Phosphoinositide 3-kinase in Health and Disease:

Phosphoinositide 3-kinase in Health and Disease, Volume 2 (Current Topics in Microbiology and Immunology,\rVolume 347)......Page 1
Front-matter......Page 2
Volume 2......Page 4
Copyright......Page 5
Contents (with page links)......Page 6
Contributors......Page 8
PI3K: From the Bench to the Clinic and Back......Page 12
1 The Discovery of the PI3K Signalling Pathway and Its Potential as a Therapeutic Target•......Page 13
2 PI3K and Human Disease......Page 15
3 The Development of PI3K Inhibitors for Human Disease Starts to Inform Basic Science......Page 16
4 Some Outstanding Questions in PI3K Biology and Signalling......Page 19
5 Concluding Remarks......Page 21
References......Page 22
Oncogenic Mutations of PIK3CA in Human Cancers......Page 32
2 Links Between the PI3K Pathway and Cancer......Page 33
4 PIK3CA is Somatically Mutated in Colorectal Cancer......Page 34
5 PIK3CA is Mutated in a Wide Variety of Human Tumor Types......Page 35
6 Somatic Mutations in the PI3K Pathway Typically Occur in a Mutually Exclusive Fashion......Page 42
7 Conclusion......Page 44
References......Page 45
Structural Effects of Oncogenic PI3Kα Mutations......Page 54
1 Introduction......Page 55
2 Description of the Structure......Page 56
3 Association with the Lipid Membrane......Page 58
4 Cancer-Specific Mutations......Page 59
5 Summary and Conclusions......Page 63
References......Page 64
Comparing the Roles of the p110α and p110beta Isoforms of PI3K in Signaling and Cancer......Page 66
1 Introduction......Page 67
3.1 Early Studies on In Vitro p110α/beta Activation......Page 68
3.2 Studies on p110 Activation Using Engineered Mice......Page 71
3.3 Unresolved Issues......Page 72
4.1 AKT Signaling......Page 74
5 PI3K Isoforms in Cancer......Page 75
5.1 Deregulated PI3K Pathway Components......Page 76
5.3 p110α as a Viable Tumor Target......Page 77
5.4 p110beta as a Drug Target......Page 79
5.6 Kinase-Independent Roles of p110-Isoforms......Page 80
References......Page 82
Phosphatidylinositol 3-Kinase: The Oncoprotein......Page 90
1 Phosphatidylinositol 3-Kinases and Cancer......Page 91
2 Cancer-Specific Mutations in PI3K......Page 92
3 Several Molecular Mechanisms Can Induce a Gain of Function in p110......Page 95
4 Non-alpha Isoforms of Class I PI3K in Cancer......Page 97
5 Class II and III PI3Ks......Page 99
6 PI3K-Driven Oncogenic Transformation: Mechanistic Considerations......Page 100
7 Conclusion......Page 104
References......Page 105
AKT Signaling in Physiology and Disease......Page 116
1 Introduction......Page 117
2.2 Domain Structure......Page 118
3 Mechanisms of AKT Activation......Page 119
3.2 Hydrophobic Motif Phosphorylation......Page 121
4.1 Lipid Phosphatases......Page 122
4.3 AKT Inhibition by Interacting Proteins......Page 123
5 AKT Substrates......Page 124
6.1 Glucose Homeostasis and Metabolism......Page 126
6.3 Cell Survival......Page 127
6.4 Cell Migration and Invasion......Page 128
6.5 Cell Growth and Protein Translation......Page 129
6.7 Apoptosis and Senescence Induction......Page 130
6.9 Brain Development, Neuronal Differentiation, and Function......Page 131
7.1 Diabetes......Page 132
7.3 Cancer......Page 133
7.3.3 Activating Mutations of PI3K......Page 134
7.3.5 Mouse Tumor Models of AKT Activation......Page 135
8 AKT Independent Signaling by PI3K......Page 136
References......Page 137
Faithfull Modeling of PTEN Loss Driven Diseases in the Mouse......Page 146
1 Introduction......Page 147
2 Spectrum of Human Diseases Associated with Loss of PTEN......Page 148
3.1 Brain......Page 149
3.2 Prostate......Page 157
3.3 Breast......Page 159
4.1 PI3K-PDK-AKT......Page 160
4.2 TSC1/2-Rheb-mTOR......Page 161
5.1 PTEN-MAPK Pathway......Page 163
5.2 Pten and Transcriptional Regulators: Erg and Myc......Page 165
5.3 Pten/p53......Page 166
6 Context-Dependent Differential Outcomes Triggered by Loss of PTEN......Page 167
References......Page 169
PI3K as a Target for Therapy in Haematological Malignancies......Page 180
1 Introduction......Page 181
2 Acute Myeloid Leukaemia......Page 183
3 Acute Lymphoblastic Leukaemia......Page 185
4 Chronic Myeloid Leukaemia and BCR-ABL Positive ALL......Page 186
5 Chronic Lymphocytic Leukaemia......Page 187
6.1 Diffuse Large B Cell Lymphoma......Page 188
7 Multiple Myeloma......Page 189
8 Effects on Normal Immune Cells and Host Immunity......Page 190
9 Conclusions......Page 191
References......Page 192
Clinical Development of Phosphatidylinositol-3 Kinase Pathway Inhibitors......Page 200
2 Pharmacological Approaches......Page 201
3 Preclinical Considerations for Drug Development......Page 203
4 Clinical Trials......Page 205
5 Patient Selection and Role of Presurgical Trials......Page 206
6 Rationale for Combination Therapies......Page 209
7 Neoadjuvant Clinical Trials......Page 211
8 Conclusions......Page 212
References......Page 213
1 Introduction......Page 220
2.1 PI3K Inhibitors in Oncology Drug Discovery and Development......Page 222
2.2 Identification of Isoform Specific PI3K Inhibitors for Oncology......Page 227
2.3 Development of PI3K Pathway Inhibitors in Non-Cancer Indications......Page 228
2.3.1 PI3K Inhibition for the Treatment of Respiratory Diseases......Page 229
2.3.2 PI3K Inhibition for the Treatment of Arthritis and Systemic Lupus Erythematosus......Page 230
3 mTOR Inhibitors: Allosteric and ATP Competitive Inhibitors......Page 231
4 Akt Kinase Inhibitors and Perifosine......Page 234
5 ATPase Inhibitors of Hsp90......Page 238
References......Page 242
New Inhibitors of the PI3K-Akt-mTOR Pathway: Insights into mTOR Signaling from a New Generation of Tor Kinase Domain Inhibitor......Page 252
1 Two TOR Complexes and Rapamycin Studies in S. Cerevisiae......Page 253
2 A Single Mammalian TOR in Two Complexes (mTORC1 and mTORC2)......Page 254
3 Regulation of AGC Kinases Through Hydrophobic Motif Phosphorylation by TOR......Page 255
4 TORC1 Substrate 4EBP-1......Page 258
5 mTOR is Both Upstream and Downstream of Akt......Page 259
6 Rapamycin Induces Feedback Activation of Akt......Page 260
7 mTOR Inhibitors for Cancer......Page 261
8 Active-Site Inhibitors of mTOR......Page 262
9 TORKinibs and Akt......Page 263
10 Cell Proliferation and Rapamycin Resistant mTORC1......Page 265
11 Inhibition of mTORC1 by Rapamycin......Page 268
12 Using Inhibitors of mTOR to Treat Cancer......Page 269
References......Page 270
1 Introduction......Page 274
2 LY294002......Page 276
3 Wortmannin......Page 278
4 p110delta Inhibitors and the Selectivity Pocket......Page 279
5 p110beta, DNA-PK, and ATM Inhibitors: A Shared Selectivity Mechanism?......Page 281
6 p110gamma Inhibitors......Page 283
7 Class I PI3-K Inhibitors......Page 284
References......Page 285
Targeting the RTK-PI3K-mTOR Axis in Malignant Glioma: Overcoming Resistance......Page 290
1 Introduction......Page 291
2 The Epidermal Growth Factor Receptor Pathway......Page 293
3 The PI3K/Akt/mTOR Axis in Glioma......Page 294
4 Isoform Specific Inhibitors of Class I PI3K Inhibitors......Page 295
5 Targeting mTOR Signaling......Page 298
6 Targeting the EGFR-PI3K-Akt-mTOR Axis: The Importance of Akt......Page 299
8 A Role for EGFR Inhibitors in Combination Therapy......Page 300
10 Inhibitors of PKC......Page 301
11.1 Therapeutic Strategies to Promote Cytotoxicity in Glioma......Page 302
13 Conclusion......Page 303
References......Page 304
Index......Page 308
Contents of Volume I......Page 314