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Preface; Contents; Contributors; About the Editor; Chapter 1: Resistance to TRAIL Pathway-Targeted Therapeutics in Cancer; 1.1 Mechanisms of TRAIL-Induced Apoptosis; 1.1.1 TRAIL Ligand and TRAIL Receptors; 1.1.2 Engagement of the Extrinsic Pathway of Apoptosis; 1.1.3 Engagement of the Intrinsic Pathway of Apoptosis; 1.2 TRAIL's Impact on Metastasis; 1.3 Development of TRAIL Pathway-Targeted Therapeutics; 1.3.1 Optimization of TRAIL Delivery; 1.3.2 TRAIL Receptor Antibodies; 1.3.3 Small Molecules to Induce TRAIL and Upregulate DR5
1.4 Mechanisms of Resistance to TRAIL Pathway-Targeted Therapeutics1.4.1 Aberration in Death Receptor Expression; 1.4.2 Strategies to Address Low Surface Levels of Death Receptors; 1.4.3 Expression of TRAIL Decoy Receptors; 1.4.4 Dysfunction in the DISC and FADD; 1.4.5 Perturbation in Downstream Pro-apoptotic Signals; 1.4.6 Strategies to Address Aberrations in Downstream Pathways of Apoptosis; 1.4.7 Resistance of Normal Cells; 1.5 Complex Nature of TRAIL Resistance; 1.5.1 Multiple Resistance Mechanisms; 1.5.2 Acquisition of Resistance
1.6 Addressing Resistance to TRAIL Pathway-Targeted Therapeutics in the Clinic1.6.1 Single Agent; 1.6.2 Combinational; 1.7 Conclusion; References; Chapter 2: TRAIL-R3/R4 and Inhibition of TRAIL Signalling in Cancer; 2.1 Introduction; 2.2 The TRAIL Signalling System; 2.2.1 Structure of TRAIL; 2.2.2 Structure and Function of TRAIL Receptors; 2.2.3 TRAIL Receptor Signalling; 2.2.3.1 Apoptotic Signalling; 2.2.3.2 Necroptotic Signalling; 2.2.3.3 Non-cytotoxic Signalling; 2.2.4 TRAIL's Role In Vivo; 2.3 The TRAIL System in Cancer
2.3.1 Predictive and Prognostic Significance of TRAIL Receptor Expression2.3.2 TRAIL Death Receptor Agonists; 2.3.3 The Role of TRAIL-R3 and TRAIL-R4 in Resistance to TRAIL-Mediated Apoptosis; 2.3.3.1 The Decoy Model for TRAIL-R3 and TRAIL-R4; 2.3.3.2 Formation of Heteromeric Complexes Affected in Signalling; 2.3.3.3 TRAIL-R3 and TRAIL-R4 Incorporation in Ligand Receptor Clusters; 2.3.3.4 Activation of Pro-Survival Pathways by TRAIL-R4; 2.4 Outlook; References; Chapter 3: IAPs and Resistance to Death Receptors in Cancer; 3.1 Introduction; 3.2 Structure and Molecular Functions
3.3 Regulation of DR Signalling Pathways by IAPs3.3.1 Regulation of RIPK-Dependent Signalling Complex; 3.3.2 Regulation of DR-Induced Apoptosis by IAPs; 3.4 Sensitization to Death Receptor-Induced Cell Death by Smac Mimetics; 3.4.1 Smac Mimetics in Combination with Tumor Necrosis Factor (TNF); 3.4.2 Smac Mimetics in Combination with CD95; 3.4.3 Smac Mimetics in Combination with TNF-Related Apoptosis-Inducing Ligand (TRAIL); References; Chapter 4: Bcl-2 Proteins and TRAIL Resistance in Melanoma; 4.1 Apoptosis Deficiency: A Major Issue in Melanoma Therapy Resistance; 4.2 Control of Apoptosis
1.4 Mechanisms of Resistance to TRAIL Pathway-Targeted Therapeutics1.4.1 Aberration in Death Receptor Expression; 1.4.2 Strategies to Address Low Surface Levels of Death Receptors; 1.4.3 Expression of TRAIL Decoy Receptors; 1.4.4 Dysfunction in the DISC and FADD; 1.4.5 Perturbation in Downstream Pro-apoptotic Signals; 1.4.6 Strategies to Address Aberrations in Downstream Pathways of Apoptosis; 1.4.7 Resistance of Normal Cells; 1.5 Complex Nature of TRAIL Resistance; 1.5.1 Multiple Resistance Mechanisms; 1.5.2 Acquisition of Resistance
1.6 Addressing Resistance to TRAIL Pathway-Targeted Therapeutics in the Clinic1.6.1 Single Agent; 1.6.2 Combinational; 1.7 Conclusion; References; Chapter 2: TRAIL-R3/R4 and Inhibition of TRAIL Signalling in Cancer; 2.1 Introduction; 2.2 The TRAIL Signalling System; 2.2.1 Structure of TRAIL; 2.2.2 Structure and Function of TRAIL Receptors; 2.2.3 TRAIL Receptor Signalling; 2.2.3.1 Apoptotic Signalling; 2.2.3.2 Necroptotic Signalling; 2.2.3.3 Non-cytotoxic Signalling; 2.2.4 TRAIL's Role In Vivo; 2.3 The TRAIL System in Cancer
2.3.1 Predictive and Prognostic Significance of TRAIL Receptor Expression2.3.2 TRAIL Death Receptor Agonists; 2.3.3 The Role of TRAIL-R3 and TRAIL-R4 in Resistance to TRAIL-Mediated Apoptosis; 2.3.3.1 The Decoy Model for TRAIL-R3 and TRAIL-R4; 2.3.3.2 Formation of Heteromeric Complexes Affected in Signalling; 2.3.3.3 TRAIL-R3 and TRAIL-R4 Incorporation in Ligand Receptor Clusters; 2.3.3.4 Activation of Pro-Survival Pathways by TRAIL-R4; 2.4 Outlook; References; Chapter 3: IAPs and Resistance to Death Receptors in Cancer; 3.1 Introduction; 3.2 Structure and Molecular Functions
3.3 Regulation of DR Signalling Pathways by IAPs3.3.1 Regulation of RIPK-Dependent Signalling Complex; 3.3.2 Regulation of DR-Induced Apoptosis by IAPs; 3.4 Sensitization to Death Receptor-Induced Cell Death by Smac Mimetics; 3.4.1 Smac Mimetics in Combination with Tumor Necrosis Factor (TNF); 3.4.2 Smac Mimetics in Combination with CD95; 3.4.3 Smac Mimetics in Combination with TNF-Related Apoptosis-Inducing Ligand (TRAIL); References; Chapter 4: Bcl-2 Proteins and TRAIL Resistance in Melanoma; 4.1 Apoptosis Deficiency: A Major Issue in Melanoma Therapy Resistance; 4.2 Control of Apoptosis