Gastrointestinal Toxicity 170
Hepatotoxicity 170
Nephrotoxicity 170
Other 170
Teratogenicity 170
Clinical Use of 5-Azacytidine 171
Early Studies 171
5-Azacytidine in Myelodysplastic Syndromes (MDS) 171
New Therapeutic Approaches 173
Future Perspective, Experimental Studies, and Conclusion 173
References 174
Cell Cycle Inhibitors 178
Bortezomib 179
Mode of Action 179
Antitumor Effects 181
Clinical Application of Proteasome Inhibitors 182
Bortezomib 183
Bortezomib-Based Combination Therapy for Multiple Myeloma 184
Treatment Options for Patients Eligible for Transplant 185
Next Generation Proteasome Inhibitors 185
References 186
Temsirolimus 194
Introduction 194
Development 195
Structure and mechanism of action 195
Clinical Data 197
Safety and Efficacy 197
Side Effects 198
Conclusion and Future Perspectives 199
References 200
Danusertib (formerly PHA-739358) – A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibit 203
Introduction 203
Structure, Localization, and Functions 204
Aurora Kinases and Cancer 205
Inhibitors 206
Danusertib (formerly PHA-739358) 208
Conclusion 212
References 213
BI_2536 - Targeting the Mitotic Kinase Polo-Like Kinase 1 (Plk1) 219
Introduction 219
Structure and Mechanism of Action 221
Clinical Data 221
Conclusion and Future Perspectives 222
References 222
Other Novel Agents 223
Imetelstat (GRN163L) -Telomerase-Based Cancer Therapy 224
Introduction 224
Telomerase-Based Approaches of Cancer Treatment 227
Telomerase Inhibition 227
Structure of Imetelstat and Mechanism of Action 227
Preclinical and Clinical Data of Imetelstat 228
Conclusion and Future Prospects 232
References 232
GDC-0449 - Targeting the Hedgehog Signaling Pathway 238
Introduction 238
Structure and Mechanism of Action 239
Clinical Data 239
Conclusion and Future Perspectives 240
References 240