Diagnostic and Prognostic Biomarkers and Therapeutic Targets in Melanoma (eBook)

Diagnostic and Prognostic Biomarkers and Therapeutic Targets in Melanoma 3
Preface 7
Contents 9
Contributors 11
1: Introduction to Diagnostic and Prognostic Biomarkers and Therapeutic Targets in Melanoma 15
References 21
2: Diagnostic and Prognostic Biomarkers in Melanoma: Current State of Play 22
Introduction 22
Tumor Tissue-Based Biomarkers 22
Serological Markers 25
Perspective 27
References 27
3: Molecular Pathogenesis of Melanoma: Established and Novel Pathways 32
Introduction 32
Molecular Pathways Involved in Melanoma 33
Established Pathways 34
RAS/RAF/MEK/ERK Signaling 34
KIT 36
High-Risk Melanoma Susceptibility Genes (CDKN2A and CDK4) 37
Low-Risk Melanoma Susceptibility Genes 38
PTEN and PI3K-AKT Pathways 39
MITF 40
Novel Pathways 41
Notch1 41
Nuclear Factor- k B 42
iNOS 43
Conclusion 44
References 45
4: Staging of Melanoma 51
TNM Classification 51
T – Primary Tumor 51
Primary Tumor Thickness 51
Ulceration 51
Mitotic Rate 52
N – Regional Lymph Nodes 53
Micrometastases Versus Macrometastases 53
Intralymphatic Metastases 54
Immunohistochemical (IHC) Detection of Micrometastases 54
M – Distant Metastasis 54
Metastatic Melanoma of Unknown Primary Site 55
Clinical Versus Histopathologic Staging 55
Clinical Staging 55
Histopathologic Staging 56
Stage Groups 56
Localized Melanoma (Stages I and II) 56
Regional Metastases (Stage III) 57
Distant Metastases (Stage IV) 57
Updates and Changes in the 7th Edition AJCC Melanoma Staging System 57
Final Comments and Future Applications 58
References 59
5: Clinical and Histopathological Parameters in Melanoma 61
Introduction 61
Age 61
Anatomic Location 62
Gender 62
Breslow Thickness 62
Clark Anatomic Level 63
Tumor Volume 64
Cross-Sectional Profile 64
Ulceration 65
Mitotic Rate 65
Radial and Vertical Growth Phases 66
Regression 67
Host Inflammatory Response 68
Tumor Vascularity 68
Vascular Invasion 69
Angiotropism 69
Histological Tumor Type 69
Cytologic Variants 70
Desmoplasia 71
Neurotropic Melanoma 71
Cytologic Atypia 71
Borderline Melanocytic Lesions 72
Association with a Benign Melanocytic Nevus 72
Paratumoral Epidermal Hyperplasia 72
Satellite and In-Transit Metastasis 73
Sentinel Lymph Nodes 73
Conclusion 73
References 75
6: Genetic/Epigenetic Biomarkers: Distinction of Melanoma from Other Melanocytic Neoplasms 80
Introduction 80
Allelic Imbalance (AI) Analysis 80
Comparative Genomic Hybridization (CGH) 81
Multiplex Ligation-Dependent Probe Amplification (MLPA) 82
Fluorescence In Situ Hybridization (FISH) 82
Analysis of BRAF, NRAS, and HRAS Gene Mutation 83
Gene Expression Analysis Using DNA Microarrays 84
Epigenetic Biomarkers 84
Combination of Mutational Analysis and Methylation-Specific MLPA 85
Case 1 85
Case 2 85
Conclusion 87
References 87
7: mRNA Biomarkers in Melanoma 89
Introduction 89
Melanomagenesis 91
Dysplastic Nevi and Melanoma Progression 92
From RGP Melanoma to VGP Melanoma: The Big Step 92
From Primary Melanoma to Metastatic Disease 93
Gene Expression Profiling and Outcome 95
Conclusion 97
References 97
8: Epigenetic Biomarkers in Melanoma 99
Introduction 99
DNA Methylation 101
Aberrant DNA Hypermethylation 101
Aberrant DNA Hypomethylation 104
Clinical Applications 105
DNA Methylation as Biomarkers in  Melanoma 105
Histone Modifications 107
Histone Acetylation and Methylation 108
Clinical Applications 108
Histone Modifications as Biomarkers in Melanoma 110
MicroRNAs 112
Conclusions 115
References 115
9: MicroRNA Biomarkers in Melanoma 123
Introduction 123
Overview of microRNAs 126
microRNAs as Novel Therapeutics 126
microRNA Nomenclature 127
Deregulated microRNAs in Melanoma 128
microRNAs and Prognostication in Melanoma Patients 132
Future of microRNAs in Melanoma Management 132
References 134
10: MicroRNAs as Biomarkers and Therapeutic Targets in Melanoma 137
miRNA Biogenesis and Function 137
Transcription of miRNA Genes and Processing in the Nucleus 137
Cytoplasmic Processing and Modes of miRNA-Mediated Gene Silencing 138
Studies on Global miRNA Expression and General Potential of miRNAs to Serve as Biomarkers in Melanoma 141
Initial Studies on Global miRNA Expression, Including Data on Melanoma Cells 141
miRNA Profiling of Melanocytes and Melanoma Cell Lines and Usefulness of Formalin-Fixed Paraffin-Embedded (FFPE) Tissue Samples for the Discovery of miRNA Biomarkers 141
Attempts to Identify miRNAs that Can Serve as Molecular Biomarkers in Melanoma Diagnosis and Prognosis 143
Potential of Blood-Based miRNA Biomarker Discovery in Clinical Samples 143
Future Prospects for miRNAs as Melanoma Biomarkers 146
Identification of miRNAs Deregulated in Melanoma and Their Potential to be Utilized for Future Targeted-Melanoma Therapy 146
Recent Progress in Exploitation of RNA Interference for Cancer Therapy 146
Advantages of Utilizing miRNAs for RNAi-Based Gene Therapy 146
miRNAs Suitable for RNAi-Based Therapeutic Approaches in Melanoma 148
Future Prospects for miRNA-Based Therapeutics in the Treatment of Melanoma 148
References 149
11: Mitochondrial DNA Biomarkers in Melanoma 155
Mitochondrial DNA Alterations in Metabolic Diseases and Cancer 155
Mitochondrial DNA Replication and DNA Instability 156
The Mitochondrial Genome 156
Mutations Related to Exposure to Ultraviolet Radiation 156
Mitochondrial DNA Deletions 157
Reactive Oxygen Species (ROS) 159
ROS Formation by Mitochondria in Cutaneous Tissues 159
Role of Melanin in ROS Formation 160
Mitochondrial DNA Alterations in Melanoma 162
Mitochondrial Resequencing Arrays (Mitochips) 163
References 165
12: Tissue-Based Protein Biomarkers in Melanoma: Immunohistochemistry: (A) Diagnosis 168
Histopathological Features of Melanoma 168
Immunohistochemical Markers of Melanocytic Differentiation 169
Protein Markers to Distinguish Benign and Malignant Melanocytic Lesions 171
Markers of Tumor Cell Proliferation 171
Melanocytic Markers 172
Cell Cycle-Related/ Anti-Apoptosis Proteins 172
Immune Modulatory Markers and Signaling Molecules 176
Protein Markers in Special Situations 176
Spitz Tumors 176
Proliferation Nodules 179
Nevoid Melanoma vs . Compound/Intradermal Nevi 179
Melanoma Arising in Association with a Nevus 179
Cellular Blue Nevi and Melanoma 179
Distinction of Desmoplastic Melanoma from Desmoplastic Nevus 180
Distinction of Desmoplastic Melanoma from Scar Tissue 180
Distinction Between Solar-Damaged Skin/Actinic Keratosis and Melanoma In Situ, Lentigo Maligna Type 180
Summary/Conclusions 180
References 181
13: Tissue-Based Protein Biomarkers in Melanoma: Immunohistochemistry: (B) Prognostication 186
Current Melanoma Risk Stratification: Challenges for Melanoma Biology-Based Prognostication 186
Mitotic Rate/Proliferation Biomarkers 188
Emerging Protein Biomarkers: Need for Systematic Study Design 189
Outlook 193
Concluding Remarks 193
References 194
14: Tissue-Based Protein Biomarkers in Melanoma: Mass Spectrometry-Based Strategies 198
References 202
15: Serological Biomarkers in Melanoma 204
Introduction 204
Metastatic Melanoma 204
The Process of Melanoma Cell Metastasis 205
Differential Gene Expression Profiles of CTCs 207
Methods of Detecting CTCs 208
Melanoma Markers: Which to Use? 210
Other Serological Markers of Melanoma 210
Circulating Melanoma Cells as a Prognostic Measure: Précis 211
Conclusion 212
References 212
16: Molecular Markers of Lymph Node Disease in Melanoma 218
Sentinel Lymph Node Biopsy (SNLB) in Melanoma: Current Standard and Open Issues 218
Prediction of SLN Status from Primary Melanoma Analysis 220
Pathological Parameters 220
Biomarkers: The Case of Lymphangiogenesis 221
SLN and Non-SLN Metastasis 223
Pathological Parameters 223
Molecular Markers: The Case of Polymerase Chain Reaction 226
Final Remarks 229
References 229
17: Melanoma Cell Propagation: Cancer Stem Cell, Clonal Evolution and Interconversion Models of Tumorigenicity 236
Introduction 236
Research on Cancer Stem Cells (CSCs) 237
Identification of CSCs 237
Methods for the Identification of CSCs 238
Animal Models for the Identification of CSCs 239
Three Theories for the Phenotypic and Functional Heterogeneity of Tumor Cells 240
Melanoma Stem Cells (MSCs) 241
The Development of Melanoma 241
MSC Markers and Limitations 242
MSCs Identified According to Tumorigenic Potential 243
Plasticity of MSCs 244
Metastasis and CSCs 245
CSCs and Drug Design for Treatment of Melanoma 245
Limitations of Drug Testing Against CSCs 246
Targeting Pathways that Regulate CSC Growth 246
Conclusion 246
References 247
18: Surgical Management of Melanoma: Concept of Field Cancerization and Molecular Evaluation of Tissue Margins 251
References 254
19: Chemotherapy for Melanoma 255
Introduction 255
Tumor Biology 255
Cell Cycle and Effects of Chemotherapeutic Agents 255
Kinetics of Tumor Growth and the Fractional Cell Kill Hypothesis 257
Chemotherapeutic Agents for Melanoma 257
Single-Agent Chemotherapy 258
Dacarbazine 258
Temozolomide 259
Fotemustine 260
Vindesine 260
Paclitaxel 260
Cisplatin and Carboplatin 261
Combination Chemotherapy 261
Biochemotherapy 263
Adjuvant Chemotherapy 263
Locoregional Chemotherapy 264
Isolated Hyperthermic Limb Perfusion 264
Electrochemotherapy 264
Hepatic Intra-Arterial Chemotherapy and Transarterial Chemoembolization (TACE) 264
Chemoresistance 265
Overcoming Chemoresistance by Stroma-Targeted Combinations of Biomodulating Agents 267
Concluding Remarks 267
References 268
20: Molecular-Targeted Therapy for Melanoma 272
Introduction 272
Activating Mutations Within the Ras/Raf/Mek/Erk Pathway 272
RAF Inhibitors 273
MEK Inhibitors 274
Dysregulation of the PI3K/AKT Pathway 275
Combined Inhibition of MAPK and mTOR Signaling 276
PI3K Inhibitors in Combination with Chemotherapeutic Agents 276
Resistance of Melanoma to Drug-Induced Apoptosis 276
Apoptosis Signaling Inhibitors 277
Novel Therapeutic Targets in Melanoma 277
C-KIT or CRAF Signaling-Driven Melanoma Subsets 278
Inactivation of Both MITF and BRAF V600E Significantly Inhibit Melanoma Growth 279
Cell Cycle Changes in Melanoma 279
Conclusions 280
References 280
21: Anti-angiogenesis Therapy for Melanoma 287
Angiogenesis in Melanoma 287
Clinical Experience with Angiogenesis-Targeting Agents in Melanoma 289
VEGF-Blocking Agents 291
Multi-Target Protein Kinase Inhibitors 292
Anti-Angiogenic and Immunomodulatory Drugs 293
Drugs Targeting Integrins 295
Key Challenges of Anti-Angiogenic Cancer Therapy 295
Conclusions 296
References 297
22: Immunological Biomarkers and Immunotherapy for Melanoma 301
Proof of Principle That Immunotherapy in Patients with Melanoma is Effective 301
Details of Current Immunotherapeutic Approaches in Melanoma 302
Basic Physiology of the Immune Response 302
Melanoma Vaccine Therapy 302
Whole-Cell and Lysed-Cell Vaccines 302
Peptide/Protein-Based Vaccines 303
Dendritic Cell-Based Vaccines 303
Viral Vectors and Plasmid Vaccines 303
Heat Shock Protein (HSP) Therapy 303
Adoptive T-Cell Transfer Therapy 304
Cytokine Therapy 304
Administration of Activating Antibodies 304
PD-1 Antibodies 305
CD40 Agonist mAbs 305
Toll-Like Receptor Agonists 305
Biochemotherapy 305
Nonspecific Immune Adjuvants 305
Immune-Evasion Strategies 305
Concluding Remarks 307
References 308
23: Diagnostic and Prognostic Biomarkers and Therapeutic Targets in Melanoma: An Overview 311
Introduction 311
Melanoma Staging 311
Host Immunity in Primary Melanoma, Regional Nodal Metastases and Advanced Disease 312
Serum Biomarkers of Prognostic and/or Therapeutic Predictive Value in Melanoma 313
Lactate Dehydrogenase (LDH) 313
S100B 313
Melanoma-Inhibiting Activity (MIA) 314
C-Reactive Protein (CRP) 314
Vascular Endothelial Growth Factor (VEGF) 314
Other Serum Biomarkers 315
Induction of Autoimmunity is Associated with the Therapeutic Benefits of Immunotherapy 315
Primary Tumor Ulceration 316
Cytokine Levels in Patients with Melanoma 316
Biomarkers Associated with Anti-CTLA4 Therapy for Advanced Melanoma 317
Molecular Biomarkers of Predictive Value for Novel Molecular-Directed Therapies 318
References 319
Index 324