Neuroblastoma: Molecular Mechanisms and Therapeutic Interventions

Cover
Neuroblastoma: Molecular Mechanisms and Therapeutic Interventions
Copyright
List of Contributors
1. Neuroblastoma Pathology and Classification for Precision Prognosis and Therapy Stratification
	Introduction
	Pathology Diagnosis
	International Neuroblastoma Pathology Classification (INPC)
		Histologic Categories and Subtypes
		Prognostic Grouping (Favorable Histology Vs. Unfavorable Histology)
	Searching for Actionable/Druggable Targets Associated with Therapy Resistance
		MYC Driven Neuroblastoma
		Neuroblastoma With ALK Mutation/Overexpression and Amplification
		Telomere Maintenance and Elongation in Neuroblastoma
	Proposed Subgroups of Unfavorable Histology Neuroblastoma for “Precision Medicine”
	Molecular Targeting Therapies for Unfavorable Histology Neuroblastoma Resistant to the Current Therapy
		Targeting of MYC Driven Neuroblastoma
		Targeting ALK in Neuroblastoma
		Targeting of Telomere Maintenance and Elongation in Neuroblastoma
	Conclusion
	References
2. Role of Genetic and Epigenetic Alterations in Pathogenesis of Neuroblastoma
	Introduction
	Genetic Alterations in Neuroblastoma Pathogenesis
		Ploidy
		MYCN
		ALK
		PHOX2B
		Chromosome 1p Loss
		Chromosome 17q Gain
		Chromosome 11q Loss
		p53/MDM2 Interaction
	Epigenetic Alterations
		DNA Methylation
		microRNAs
		Long Non-coding RNAs
	Conclusions
	References
3. Neuroblastoma: Molecular Mechanisms and Therapeutic Interventions
	Introduction
	Growth Factor Signaling and Oncogenes
		Small-molecule ALK Kinase Inhibitors
		Targeting MYCN
		RAS Pathway Inhibitors
		ATRX and Telomere Stability
	Immunotherapy
		Thalidomide and IMiDs
	Norepinephrine-Targeted Therapy
		131I-Metaiodobenzylguanidine Radiotherapy
	Conclusions
	References
4. GD2-Targeted Immunotherapy of Neuroblastoma
	Introduction
	Structure, Biosynthesis, and Distribution of GD2
	Functions of GD2
	Cancer Immunotherapeutics
	GD2-Specific Antibodies
	Anti-GD2 Monoclonal Antibodies
	Chimeric Anti-GD2 Monoclonal Antibody
	Humanized Anti-GD2 Antibody
	GD2-Specific Antibodies and Cytokines
	GD2-Specific Antibody in Combination With Chemotherapy
	Bispecific Antibody
	GD2 Chimeric Antigen Receptor
	GD2 Specific Vaccines
	GD2 Peptide Mimotope
	Anti-GD2 Idiotype Monoclonal Antibody
	O-Acetyl GD2-Specific Antibody
	Conclusions
	References
5. Targeting Angiogenesis in Neuroblastoma
	Biological and Clinical Aspects of Neuroblastoma
	Angiogenesis in Neuroblastoma
	Antiangiogenesis in Neuroblastoma
	Concluding Remarks
	Acknowledgments
	References
6. Autophagy and Novel Therapeutic Strategies in Neuroblastoma
	Introduction
	The Autophagy-Lysosome System
		Molecular Mechanisms of Autophagy
	Autophagy in Neuroblastoma
	The Cross-talk Between Autophagy and Apoptosis
	Molecular Mechanisms of Autophagy Activation in Neuroblastoma Cells
		Autophagy as a Pro-survival Mechanism in Neuroblastoma
		Autophagy as a Pro-death Mechanism in Neuroblastoma
		Modulation of Autophagy as a New Therapeutic Approach in Neuroblastoma
	Conclusions
	Acknowledgments
	References
7. Energy Metabolism and Metabolic Targeting of Neuroblastoma
	Introduction
	Alterations in the OXPHOS System in NB
	Glucose Metabolism
		Glucose Transport
		Hexokinase
		Pyruvate Oxidation
		Lactate Production
	Amino Acid Metabolism
		Glutamine
		Serine
	Lipid Metabolism
	The Nexus Between Common Genetic Abnormalities and Energy Metabolism in NB
		Segmental Chromosomal Alterations
		MYCN Proto-Oncogene Protein
		Telomerase Reverse Transcriptase Protein
	Metabolic Adaption to Hypoxia in NB
	Therapeutic Opportunities
		Glucose Deprivation
		Inhibition of Glycolysis
		Inhibition of Mitochondrial Energy Metabolism
		Targeting mTOR
		Repurposing of Common Drugs to Target Cancer Metabolism
			Antidiabetics
			Antibiotics
			Differentiating Agents and Induction of Energy Metabolism
			Targeting NB Energy Metabolism via Inhibition of Oncogenic Signaling
	Conclusion
	Acknowledgments
	References
8. Molecular Imaging in Neuroblastoma
	Metaiodobenzylguanidine (MIBG) Scintigraphy
	Skeletal Scintigraphy
	Fluorodeoxyglucose (FDG) PET
	Somatostatin Receptor Scintigraphy
		Newer PET Radiopharmaceuticals
	131I-MIBG Therapy
		Basic Principle
		Method and Precautions
		Adverse Effect
	Conclusion
	Disclosure
	References
9. Immunotherapy for Neuroblastoma
	Introduction
	Targets for NB Immunotherapy
		GD2
		L1-CAM
		B7H3
		Oncofetal Antigens
		Others
	Effectors of Immunotherapy for NB
	Cytokines
		Interleukin-2
		Granulocyte Macrophage Colony Stimulating Factor
		Other Cytokines
	Monoclonal Antibodies
		Monoclonal Antibodies Targeting GD2
			Murine Anti-GD2 MoAbs
			Chimeric Anti-GD2 MoAbs
			Humanized Anti-GD2 MoAbs
				Naxitamab
				Hu14.18K322A
	Chemoimmunotherapy
	Immunocytokines
	Radioimmunotherapy
	Adoptive Cell Therapy
		Natural Killer Cells
		T-Cells
			Chimeric Antigen Receptors (CARs)
			Bispecific Antibodies
			γδ T Cells
	Vaccines
		Whole Tumor Cell Vaccines
		Glycolipid Vaccines
		Antiidiotype Vaccines
		Antigen Presenting Cell Vaccines
	Limitations of Immunotherapy for NB
	Future Directions
		Identification of Newer Antigens
		Improving MoAbs and Immunoconjugates
		Improving Adoptive Cell Therapy
		Improving Vaccines
		Manipulating the Tumor Microenvironment
		Monitoring Effectiveness of Immunotherapy
	Conclusions
	Acknowledgments
	References
10. Advances in the Surgical Treatment of Neuroblastoma
	Introduction
		History
		Staging and Risk Status
			Very Low and Low Risk
			Intermediate Risk
			High Risk
		Surgical Technique
			Cervical Lesions
			Cervicothoracic Lesions
			Mediastinal Lesions
			Upper Abdominal and Retroperitoneal Lesions
			Pelvic Lesions
			Minimally Invasive Surgery
		Surgical Complications and Mortality
		Conclusion
	References
11. Role of Stemness Factors in Neuroblastoma: Neuroblastoma Stem Cells, Tumor Microenvironment, and Chemoresistance
	Cancer Stem Cells
	Heterogeneity and CSCs in Neuroblastoma
	Identification of CSCs in Neuroblastoma
		Cell-Surface Markers
		Intracellular Proteins
		Hoechst/Side Population
	Microenvironment
	Tumor-Associated Macrophages (TAMs) and Cancer-Associated Fibroblasts (CAFs)
	Immune Cells of the Microenvironment
		NK Cells
		DCs
		T Cells
	Mesenchymal Stromal Cells and the Microenvironment
	The Extracellular Matrix
	Cell Adhesion Molecules (CAMs)
		Integrins
		Cadherins and CD44
		Ig-like CAMs
	Angiogenesis and the Microenvironment
		Role of Matrix Metalloproteinases (MMPs) in Angiogenesis
		Role of Schwann Cells in Angiogenesis
	Hypoxia and the Microenvironment
	Chemoresistance
		CSCs and Chemoresistance
		Microenvironment and Chemoresistance
	Conclusions
	References
12. Current Pharmacotherapy for Neuroblastoma
	Introduction
		General Principles
	Stage-Guided Chemotherapy
		Low-Risk Disease
		Intermediate-Risk Disease
		High-Risk Disease
			Induction
			Myeloablation+Autologous Hematopoietic Stem Cell Transplantation
			Maintenance
		Stage IV-S Neuroblastoma
		Symptomatic Intraspinal Extension of Neuroblastoma
		Recurrent Disease
	Chemotherapy for Adults With Neuroblastoma
	Late Effects of Chemotherapy for Neuroblastoma
	Future Directions
	Conclusions
	References
13. Current Challenges in the Management of Neuroblastoma: Noncoding RNA Influences
	Introduction
	Current Status of Neuroblastoma Theranostics
		Diagnostic Protocols
		Therapeutic Protocols and Other Options
	Noncoding RNAs
		miRNA Influences in NB
			miR-17-92 Cluster
			miR-9
			miR-137
			miR-34a
		lncRNA Influences in NB
			MALAT1
			GAS5
	Clinical Importance of ncRNAs in NB Management Challenges
	Conclusion and Perspectives
	References
14. Novel Therapeutic Targets in Neuroblastoma
	Introduction
	Clinical and Molecular Features of Neuroblastoma
		Clinical Presentation, Diagnostic Evaluation, and Risk Stratification
		Staging
		Risk Stratification
		Response to Therapy
		Molecular Features and Risk Factors
	Current Approach to Treatment
		Induction Chemotherapy
		Local Surgical Control
		Myeloablative Chemotherapy With Autologous Stem Cell Transplant
		Conventional External Beam Radiation
		Maintenance Therapy and Immunotherapy
	Clinical Trials of Targeted Therapies
		Radiopharmaceuticals: MIBG and Beyond
		Somatostatin Receptor Analogs
		Kinase Targeted Therapies
		MYCN Targeted Therapies
		Epigenetic Regulators
		Immunotherapy
	Precision Medicine
	Future Directions
	Conclusion
	References
15. Current and Future Strategies for Treatment of Relapsed Neuroblastoma
	Introduction
	Standard Chemotherapy Approaches
	Novel Chemotherapy Combinations
		Immunotherapy Plus Chemotherapy
	Targeted Molecular Radiotherapy
	Precision Medicine Approaches
	Genetic and Molecular Targeted Agents
		Anaplastic Lymphoma Kinase (ALK) Inhibitors
		RAS/MAPK/MEK Pathway Inhibitors
		PI3K/mTOR/AKT Inhibitors
		Targeting MYCN
		Aurora Kinase Inhibitors
		Bromodomain Inhibitors
		Difluoromethylornithine (DFMO)
		Cyclin-Dependent Kinases
		Additional Agents and Emerging Targets
	Novel Immunotherapy Strategies
		Chimeric Antigen Receptor (CAR) T Cells
		NK Cells
		Other Approaches
	Challenges, Controversies, and Conclusions
	References
16. Emerging Evidence for Krüppel-Like Factor 4 (KLF4) as a Tumor Suppressor in Neuroblastoma
	Introduction
	Neuroblastoma in Need for New and More Reliable Prognostic Biomarkers
	Members of KLF Family and Subfamilies
	Molecular Structure of KLF4 to Account for Its Transcription Regulatory Roles
	Regulation of Expression and Activity of KLF4
	Involvement of KLF4 in Mechanism of Transactivation of Its Target Genes
	Involvement of KLF4 in Mechanism of Transrepression of Its Target Genes
	Neuroblastoma Shows Rare Genetic Complexion and Paradoxical Outcomes
	Evidence for KLF4 as a Tumor Suppressor in Neuroblastoma
	Conclusions
	Acknowledgments
	References
17. Modulation of Expression of miRNAs for Therapeutic Effects in Human Malignant Neuroblastoma
	Introduction
	Biogenesis of miRNAs and Their Roles in Cancers
	Deregulation of miRNAs in Human Malignant Neuroblastoma
	Suppression of Expression of Oncogenic miRNAs in Malignant Neuroblastoma in Preclinical Models
	Promotion of Expression of Tumor Suppressor miRNAs in Malignant Neuroblastoma in Preclinical Models
	Transcriptional Activation of the Epigenetically Silenced Tumor Suppressor miRNA Genes in Malignant Neuroblastoma in Precli ...
	Inhibition of Oncogenic miRNA or Induction of Tumor Suppressor miRNA and Pharmacotherapy to Enhance Therapeutic Effects in  ...
	Conclusions
	Acknowledgments
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	K
	L
	M
	N
	O
	P
	R
	S
	T
	U
	V
	W
	Z
Back Cover