mTOR Pathway and mTOR Inhibitors in Cancer Therapy (eBook)

Vitaly A. Polunovsky, Peter J. Houghton (Herausgeber)

eBook Download: PDF

2010 | 2010
XII, 304 Seiten
Humana Press (Verlag)
978-1-60327-271-1 (ISBN)

Infos

The main objective of this book is to provide an up-to-date survey of the rapidly advancing eld of cancer therapy. Moreover, since our knowledge in this area rapidly evolves, some data have got obsolete during the process of book editing. Our understanding of the mechanisms involved in cancer genesis and progression underwent unprecedented expansion during the last decade, opening a new era of cancer treatment - targeted therapy. The surge in this area results in no small part from studies conducted jointly by basic health scientists and clinical investigators. It is our hope that this book will help foster even further collaboration between investigators in these two disciplines. The target of rapamycin (TOR) was rst identi ed in Saccharomyces cerevisiae and subsequently in mammals (mTOR) as a conserved atypical serine/threonine kinase. In mammalian cells, mTOR exists in at least two multi-protein complexes that have critical roles in regulating cellular homeostasis and survival. As with many other areas of science, discovery of TOR signaling was fortuitous. Rapamycin was isolated as a product of the soil bacteria Streptomyces hygroscopicus, identi ed in a soil sample taken from the island of Rapa Nui (Easter Island). Rapamycin was rst discovered to be a potent antifungal agent and next as an immune suppressive drug. It was only later that it was found to be active as an antitumor agent in non-clinical models; although it was not developed for this indication. The history of rapamycin presents one of the rst examples of chemical genetics.

Inhalt

Preface 6
Contents 8
Contributors 10
mTORC1: A Signaling Integration Node Involved in Cell Growth 12
1 Introduction 13
2 The Domain Structure and Protein Complex Assembly of mTOR 13
3 Cellular Signaling Upstream of mTORC1: Integration of Anabolic and Catabolic Cues 15
3.1 Growth Factor Signaling 15
3.2 Nutrients 21
3.3 Stress Signals 23
4 Downstream Targets of mTORC1 Regulate Cell Growth Control 26
4.1 mRNA Translational Control 26
4.2 Ribosomal Biogenesis 31
5 Conclusion 33
References 34
The Regulation of the IGF-1/mTOR Pathway by the p53 Tumor Suppressor Gene Functions 48
1 The p53 Pathway 48
2 The Coordinate Regulation Between the p53 and IGF-1/mTOR Pathways 51
3 The p53 Regulation of Energy Metabolism 54
4 Summary 56
References 57
mTOR Signaling in Angiogenesis 60
1 mTOR Signaling in Angiogenesis 62
1.1 Tumor Angiogenesis 62
1.2 mTORC1 Signaling: Upstream Activation of Angiogenesis 63
1.3 The Role of mTOR Signaling in Downstream Endothelial Cell Signaling 66
1.3.1 VEGF/VEGF-R-Mediated Signaling in Endothelial Cells 66
1.3.2 Regulation and Function of the PI3K/Akt/mTOR Pathway in Endothelial Cells 67
1.3.3 PI3K/Akt/mTOR Signaling Pathway in Tumor Angiogenesis 69
1.4 mTOR Kinase as a Therapeutic Target in Tumor Angiogenesis 71
1.5 Malignant Diseases Associated with Activated Angiogenesis Due to Disturbance of mTOR Signaling 72
1.6 mTOR: Integrating Inflammation and Tumor Angiogenesis 77
1.7 mTOR and Lymphangiogenesis 77
1.8 Targeting Angiogenesis by mTOR Inhibitors 79
References 81
mTORC1 Signaling and Hypoxia 86
1 Introduction 87
2 mTORC1 Signaling Is Regulated by Oxygen Levels 87
3 mTORC1 Regulation by Hypoxia Requires the TSC1/TSC2 Complex 88
4 The Energy Signaling Kinase AMPK Is Dispensable for mTORC1 Inhibition by Hypoxia 91
5 The REDD1 Protein Is an Important Mediator of mTORC1 Inhibition by Hypoxia 92
5.1 Identification of the REDD1 Orthologues Scylla and Charybdis 92
5.2 REDD1 Is Induced by Hypoxia and Is Both Necessary and Sufficient for mTORC1 Inhibition 93
5.3 Hypoxia-Independent Regulation of REDD1 95
5.4 REDD1 in Cancer 97
6 Other Hypoxia Effector Pathways 99
7 A Negative Feedback Loop: HIF-1 Regulation by mTORC1 100
References 101
mTOR Signaling in Glioblastoma: Lessons Learned from Bench to Bedside 109
1 Introduction: mTOR Signaling in Glioblastoma 109
2 Constitutive PI3K Pathway Activation Is a Hallmark of Glioblastoma 110
3 mTOR as a Therapeutic Target in GBM 111
4 Targeting the EGFR/PI3K/mTOR Signaling Pathway in Glioma Patients in the Clinic Lessons Learned 113
5 Pathway Cross Talk and Feedback Loops in Patients 115
6 Dual PI3K/mTOR and a Role for mTOR/Erk Inhibition 115
7 mTOR at the Interface of Signal Transduction and Cellular Metabolism 116
8 Concluding Thoughts 117
References 118
mTOR and Cancer Therapy: General Principles 122
1 Introduction 122
2 Activation of the PI3K/mTOR Pathway in Cancer 124
2.1 Amplification/Overexpression of Growth Factor Receptors 124
2.2 Activation of the PI3K Catalytic Subunit p110 125
2.3 PTEN Mutation/Deletion/Silencing 126
2.4 AKT Amplification 127
2.5 TSC/LKB Mutations 127
3 Rheb Amplification/Overexpression 128
3.1 Alterations Downstream of mTORC1 in Cancer 128
4 Cooperation Between the PI3K/mTORC1 Pathway and Other Oncogenes in Tumorigenesis 129
5 mTORC1 Signaling in Solid Tumors 129
5.1 Regulation of mTORC1 by Cellular Stress 129
5.2 mTORC1 Signaling in Survival 130
5.3 Role of mTORC1/C2 Signaling in Motility and Invasion 131
6 mTOR Signaling in Angiogenesis 131
7 mTOR in Tumor Stem Cells 132
8 mTOR Signaling in Drug Resistance 133
8.1 Resistance to Cancer Chemotherapeutic Agents 133
8.2 Resistance to Molecularly Targeted Agents 134
9 Concluding Remarks 134
References 135
mTOR and Cancer Therapy: Clinical Development and NovelProspects 141
1 Introduction 141
2 mTOR Inhibitors Entered in Clinical Trials 142
3 Dose and Schedule Impact on Toxicity of Rapalogs 143
4 Pharmacokinetics of Rapalogs 144
5 Current Imaging of the Antitumor Effects of Rapalogs 144
6 Monitoring the Biological Activity of Rapalogs 145
7 Potential Novel Indications Beyond Renal Cell Carcinoma 146
7.1 Hepatocellular Carcinomas (HCC) 146
7.2 Endometrial Cancers 147
7.3 Breast Cancers 149
7.4 Neuroendocrine Tumors 149
7.5 Non-small Cell Lung Cancers 149
7.6 Colon Cancers 150
7.7 Gliomas 150
7.8 Mantle Cell Lymphomas 150
8 Optimizing Activity of Rapalogs Using Combinations with Other Anticancer Drugs 151
9 Non-rapalog mTOR Kinase Inhibitors 152
10 Conclusions 152
References 153
Drug Combinations as a Therapeutic Approach for mTORC1 Inhibitors in Human Cancer 157
1 Why Target the mTORC1 Pathway in Cancer 158
2 Combination with Receptor Tyrosine Kinase (RTK) Inhibitors 160
2.1 Combination with ErbB Receptor Tyrosine Kinase Inhibitors 161
2.1.1 IGF-1 Receptor Tyrosine Kinase 162
2.2 Synergistic Inhibition of the PI3K/AKT/mTOR Pathway 164
2.3 Targeting Multiple Kinases 166
2.4 Combination with E2 Antagonists 168
2.5 Combination with Cytotoxic Agents 170
2.5.1 Combination with DNA-Damaging Agents 170
2.5.2 Microtubule-Targeted Agents 171
2.6 Interfering with Tumor Cell Metabolism 172
2.7 Inhibiting Autophagy 173
3 Perspectives 174
References 176
Downstream Targets of mTORC1 187
1 Introduction 187
2 Signaling Downstream of mTORC1 188
3 Raptor Mediates the Phosphorylation of mTORC1 Substrates That Contain TOR-Signaling (TOS) Motifs 189
4 The eIF4E-Binding Proteins (4E-BPs) 189
5 The Roles of eIF4E and 4E-BP1 in Cell Transformation 191
6 The Ribosomal Protein S6 Kinases 193
7 Other Recently Discovered Proteins That Are Regulated via TOS Motifs 194
8 Hypoxia-Inducible Factor 1 196
9 Regulation of Translation Elongation by mTORC1 197
10 mTORC1 and the Control of Autophagy 198
11 mTORC1 and the Control of Transcription 200
12 mTORC1 and Lipin 1 200
12.1 mTORC1 and CLIP-170 200
13 SGK1, mTORC1, and mTORC2 201
14 Concluding Remarks 201
References 201
Downstream of mTOR: Translational Control of Cancer 209
1 Introduction 209
2 Translation Initiation 210
3 TOR Complex Formation 211
4 Regulation of Translation Initiation by mTOR Signalling 211
4.1 The 4E-BPs 212
4.1.1 S6 Kinase 213
4.1.2 eIF4G 215
4.1.3 Other Targets of mTORC1 216
4.1.4 mTORC2 Regulation of AKT 216
5 Translation and Cancer 216
6 Downstream Targets of mTOR and Their Role in Cancer 217
6.1 The 4E-BPs 217
6.2 S6 Kinase 218
6.3 eIF4G 218
6.4 AKT Regulation by mTORC2 in Cancer 219
7 Conclusions 219
References 220
Genome-Wide Analysis of Translational Control 225
1 Introduction 225
2 Methods to Assess Ribosome Recruitment Genome Wide 226
3 Some Important Aspects of Polysome Microarray Data Analysis 228
4 What Insights Have We Gathered from Genome-Wide Analysis of Translational Activity 232
4.1 Global Translational Regulation Downstream of eIF4E 232
4.2 Other Cancer-Related Systems That Have Been Characterized Genome Wide at the Translational Level 234
5 What Is Integrative Translatomics and What Will We Learn from It 237
6 How to Advance from Integrative Translatomics to Mechanisms 239
7 Conclusions 241
References 242
Translational Control of Cancer: Implications for Targeted Therapy 245
1 Challenges in Cancer Drug Discovery 245
2 Rise of Targeted Cancer Therapy and Its Limitations 246
3 The Paradigm: Targeting a Nexus of Cancer Pathways 247
4 Receptor Signaling Networks Include the Initiation Stage of Translation as a Regulatory Hub 248
5 Translational Control of the Cell Cycle Machinery 249
6 Translational Control of the Antitumor Defense Systems 250
7 Translational Addiction of Cancer 251
8 What Triggers Pro-oncogenic Recruitment of Ribosomes to mRNA 252
9 Strategy to Target eIF4F 253
10 Molecular Biomarkers of Successful Translational Therapy 254
11 Why Would Not Inhibition of eIF4F Simply Kill All Cells Not Just Cancer 255
12 Can Antitranslational Therapeutics Kill All Tumor Cells 255
13 Anticipated Therapeutic Limitations: Signaling Feedback Loops Downstream of Deregulated eIF4F 257
14 Concluding Remarks 257
References 257
Downstream from mTOR: Therapeutic Approachesto Targeting the eIF4F Translation Initiation Complex 264
1 The Ribosome Recruitment Phase of Translation Initiation 264
2 Trans -Acting Factors in Ribosome Recruitment 266
2.1 eIF4E 266
2.2 eIF4A 266
2.3 eIF4G 267
2.4 eIF4B and eIF4H 267
2.5 Poly(A)-Binding Protein 268
3 Cis-Acting mRNA Elements That Impact on the Efficiency of Ribosome Recruitment 268
3.1 The m7G Cap Structure 268
3.2 5 -Terminal Oligopyrimidine (5 -TOP) Tracts 269
3.3 mRNA Secondary Structure 270
3.4 Protein--mRNA Interactions 270
3.5 Poly(A) Tail 270
4 Signal Transduction Pathways Regulating eIF4F Complex Assembly and Activity 271
5 Impact of Elevated eIF4F Activity in Cancer Progression 272
5.1 The eIF4F Complex and mRNA Discrimination 272
5.2 eIF4E in Cancer 273
6 Targeting eIF4F Activity for Cancer Therapy 274
6.1 Blocking eIF4E0m 7 G Cap Recognition with Cap Analogues 274
6.2 Disrupting the eIF4F Complex 275
6.3 Reducing eIF4F Activity by Targeting eIF4A 275
6.3.1 Pateamine -- A Chemical Inducer of Dimerization 276
6.3.2 Inhibition of eIF4A RNA Binding by Hippuristanol 277
6.3.3 Cyclopenta[ b ]benzofurans (CBFs) -- Modulators of eIF4A Activity 278
7 Reducing eIF4F Activity by Decreasing eIF4E Expression 279
8 Concluding Remarks 281
References 282
Index 293

Produkt-Details

• Erscheint lt. Verlag: 23.7.2010
• Reihe/Serie: Cancer Drug Discovery and Development
• Reihe/Serie: Cancer Drug Discovery and Development
• Zusatzinfo: XII, 304 p.
• Verlagsort: Totowa
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie
• Themenwelt: Technik
• Schlagworte: angiogenesis • Cancer Therapy • genes • mTOR Inhibitors • mTOR Pathway • Regulation • Saccharomyces cerevisiae • Translation
• ISBN-10: 1-60327-271-2 / 1603272712
• ISBN-13: 978-1-60327-271-1 / 9781603272711