Phosphoinositide 3-kinase in Health and Disease (eBook)

Phosphoinositide 3-kinase in Health and Disease 3
Volume 2 3
Contents 5
Contributors 7
PI3K: From the Bench to the Clinic and Back 11
1 The Discovery of the PI3K Signalling Pathway and Its Potential as a Therapeutic Target 12
2 PI3K and Human Disease 14
3 The Development of PI3K Inhibitors for Human Disease Starts to Inform Basic Science 15
4 Some Outstanding Questions in PI3K Biology and Signalling 18
5 Concluding Remarks 20
References 21
Oncogenic Mutations of PIK3CA in Human Cancers 30
1 Introduction 31
2 Links Between the PI3K Pathway and Cancer 31
3 High Throughput Sequencing of Gene Families in Human Cancer 32
4 PIK3CA is Somatically Mutated in Colorectal Cancer 32
5 PIK3CA is Mutated in a Wide Variety of Human Tumor Types 33
6 Somatic Mutations in the PI3K Pathway Typically Occur in a Mutually Exclusive Fashion 40
7 Conclusion 42
References 43
Structural Effects of Oncogenic PI3Ka Mutations 51
1 Introduction 52
2 Description of the Structure 53
3 Association with the Lipid Membrane 55
4 Cancer-Specific Mutations 56
5 Summary and Conclusions 60
References 61
Comparing the Roles of the p110a and p110beta Isoforms of PI3K in Signaling and Cancer 62
1 Introduction 63
2 Class IA PI3Ks 64
3 Mechanisms of Activation of Class IA p110 Isoforms 64
3.1 Early Studies on In Vitro p110a/beta Activation 64
3.2 Studies on p110 Activation Using Engineered Mice 67
3.3 Unresolved Issues 68
4 Downstream Signaling: Acting Out Through AKT and PDK1 70
4.1 AKT Signaling 70
5 PI3K Isoforms in Cancer 71
5.1 Deregulated PI3K Pathway Components 72
5.2 Targeting PI3K in Cancer 73
5.3 p110a as a Viable Tumor Target 73
5.4 p110beta as a Drug Target 75
5.5 What Are the Take-Home Messages from p110-Isoform Knock-Out Studies In Vivo? 76
5.6 Kinase-Independent Roles of p110-Isoforms 76
6 Conclusions 78
References 78
Phosphatidylinositol 3-Kinase: The Oncoprotein 85
1 Phosphatidylinositol 3-Kinases and Cancer 86
2 Cancer-Specific Mutations in PI3K 87
3 Several Molecular Mechanisms Can Induce a Gain of Function in p110 90
4 Non-alpha Isoforms of Class I PI3K in Cancer 92
5 Class II and III PI3Ks 94
6 PI3K-Driven Oncogenic Transformation: Mechanistic Considerations 95
7 Conclusion 99
References 100
AKT Signaling in Physiology and Disease 111
1 Introduction 112
2 AKT Kinases 113
2.1 Isoforms 113
2.2 Domain Structure 113
3 Mechanisms of AKT Activation 114
3.1 PDK1-Dependent AKT Phosphorylation 116
3.2 Hydrophobic Motif Phosphorylation 116
3.3 Phosphorylation of Other AKT Residues 117
4 Negative Regulation of AKT Signaling 117
4.1 Lipid Phosphatases 117
4.2 AKT-Specific Protein Phosphatases 118
4.3 AKT Inhibition by Interacting Proteins 118
4.4 Lipid Binding PH Domain-Only Proteins 119
4.5 Feedback Regulation of AKT Signaling 119
5 AKT Substrates 119
6 AKT Signaling in Physiology 121
6.1 Glucose Homeostasis and Metabolism 121
6.2 Cell Proliferation 122
6.3 Cell Survival 122
6.4 Cell Migration and Invasion 123
6.5 Cell Growth and Protein Translation 124
6.6 Angiogenesis 125
6.7 Apoptosis and Senescence Induction 125
6.8 Immunity 126
6.9 Brain Development, Neuronal Differentiation, and Function 126
7 Roles of the AKT Signaling Pathway in Human Disease 127
7.1 Diabetes 127
7.2 Neurological Diseases 128
7.3 Cancer 128
7.3.1 Genetic Alterations in the Upstream RTK Signaling Axis 129
7.3.2 Inactivating Mutations of PTEN 129
7.3.3 Activating Mutations of PI3K 129
7.3.4 Activating Mutations of AKT 130
7.3.5 Mouse Tumor Models of AKT Activation 130
8 AKT Independent Signaling by PI3K 131
9 Conclusions 132
References 132
Faithfull Modeling of PTEN Loss Driven Diseases in the Mouse 140
1 Introduction 141
2 Spectrum of Human Diseases Associated with Loss of PTEN 142
3 Modeling PTEN Loss in Specific Murine Organs 143
3.1 Brain 143
3.2 Prostate 151
3.3 Breast 153
4 In Vivo Deconstruction of the PI3K-AKT-mTOR Axis 154
4.1 PI3K-PDK-AKT 154
4.2 TSC1/2-Rheb-mTOR 155
5 PTEN Network: Linking the PI3K Signaling Cascade to Other Oncogenic Pathways Through In Vivo Genetic Analysis 157
5.1 PTEN-MAPK Pathway 157
5.2 Pten and Transcriptional Regulators: Erg and Myc 159
5.3 Pten/p53 160
6 Context-Dependent Differential Outcomes Triggered by Loss of PTEN 161
7 Conclusion 163
References 163
PI3K as a Target for Therapy in Haematological Malignancies 174
1 Introduction 175
2 Acute Myeloid Leukaemia 177
3 Acute Lymphoblastic Leukaemia 179
4 Chronic Myeloid Leukaemia and BCR-ABL Positive ALL 180
5 Chronic Lymphocytic Leukaemia 181
6 Lymphomas 182
6.1 Diffuse Large B Cell Lymphoma 182
6.2 Anaplastic Large Cell Lymphoma 183
6.3 Mantle Cell Lymphoma 183
7 Multiple Myeloma 183
8 Effects on Normal Immune Cells and Host Immunity 184
9 Conclusions 185
References 186
Clinical Development of Phosphatidylinositol-3 Kinase Pathway Inhibitors 194
1 Introduction 195
2 Pharmacological Approaches 195
3 Preclinical Considerations for Drug Development 197
4 Clinical Trials 199
5 Patient Selection and Role of Presurgical Trials 200
6 Rationale for Combination Therapies 203
7 Neoadjuvant Clinical Trials 205
8 Conclusions 206
References 207
From the Bench to the Bed Side: PI3K Pathway Inhibitors in Clinical Development 214
1 Introduction 214
2 PI3K Inhibitors: Path to the Clinic 216
2.1 PI3K Inhibitors in Oncology Drug Discovery and Development 216
2.2 Identification of Isoform Specific PI3K Inhibitors for Oncology 221
2.3 Development of PI3K Pathway Inhibitors in Non-Cancer Indications 222
2.3.1 PI3K Inhibition for the Treatment of Respiratory Diseases 223
2.3.2 PI3K Inhibition for the Treatment of Arthritis and Systemic Lupus Erythematosus 224
2.3.3 PI3K Inhibition for the Treatment of Atherosclerosis 225
3 mTOR Inhibitors: Allosteric and ATP Competitive Inhibitors 225
4 Akt Kinase Inhibitors and Perifosine 228
5 ATPase Inhibitors of Hsp90 232
6 Outlook 236
References 236
New Inhibitors of the PI3K-Akt-mTOR Pathway: Insights into mTOR Signaling from a New Generation of Tor Kinase Domain Inhibitors (TORKinibs) 245
1 Two TOR Complexes and Rapamycin Studies in S. Cerevisiae 246
2 A Single Mammalian TOR in Two Complexes (mTORC1 and mTORC2) 247
3 Regulation of AGC Kinases Through Hydrophobic Motif Phosphorylation by TOR 248
4 TORC1 Substrate 4EBP-1 251
5 mTOR is Both Upstream and Downstream of Akt 252
6 Rapamycin Induces Feedback Activation of Akt 253
7 mTOR Inhibitors for Cancer 254
8 Active-Site Inhibitors of mTOR 255
9 TORKinibs and Akt 256
10 Cell Proliferation and Rapamycin Resistant mTORC1 258
11 Inhibition of mTORC1 by Rapamycin 261
12 Using Inhibitors of mTOR to Treat Cancer 262
References 263
Small Molecule Inhibitors of the PI3-Kinase Family 267
1 Introduction 267
2 LY294002 269
3 Wortmannin 271
4 p110delta Inhibitors and the Selectivity Pocket 272
5 p110beta, DNA-PK, and ATM Inhibitors: A Shared Selectivity Mechanism? 274
6 p110gamma Inhibitors 276
7 Class I PI3-K Inhibitors 277
8 Conclusions 278
References 278
Targeting the RTK-PI3K-mTOR Axis in Malignant Glioma: Overcoming Resistance 283
1 Introduction 284
2 The Epidermal Growth Factor Receptor Pathway 286
3 The PI3K/Akt/mTOR Axis in Glioma 287
4 Isoform Specific Inhibitors of Class I PI3K Inhibitors 288
5 Targeting mTOR Signaling 291
6 Targeting the EGFR-PI3K-Akt-mTOR Axis: The Importance of Akt 292
7 Combination Strategies Within the EGFR-PI3K-mTOR Axis to Improve Therapeutic Efficacy 293
8 A Role for EGFR Inhibitors in Combination Therapy 293
9 Inhibitors of mTOR, PI3K and Dual PI3K/mTOR Inhibitors 294
10 Inhibitors of PKC 294
11 Future Directions 295
11.1 Therapeutic Strategies to Promote Cytotoxicity in Glioma 295
12 Biomarkers to Stratify Patients and to Measure Responses 296
13 Conclusion 296
References 297
Index 301
Contents of Volume I 306