Rommel / Vanhaesebroeck / Vogt Phosphoinositide 3-kinase in Health and Disease

Volume 2
1. Auflage 2010
ISBN: 978-3-642-14816-3
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 347, 306 Seiten, eBook

Reihe: Current Topics in Microbiology and Immunology

PI3K has become a very intense area of research, with over 2000 publications on PI3K in PubMed for 2009 alone. The expectations for a therapeutic impact of intervention with PI3K activity are high, and progress in the clinical arena is being monitored by many. However, targeted therapies almost invariably encounter roadblocks, often exposing unresolved questions in the basic understanding of the target

Zielgruppe

Research

Autoren/Hrsg.

Rommel, Christian

Vanhaesebroeck, Bart

Vogt, Peter K.

Inhaltsverzeichnis

1;Phosphoinositide 3-kinase in Health and Disease;3
1.1;Volume 2;3
1.2;Contents;5
1.3;Contributors;7
1.4;PI3K: From the Bench to the Clinic and Back;11
1.4.1;1 The Discovery of the PI3K Signalling Pathway and Its Potential as a Therapeutic Target;12
1.4.2;2 PI3K and Human Disease;14
1.4.3;3 The Development of PI3K Inhibitors for Human Disease Starts to Inform Basic Science;15
1.4.4;4 Some Outstanding Questions in PI3K Biology and Signalling;18
1.4.5;5 Concluding Remarks;20
1.4.6;References;21
1.5;Oncogenic Mutations of PIK3CA in Human Cancers;30
1.5.1;1 Introduction;31
1.5.2;2 Links Between the PI3K Pathway and Cancer;31
1.5.3;3 High Throughput Sequencing of Gene Families in Human Cancer;32
1.5.4;4 PIK3CA is Somatically Mutated in Colorectal Cancer;32
1.5.5;5 PIK3CA is Mutated in a Wide Variety of Human Tumor Types;33
1.5.6;6 Somatic Mutations in the PI3K Pathway Typically Occur in a Mutually Exclusive Fashion;40
1.5.7;7 Conclusion;42
1.5.8;References;43
1.6;Structural Effects of Oncogenic PI3Ka Mutations;51
1.6.1;1 Introduction;52
1.6.2;2 Description of the Structure;53
1.6.3;3 Association with the Lipid Membrane;55
1.6.4;4 Cancer-Specific Mutations;56
1.6.5;5 Summary and Conclusions;60
1.6.6;References;61
1.7;Comparing the Roles of the p110a and p110beta Isoforms of PI3K in Signaling and Cancer;62
1.7.1;1 Introduction;63
1.7.2;2 Class IA PI3Ks;64
1.7.3;3 Mechanisms of Activation of Class IA p110 Isoforms;64
1.7.3.1;3.1 Early Studies on In Vitro p110a/beta Activation;64
1.7.3.2;3.2 Studies on p110 Activation Using Engineered Mice;67
1.7.3.3;3.3 Unresolved Issues;68
1.7.4;4 Downstream Signaling: Acting Out Through AKT and PDK1;70
1.7.4.1;4.1 AKT Signaling;70
1.7.5;5 PI3K Isoforms in Cancer;71
1.7.5.1;5.1 Deregulated PI3K Pathway Components;72
1.7.5.2;5.2 Targeting PI3K in Cancer;73
1.7.5.3;5.3 p110a as a Viable Tumor Target;73
1.7.5.4;5.4 p110beta as a Drug Target;75
1.7.5.5;5.5 What Are the Take-Home Messages from p110-Isoform Knock-Out Studies In Vivo?;76
1.7.5.6;5.6 Kinase-Independent Roles of p110-Isoforms;76
1.7.6;6 Conclusions;78
1.7.7;References;78
1.8;Phosphatidylinositol 3-Kinase: The Oncoprotein;85
1.8.1;1 Phosphatidylinositol 3-Kinases and Cancer;86
1.8.2;2 Cancer-Specific Mutations in PI3K;87
1.8.3;3 Several Molecular Mechanisms Can Induce a Gain of Function in p110;90
1.8.4;4 Non-alpha Isoforms of Class I PI3K in Cancer;92
1.8.5;5 Class II and III PI3Ks;94
1.8.6;6 PI3K-Driven Oncogenic Transformation: Mechanistic Considerations;95
1.8.7;7 Conclusion;99
1.8.8;References;100
1.9;AKT Signaling in Physiology and Disease;111
1.9.1;1 Introduction;112
1.9.2;2 AKT Kinases;113
1.9.2.1;2.1 Isoforms;113
1.9.2.2;2.2 Domain Structure;113
1.9.3;3 Mechanisms of AKT Activation;114
1.9.3.1;3.1 PDK1-Dependent AKT Phosphorylation;116
1.9.3.2;3.2 Hydrophobic Motif Phosphorylation;116
1.9.3.3;3.3 Phosphorylation of Other AKT Residues;117
1.9.4;4 Negative Regulation of AKT Signaling;117
1.9.4.1;4.1 Lipid Phosphatases;117
1.9.4.2;4.2 AKT-Specific Protein Phosphatases;118
1.9.4.3;4.3 AKT Inhibition by Interacting Proteins;118
1.9.4.4;4.4 Lipid Binding PH Domain-Only Proteins;119
1.9.4.5;4.5 Feedback Regulation of AKT Signaling;119
1.9.5;5 AKT Substrates;119
1.9.6;6 AKT Signaling in Physiology;121
1.9.6.1;6.1 Glucose Homeostasis and Metabolism;121
1.9.6.2;6.2 Cell Proliferation;122
1.9.6.3;6.3 Cell Survival;122
1.9.6.4;6.4 Cell Migration and Invasion;123
1.9.6.5;6.5 Cell Growth and Protein Translation;124
1.9.6.6;6.6 Angiogenesis;125
1.9.6.7;6.7 Apoptosis and Senescence Induction;125
1.9.6.8;6.8 Immunity;126
1.9.6.9;6.9 Brain Development, Neuronal Differentiation, and Function;126
1.9.7;7 Roles of the AKT Signaling Pathway in Human Disease;127
1.9.7.1;7.1 Diabetes;127
1.9.7.2;7.2 Neurological Diseases;128
1.9.7.3;7.3 Cancer;128
1.9.7.3.1;7.3.1 Genetic Alterations in the Upstream RTK Signaling Axis;129
1.9.7.3.2;7.3.2 Inactivating Mutations of PTEN;129
1.9.7.3.3;7.3.3 Activating Mutations of PI3K;129
1.9.7.3.4;7.3.4 Activating Mutations of AKT;130
1.9.7.3.5;7.3.5 Mouse Tumor Models of AKT Activation;130
1.9.8;8 AKT Independent Signaling by PI3K;131
1.9.9;9 Conclusions;132
1.9.10;References;132
1.10;Faithfull Modeling of PTEN Loss Driven Diseases in the Mouse;140
1.10.1;1 Introduction;141
1.10.2;2 Spectrum of Human Diseases Associated with Loss of PTEN;142
1.10.3;3 Modeling PTEN Loss in Specific Murine Organs;143
1.10.3.1;3.1 Brain;143
1.10.3.2;3.2 Prostate;151
1.10.3.3;3.3 Breast;153
1.10.4;4 In Vivo Deconstruction of the PI3K-AKT-mTOR Axis;154
1.10.4.1;4.1 PI3K-PDK-AKT;154
1.10.4.2;4.2 TSC1/2-Rheb-mTOR;155
1.10.5;5 PTEN Network: Linking the PI3K Signaling Cascade to Other Oncogenic Pathways Through In Vivo Genetic Analysis;157
1.10.5.1;5.1 PTEN-MAPK Pathway;157
1.10.5.2;5.2 Pten and Transcriptional Regulators: Erg and Myc;159
1.10.5.3;5.3 Pten/p53;160
1.10.6;6 Context-Dependent Differential Outcomes Triggered by Loss of PTEN;161
1.10.7;7 Conclusion;163
1.10.8;References;163
1.11;PI3K as a Target for Therapy in Haematological Malignancies;174
1.11.1;1 Introduction;175
1.11.2;2 Acute Myeloid Leukaemia;177
1.11.3;3 Acute Lymphoblastic Leukaemia;179
1.11.4;4 Chronic Myeloid Leukaemia and BCR-ABL Positive ALL;180
1.11.5;5 Chronic Lymphocytic Leukaemia;181
1.11.6;6 Lymphomas;182
1.11.6.1;6.1 Diffuse Large B Cell Lymphoma;182
1.11.6.2;6.2 Anaplastic Large Cell Lymphoma;183
1.11.6.3;6.3 Mantle Cell Lymphoma;183
1.11.7;7 Multiple Myeloma;183
1.11.8;8 Effects on Normal Immune Cells and Host Immunity;184
1.11.9;9 Conclusions;185
1.11.10;References;186
1.12;Clinical Development of Phosphatidylinositol-3 Kinase Pathway Inhibitors;194
1.12.1;1 Introduction;195
1.12.2;2 Pharmacological Approaches;195
1.12.3;3 Preclinical Considerations for Drug Development;197
1.12.4;4 Clinical Trials;199
1.12.5;5 Patient Selection and Role of Presurgical Trials;200
1.12.6;6 Rationale for Combination Therapies;203
1.12.7;7 Neoadjuvant Clinical Trials;205
1.12.8;8 Conclusions;206
1.12.9;References;207
1.13;From the Bench to the Bed Side: PI3K Pathway Inhibitors in Clinical Development;214
1.13.1;1 Introduction;214
1.13.2;2 PI3K Inhibitors: Path to the Clinic;216
1.13.2.1;2.1 PI3K Inhibitors in Oncology Drug Discovery and Development;216
1.13.2.2;2.2 Identification of Isoform Specific PI3K Inhibitors for Oncology;221
1.13.2.3;2.3 Development of PI3K Pathway Inhibitors in Non-Cancer Indications;222
1.13.2.3.1;2.3.1 PI3K Inhibition for the Treatment of Respiratory Diseases;223
1.13.2.3.2;2.3.2 PI3K Inhibition for the Treatment of Arthritis and Systemic Lupus Erythematosus;224
1.13.2.3.3;2.3.3 PI3K Inhibition for the Treatment of Atherosclerosis;225
1.13.3;3 mTOR Inhibitors: Allosteric and ATP Competitive Inhibitors;225
1.13.4;4 Akt Kinase Inhibitors and Perifosine;228
1.13.5;5 ATPase Inhibitors of Hsp90;232
1.13.6;6 Outlook;236
1.13.7;References;236
1.14;New Inhibitors of the PI3K-Akt-mTOR Pathway: Insights into mTOR Signaling from a New Generation of Tor Kinase Domain Inhibitors (TORKinibs);245
1.14.1;1 Two TOR Complexes and Rapamycin Studies in S. Cerevisiae;246
1.14.2;2 A Single Mammalian TOR in Two Complexes (mTORC1 and mTORC2);247
1.14.3;3 Regulation of AGC Kinases Through Hydrophobic Motif Phosphorylation by TOR;248
1.14.4;4 TORC1 Substrate 4EBP-1;251
1.14.5;5 mTOR is Both Upstream and Downstream of Akt;252
1.14.6;6 Rapamycin Induces Feedback Activation of Akt;253
1.14.7;7 mTOR Inhibitors for Cancer;254
1.14.8;8 Active-Site Inhibitors of mTOR;255
1.14.9;9 TORKinibs and Akt;256
1.14.10;10 Cell Proliferation and Rapamycin Resistant mTORC1;258
1.14.11;11 Inhibition of mTORC1 by Rapamycin;261
1.14.12;12 Using Inhibitors of mTOR to Treat Cancer;262
1.14.13;References;263
1.15;Small Molecule Inhibitors of the PI3-Kinase Family;267
1.15.1;1 Introduction;267
1.15.2;2 LY294002;269
1.15.3;3 Wortmannin;271
1.15.4;4 p110delta Inhibitors and the Selectivity Pocket;272
1.15.5;5 p110beta, DNA-PK, and ATM Inhibitors: A Shared Selectivity Mechanism?;274
1.15.6;6 p110gamma Inhibitors;276
1.15.7;7 Class I PI3-K Inhibitors;277
1.15.8;8 Conclusions;278
1.15.9;References;278
1.16;Targeting the RTK-PI3K-mTOR Axis in Malignant Glioma: Overcoming Resistance;283
1.16.1;1 Introduction;284
1.16.2;2 The Epidermal Growth Factor Receptor Pathway;286
1.16.3;3 The PI3K/Akt/mTOR Axis in Glioma;287
1.16.4;4 Isoform Specific Inhibitors of Class I PI3K Inhibitors;288
1.16.5;5 Targeting mTOR Signaling;291
1.16.6;6 Targeting the EGFR-PI3K-Akt-mTOR Axis: The Importance of Akt;292
1.16.7;7 Combination Strategies Within the EGFR-PI3K-mTOR Axis to Improve Therapeutic Efficacy;293
1.16.8;8 A Role for EGFR Inhibitors in Combination Therapy;293
1.16.9;9 Inhibitors of mTOR, PI3K and Dual PI3K/mTOR Inhibitors;294
1.16.10;10 Inhibitors of PKC;294
1.16.11;11 Future Directions;295
1.16.11.1;11.1 Therapeutic Strategies to Promote Cytotoxicity in Glioma;295
1.16.12;12 Biomarkers to Stratify Patients and to Measure Responses;296
1.16.13;13 Conclusion;296
1.16.14;References;297
1.17;Index;301
1.18;Contents of Volume I;306