Cover
Oncogenomics
Copyright
Dedications
Contents
List of Contributors
Preface
PART I MOLECULAR MEDICINE: A NOVEL APPROACH TO CANCER INVESTIGATION
1 From the Double Helix to Oncogenomics and Precision Cancer Medicine: An Evolving Story
Abbreviations
The Double Helix and the Human Genome Project
Precision Medicine Initiative and Precision Cancer Medicine
Oncogenomics in the Fight Against Cancer
Master Protocols and Clinical Trials of Targeted Drugs
NSCLC and Melanoma: Successful Examples of Precision Cancer Medicine
NSCLC
Melanoma
Precision Cancer Medicine: Uncertainties and Drawbacks
Conclusions
References
2 Intratumor Heterogeneity: Biological and Clinical Implications
Introduction
Levels of Intratumor Heterogeneity
Genetic Heterogeneity
Transcriptomic and Proteomic Heterogeneity
Spatial Heterogeneity
Phenotypic Heterogeneity
Clinical Implications of Intratumor Heterogeneity and Novel Approaches
Conclusions
Acknowledgments
References
3 The Role of Proteomics in Cancer Research
What Is a Proteome?
Proteomics Approaches in Cancer Research
The Role of Proteomics in Cancer Research
Advantages of the Proteome in Understanding the Biology of Cancer
Applying Proteomics Tools for Cancer Research
Post-translational Modifications in Cancer
Tumor Biomarkers and Liquid Biopsy
Monitoring Drug Effects With Proteomics
Conflict of Interest
References
Further Reading
4 Next-Generation Sequencing in Clinical Practice
References
Further Reading
5 Cancer Epigenetics: Aberrant DNA Methylation in Cancer Diagnosis and Treatment
Introduction
DNA Methylation and Transcriptional Regulation
Alterations of DNA Methylation in Cancer Cells
The CpG Island Methylator Phenotype
Cancer Diagnosis Using Aberrant DNA Methylation
Cancer Detection Diagnosis
Diagnosis of Cancer Pathophysiology
Advantages of Pathophysiology Diagnosis Using Aberrant DNA Methylation
Cancer Risk Diagnosis
Cancer Therapy by Targeting Aberrant DNA Methylation
Importance of Treatment Dose and Schedule for DNA Demethylating Drugs
Mechanisms of DNA Demethylating Therapy
Applications of DNA Demethylating Therapy to Solid Tumors
Future Perspective of DNA Demethylating Therapy
Epilogue
References
6 Cancer Stem Cells: Role in Tumor Progression and Treatment Resistance
Introduction
Role of Cancer Stem Cells in Tumor Progression
Cancer Stem Cells in Therapy Resistance
Mechanisms of Cancer Stem Cell Therapy Resistance
Conclusion
References
7 Cancer Stem Cells, Apoptosis Pathways and Mechanisms of Death Resistance
Introduction
Cancer Stem Cells Phenotype
Cancer Stem Cells Signaling Pathways
Drug Resistance in CSCs
MicroRNAs and Other Epigenetic Factors in CSCs
Cancer Stem Cells and Apoptosis Pathways
Mitochondrial Pathway
Death Receptor Pathway
Endoplasmic Reticulum (ER) Stress-Induced Apoptosis Pathway
Mechanisms of Death Resistance in Cancer Stem Cells
Multidrug Resistance (MDR) Transporters
PI3K/Akt/mTOR Signaling Pathway Plays a Crucial Role in CSCs
Dysregulated Antiapoptotoic Proteins in CSCs
Bcl-2 Family of Proteins
TRADD Expression and NF-κB Activity
Inhibitor of Apoptosis (IAP) Family of Proteins in CSC
c-FLIP Overexpression in CSCs
Resistance to ER Stress-Induced Apoptosis in CSCs
Conclusions and Future Directions
Acknowledgments
References
8 Targeting the Hedgehog and Notch Signaling Pathways in Cancer Stem Cells
Introduction
Hedgehog Pathway
Notch Pathway
Therapies Targeting Hedgehog and Notch Signaling in Cancer Stem Cells
Hedgehog Pathway Antagonists
Notch Pathway Antagonists
Conclusions and Future Perspectives
References
9 Cancer Stem Cells in Multiple Myeloma and the Development of Novel Therapeutic Strategies
Abbreviations
Introduction
Multiple Myeloma Cancer Stem Cells: General Concepts
Clonotypic B Cells
Clonogenic Plasma Cells
Interconversion Between Differentiated and Undifferentiated Clonotypic Cells
Side Population Cells
Drug Resistance
Signaling Pathways
MicroRNAs
Bone Marrow Microenvironment
Targeting Multiple Myeloma Cancer Stem Cells
Conclusions
References
PART II ONCOGENOMICS: CIRCULATING BIOMARKERS IN CLINICAL ONCOLOGY
10 Bone Metastases from Solid Tumors: In Search of Predictive Biomarkers for Clinical Translation
Abbreviations
Introduction
Epidemiological and Clinical Features of Bone Metastases
Pathogenesis of Bone Metastases
The “Omics Sciences” in the Prediction of Bone Metastases From Most Common Solid Cancers
In Search of a “Genomic Osteotropism Signature” in Solid Tumors
Prediction of Bone Metastases: A Clinical and Socioeconomic Issue
Conclusions
References
11 Liquid Biopsy and Genomic Assessment for Lung Cancer: The Role in Clinical Practice?
Introduction
Which Biological Source?
Importance of the Preanalytical Steps for the Reliability of the Results
Which Analytical Platform for Which Evaluation?
Targeted Evaluation of Mutations in EGFR
Targeted Investigation Into Genomic Alterations Other That Those Present in EGFR
Detection With a Selected Panel of Genes
Perspectives and Conclusion
References
12 Prognostic and Predictive Role of Circulating Tumor Cells
Introduction
CTC Isolation and Detection
Prognostic Role of CTCs in Solid Tumors
Enumeration and Analysis of CTCs to Predict Treatment Response in Solid Tumors
Clinical Utility of CTCs: Current Status and Future Directions
References
13 Circulating miRNAs as Tumor Biomarkers
MicroRNAs: Biosynthesis and Function
miRNAs Dysregulated in Cancer
Extracellular Vesicles and Extracellular miRNAs
Circulating miRNAs as Potential Biomarkers for Cancers
Breast Cancer
Colorectal Cancer
Lung Cancer
Pancreatic Cancer
Challenges and Opportunities for miRNA Based Biomarkers
Acknowledgments
References
14 Circulating DNA in Cancer Diagnosis and Prognosis
Introduction
Circulating Cell-Free DNA
Circulating Tumor DNA (ctDNA)
Circulating DNA Levels in Patients With Cancer
Circulating Mutant Tumor DNA
Presence of Mutant Circulating Tumor DNA as a Prognostic Marker
Mutant Circulating Tumor DNA to Identify Therapy Sensitive or Resistant Cancer Subpopulations
Direct Comparison of Cancer Tissue DNA Mutations and Circulating Tumor DNA Mutations
Healthy Cells Can Take Up Mutant ctDNA
Copy Number Variations in Circulating Tumor DNA
Gene Methylation in Circulating Tumor DNA
Conclusions
References
15 Sequencing a Single Circulating Tumor Cell for Genomic Assessment
Single-Cell Whole-Genome Sequencing Technologies
Isolation of a Single CTC
Single-Cell Whole-Genome Amplification Methods
Linker Adapter PCR
Primer Extension Preamplification PCR
Degenerate Oligonucleotide-Primed Polymerase Chain Reaction
Multiple Displacement Amplification
Multiple Annealing and Looping-Based Amplification Cycles
Single CTC NGS for Genetic Study of CTCs and Clinical Applications
Challenges and Future Prospects
References
16 Single Nucleotide Polymorphisms in Cancer Research and Treatment
Introduction
Potential Applications of SNPs in Oncology: Tumor Susceptibility
Potential Applications of Snps in Oncology: Association With Prognosis
Potential Applications of SNPs in Oncology: Association With Treatment Outcome
References
PART III GASTROINTESTINAL TUMORS: MOLECULAR DIAGNOSIS AND TREATMENT
17 Gastric Cancers: A Molecular Roadmap for Patient Stratification and Targeted Therapies
Introduction
Molecular Classification of Gastroesophageal Cancer
Microsatellite Instability as a Biomarker
Immuno-oncology Agent Biomarkers
Current and Potential Targeted Therapeutic Strategies
Receptor Tyrosine Kinase (RTK) Amplifications
Targeting DNA Damage Repair (DDR) Pathways
Antiangiogenesis Therapies
Immune Checkpoint Inhibition
Other Molecular Targets of Interest in Gastrointestinal Adenocarcinomas
Future Directions
References
Further Reading
18 Resistance to EGFR Targeting Treatments in Colorectal Cancer
Anti-EGFR Therapeutic Strategies in Colorectal Cancer
Resistance to Anti-EGFR Therapies: Heterogeneity Matters
Mechanisms of Resistance
Mutations
Epigenetic Abnormalities
Microenvironment
Signaling Reactivation and Pathway Bypass
Conclusions
Acknowledgment
References
19 Circulating DNA and Protein Biomarkers for the Treatment of Metastatic Colorectal Cancer with Tyrosine Kinase Inhibitors
Introduction
Mutational profiles and targeted therapies in metastatic colorectal cancer
TKIs and monoclonal antibodies in metastatic Colorectal Cancer
Tissue testing
Liquid biopsies in metastatic colorectal cancer
Circulating cell-free DNA in metastatic colorectal cancer
Plasma protein biomarkers to monitor the effect of TKI in metastatic colorectal cancer
Further research and the way forward
References
20 Rationale for Immunotherapy in Gastrointestinal Malignancies
Introduction
Esophageal and Gastric Cancer
Anti-PD-1 Therapy in Gastroesophageal Cancer
Esophageal Squamous Cell Carcinoma
Colorectal Cancer
Pancreatic Cancer
Hepatocellular Carcinoma
Biliary Tract Cancer
Conclusions
References
Further Reading
21 Proteomics Profiling of Pancreatic Cancer: Roles in Biomarker Discovery
Introduction
MS-Based Proteomics Methodologies
Global Proteomics Profiling in Cancer Biomarker Discovery
Candidate-Based Quantitative Analysis for Biomarker Detection
Recent Proteomics Discovery in Pancreatic Cancer
Pancreatic Tissue
Plasma/Serum
Pancreatic Juice
Cyst Fluid
Urine
Conclusion
Acknowledgment
References
22 Emerging Technologies for the Diagnosis and Treatment of Pancreatic Cancer
Histopathologic and Molecular Diversity of Pancreatic Cancer
Conventional and Nanomedicine Treatment Strategies
Surgery and Chemotherapy
Nanotechnology-Based Drug Delivery
Personalized Medicine
Patient Stratification Based on Biomarkers
Patient Stratification Based on Noninvasive Imaging
Emerging Therapies and Diagnostics
Predictive Preclinical Models of PDAC Carcinogenesis
Image-Guided Surgery
Therapeutic Gene Silencing
Noninvasive Treatment Modalities
Diagnostics
Summary
Acknowledgment
References
Further Reading
23 Personalized Medicine in Gastrointestinal Stromal Tumors
References
24 Circulating MicroRNAs as Tumor Biomarkers in Hepatocellular Carcinoma
Background
Extracellularly Circulating miRNAs in HCC: Diagnostic Performance
Extracellularly Circulating miRNAs as Prognostic Markers in Patients With HCC
miRNAs Associated With Exosomes, Microvesicles, and High-density Lipoprotein: Different Function, Different Information as ...
Considerations on the Shift of Extracellular Circulating miRNAs Into the Clinic
Conclusions
References
PART IV PERSPECTIVES IN BREAST CANCER GENOMICS
25 Gene Profiles in Breast Cancer: Translation to Clinical Medicine
The Clinical Problem
Molecular Diagnostic Tests Commercially Available
Clinical Utility of Molecular Diagnostic Tests and Open Questions
Gene Signatures Developed by the Milano Group
Molecular Subtypes Are Here to Stay
The FFPE Revolution: Unlocking Pathology Tissue Blocks
Puttings Things Together: The Development of FFPE-Resilient Metagene-Based Risk Predictors
Hints Also Come from in Vitro Models
Conclusion
Note
References
26 Novel Biomarkers Predicting the Development of Bone Metastasis in Early Breast Cancer
Introduction
Expression Profile
Mutation Profile
miRNA
Biochemical Markers of Bone Turnover
Conclusions
References
27 HER2-Positive Early Breast Cancer: Affordable Risks, Affordable Therapies, and New Developments
Introduction
Trastuzumab for Early HER2-Positive Breast Cancer
Trastuzumab and Landmark Achievements in Metastatic Disease
Adjuvant Setting
Neoadjuvant Setting
Trastuzumab Cardiotoxicity
Moving Beyond Trastuzumab for Early HER2-positive Breast Cancer
Need for Treatment Optimization
Escalated Anti-HER2 Strategies for Early BC
Extended Duration of Anti-HER2 Therapy
Dual HER2 Blockade
Deescalated Anti-HER2 Strategies
Shortened Trastuzumab Duration
De-escalated Chemotherapy
Conclusions
References
28 Role of Circulating Tumor Cells in Breast Cancer Patients
Abbreviations
Cells Released by Solid Tumors as “Liquid Biopsy” in Breast Cancer
Clinical Validity of CTC Counts and Dynamic Changes in Metastatic Breast Cancer
Clinical Validity of CTCs with Epithelial–Mesenchymal Plasticity
Clinical Validity of CTCs in Nonmetastatic Breast Cancer
Clinical Utility of CTC Characterization
Conclusions and Future perspectives
References
29 Overcoming Endocrine Resistance in Breast Cancer: mTOR Inhibitors and New Drugs
Introduction
Endocrine Therapy in Metastatic Breast Cancer
Hormone Resistance
Strategies to Overcome Hormone Resistance
Epigenetic Modifiers
Agents Targeting Angiogenesis, the FGFR Pathway, or Cross-Talk Between ER and EGFR, HER2
Antiangiogenic Agents
Agents Targeting the FGFR Pathway
Anti-HER2 Agents
Fulvestrant Combined with AIs
Next-Generation SERDs
Targeting the PI3K/Akt/mTOR Pathway
mTOR Inhibitors
PI3K Inhibitors
Dual PI3K/mTOR Inhibitors
Dual PI3K/IGF-1 Inhibitors
Dual mTorc1/2 Inhibitors
Akt Inhibitors
SGK1 Inhibitors
Targeting Cell Cycle
Cyclin-Dependent Kinase Inhibitors
PI3K/mTOR and Cycline-Dependent Kinases Inhibitors Combination Therapy
Inhibition of the Proteasome
Targeting Immune Response as a Novel Strategy to Delay or Overcome Hormone Resistance
Anti-PD-1/PD-L1 Agents
CK Inhibitors Combined with Checkpoint Inhibitors and Hormone Therapy
Epigenetic Therapy Combined with Checkpoint Inhibitors or Hormone Therapy
Stimulation and/or Modulation of the Immune Response by Cytokines Given in Addition to Hormone Therapy
Conclusion
References
30 Explore Genomic Profiles for Triple-Negative Breast Cancer to Discover Drug Targets
Introduction
TNBC Gene Expression Profiling
TNBC Somatic Mutation Profiling
TNBC Copy Number Alteration Profiling
TNBC Methylation Profiling
TNBC microRNA Expression Profiling
Integrative TNBC Genomic Profiling
Deregulated Pathways in TNBC
Targeted Therapy for TNBC
Immunotherapy of TNBC
Conclusion and Perspectives
Acknowledgment
References
PART V LUNG CANCER: ROLE OF GENOMICS IN CLINICAL PRACTICE
31 Gene Fusion in NSCLC: ALK, ROS1, RET, and Related Treatments
Introduction
NSCLC: Past and Future
ALK, ROS1, and RET: Roles in Normal Physiology and Cancer Development
Methods to Detect Gene Fusions
Target Therapy Against Fused Genes in NSCLC
ALK Inhibitors
ROS1 Inhibitors
RET Inhibitors
Future Perspectives
References
32 Circulating Tumor Cells and ctDNA in NSCLC: A Role for Treatment Decision
Introduction
Circulating Tumor DNA
Circulating Tumor Cells
Conclusions
References
33 EGFR Mutations: Best Results from Second- and Third-Generation Tyrosine Kinase Inhibitors
Introduction
Second-Generation EGFR TKIs
Afatinib
Dacomitinib
Neratinib
Third-Generation EGFR TKIs
Conclusions
References
Further Reading
34 Immuno-Oncology in Lung Cancer: A Focus on Anti-PD-1 and Anti-CTLA-4 Therapy in NSCLC
Introduction
Molecular Mechanism of Immuno-Oncology Therapies
Programmed Cell Death Protein 1(PD-1) Pathway in NSCLC
Combination Therapy With PD-1/PD-L1 Inhibitors
Targeting Cytotoxic T-Lymphocyte Associated Protein 4 in NSCLC
Conclusion
References
PART VI GENOMICS IN GENITOURINARY CANCER
35 Molecular Assessment of Ovarian Cancer and Translation to Clinical Management
Introduction
Clinical Patterns of Ovarian Cancer
Molecular Patterns of Ovarian Cancer
Inherited Ovarian Cancer
High-Grade Serous Ovarian Cancer
Low-Grade Serous Ovarian Cancer
Clear Cell Carcinoma
Endometrioid Carcinoma
Mucinous Carcinoma
Nonepithelial Ovarian Cancer
Epigenetic Factors in Ovarian Cancer
Targeted Therapy of Ovarian Cancer
Angiogenesis Inhibitors
Bevacizumab
Pazopanib
Cediranib
PARP Inhibitors
HER2 Inhibitors
Antiepigenetic Approaches to Ovarian Cancer
Conclusion
References
Further Reading
36 Development of PARP Inhibitors for BRCA-Deficient Epithelial Ovarian Cancer
Introduction
DNA Repair Pathways
PARP and DNA Repair
Clinical Applications of PARP Inhibitors
Early Phase Trials of PARP Inhibitors in Ovarian Cancer
Clinical Approvals for Olaparib in Ovarian Cancer
Rucaparib in Ovarian Cancer
Niraparib in Ovarian Cancer
Predictive Biomarkers for PARP Inhibitors
Conclusions
References
37 New Treatment Options for Ovarian Cancer
Introduction
Molecular Analysis and Emerging Therapeutics in Ovarian Cancer
Targeted Therapy in Ovarian Cancer
PARP Inhibitors
Antiangiogenic Therapies: Bevacizumab
Emerging Therapeutic Considerations
References
38 Emerging Immunotherapies for Renal Cell Carcinoma
Nivolumab
Ipilimumab
Pembrolizumab
Anti-PD-L1 Antibodies
Combination Strategies With Conventional Treatments
Adjuvant Treatments
References
39 TKIs in Renal Cell Carcinoma: What Can We Expect in the Future?
Introduction
Renal Cell Carcinoma
TKIs Used in Clear Cell Renal Cell Carcinoma (ccRCC)
Sunitinib
Sorafenib
Pazopanib
Axitinib
Cabozantinib
First-Line Treatment
Second-Line Treatment
Levantinib
Second-Line Treatment
TKIs Within Treatment of Nonclear cell RCC
Adjuvant or Not?
Combining TKIs With Immunotherapies
Biomarkers for Use Within Treatment of RCC
Toxicities and Intermittent Therapy
References
40 Circulating Tumor Cells as Surrogate Biomarker for Overall Survival in Metastatic Prostate Cancer
Introduction
Biology of Circulating Tumor Cells
Current Approaches for CTC Detection
CTCs as Surrogate Biomarker for Prostate Cancer in the Clinic
Challenges and Future Aspects When Including CTC Analysis in the Clinic
Conclusion
References
PART VII GENOMICS IN NEUROENDOCRINE TUMORS, MELANOMA, AND SARCOMA
41 Management of NETs in the Precision Medicine Era
Introduction
Clinical Heterogeneity of NETs
Genomic Heterogeneity of NETs
Pancreatic NETs
Small Bowel NETs
Lung NETs
Innovative Approaches for the Diagnosis and Follow-Up of NETs
Systemic Treatment of Metastatic NETs: Towards Personalized Medicine Strategies
Palliation of Hormonal Symptoms
Precision Medicine Approaches
Control of Tumor Growth
Somatostatin Analogs
Precision Medicine Approaches
Radiolabeled Somatostatin Analogs
Precision Medicine Approaches
Biologic Agents
Precision Medicine Approaches
Chemotherapy
Precision Medicine Approaches
Immunotherapy
Precision Medicine Approaches
Conclusions
References
Further Reading
42 Immunological and Genetic Biomarkers of Sarcomas: Implication for Future Treatment Strategies
The Sarcoma Scenario
Background of Immunotherapy in Sarcomas
Tumor–Host Interplay
Immune Infiltrate
Cytokines
Antigen Presentation
Metabolism
Therapeutic Strategies to Overcome Immune Tolerance
Angiogenesis
Increased Immunogenicity
Adoptive Cell Therapy
Conclusions
References
43 Advances in Sarcoma Genomics and Therapeutic Management
Soft Tissue Sarcoma
Kinase Mutation
Recurrent Chromosomal Translocation
Gene Amplification
Loss of Tumor Suppressor Genes
Complex Genomics
Bone Sarcoma
Sarcoma in Hereditary Cancer Predisposition Syndromes
Li–Fraumeni Syndrome
Neurofibromatosis Type 1
Hereditary Retinoblastoma Syndrome
GIST Predisposition Syndromes
Tuberous Sclerosis Complex
Management of Specific Sarcomas Accounting for the Possibility of Inherited Cancer Predisposition
GIST
Osteosarcoma
Rhabdomyosarcoma
Soft Tissue Sarcomas
Conclusion
References
Further Reading
44 Molecular Pathways in Melanomagenesis: Characterization of New Therapeutic Targets
Introduction to Melanoma: Classification, Epidemiology, and Clinical Course
Biology and Pathology of Melanoma
Cutaneous Melanoma
Ocular and Mucosal Melanoma
Fundamental Pathways Driving Melanoma Initiation and Progression
Cell signaling Pathways in Cutaneous Melanoma
RAS/RAF/MEK/ERK Pathway
PI3K/AKT/mTOR Pathway
Developmental Pathways: WNT/β-Catenin and Notch
Cell Cycle and Apoptosis
Melanocyte-lineage specific pathway: the MITF axis
Crossroads Between Signaling Pathways and Immune Function
Cell Signaling Pathways in Uveal and Mucosal Melanoma
Targeted Therapies Approved for Melanoma Treatment
The Mutational Signature of Melanoma and Characterization of Novel Therapeutic Targets
The Genomic Landscape and Mutational Signature of Melanoma
Discovery of Candidate Pathways for Molecularly Targeted Strategies in Melanoma
Targeted Therapies in Clinical Development for Melanoma
Conclusive Remarks and Perspectives
References
Further Reading
45 Immunotherapies and Novel Combinations: Advances in the Treatment of Melanoma
Introduction
Ipilimumab
Anti-PD-1 Agents (Nivolumab and Pembrolizumab)
Combined Anti-PD-1 and anti-CTLA-4 Therapy
Combination of Anti-PD-1/Anti-CTLA-4 Therapy With Other Immunotherapies
Combination of Immunotherapy With BRAF or MEK Inhibitors
Combination of Immunotherapy With Other Treatment Modalities
Conclusions
References
46 BRAF-Mutant Melanoma: Treatment Approaches and Resistance Mechanisms
Introduction
Targeted Inhibition With BRAF and MEK Inhibitors
BRAF and MEK Inhibitor Resistance Mechanisms
Immune Therapy in BRAF-Mutant Patients
Future Therapies
Conclusion
Acknowledgments
References
Index
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