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Molecularly Targeted Therapy for Childhood Cancer

:	Peter Houghton, Robert Arceci
:	Peter J. Houghton, Robert J. Arceci
:	Molecularly Targeted Therapy for Childhood Cancer
:	Springer-Verlag
:	9780387690629
:	1
:	CHF 193.20
:

:	Nichtklinische Fächer
:	English

:	536
:	Wasserzeichen/DRM
:	PC/MAC/eReader/Tablet
:	PDF

Each chapter will focus on the known molecular characteristics of specific childhood cancers, focusing on how the molecular 'drivers' can be exploited from a therapeutic standpoint with currently available targeted agents. Where applicable, integration of targeted therapies with conventional cytotoxic agents will be considered.

This volume will provide a comprehensive summary of molecular characteristics of childhood cancers, and how the changes involved in transformation provide us with opportunities for developing relatively less toxic, but curative, therapies.

	Acknowledgments	6
	Contents	8
	Introduction to Targeted Therapy Text	12
	Contributors	16
	Part I Hematologic Malignancies	20
	The Emerging Era of Targeted Therapy in Childhood Acute Lymphoblastic Leukemia	21
	The BCR/ABL Tyrosine Kinase and Ph+ ALL	22
	The FLT-3 Pathway in MLL Rearranged Infant ALL	24
	The Notch Pathway in T-ALL	26
	Monoclonal Antibodies in the Treatment of ALL	28
	Cancer Stem Cells in ALL	30
	Summary	31
	References	32
	Molecular Targeted Therapies in T-CellAcute Lymphoblastic Leukemia	37
	Introduction	37
	Oncogenic Transcription Factors	38
	NOTCH1	39
	The NOTCH1 Pathway	39
	Strategies for NOTCH1 Inhibition	41
	Resistance to NOTCH1 Inhibitors and Therapeutic Strategies to Overcome Resistance	42
	PTEN, PI3K-AKT, and mTOR	44
	Tyrosine Kinase Genes	44
	RAS	45
	Conclusions	46
	References	46
	Molecularly Targeted Therapy for Infant ALL	49
	FLT3 Tyrosine Kinase Inhibition	51
	Targeting Anti-apoptotic BCL-2 Family Members	56
	Targeting MLL Fusion Transcripts	63
	PFWT Targeting of MLL Partner Protein Interactions	63
	Targeting Glycogen Synthase Kinase 3	64
	HSP90 as a Potential Therapeutic Target	65
	Epigenetic Strategies	66
	mTOR Inhibition	66
	Targeting CD33 Cell Surface Antigen	67
	Conclusions	67
	References	68
	Targeted Therapeutic Approaches for AML	77
	Introduction	77
	Mechanisms of Leukemogenesis: Implications for Targeted Therapy Development	78
	Refining the Definition and Relevance of Targeted Therapy	79
	Development of Targeted Therapies for AML	79
	Specific Examples of Targeting AML	80
	Targeting Pathways that Alter Leukemia Cell Proliferation and Survival	80
	Tyrosine Kinases	80
	Inhibition of Signaling Pathways Downstream of TK Receptors	84
	Drug Resistance Mechanisms and Leukemic Cell Survival	86
	Epigenetic and Chromatin Remodeling-Directed Targets	88
	Targeted Immunotherapy and Immunostimulatory Therapy	90
	Future Challenges	92
	References	93
	Acute Promyelocytic Leukaemia	101
	Introduction	101
	Demographic Features	101
	Pathogenesis of APL	102
	Diagnosis of APL	104
	Treatment of APL	106
	Induction Therapy	107
	Complications of Induction Therapy	108
	Consolidation Therapy	110
	Maintenance Treatment	112
	Molecular Monitoring in APL	112
	MRD Detection Is an Independent Predictor of Outcome in APL	112
	Real-Time Quantitative RT-PCR Assays Enhance MRD Detection in APL	113
	Anthracycline Cumulative Dose and Cardiotoxicity	114
	Stem Cell Transplantation	114
	Arsenic Trioxide	114
	What to Do When Treatment Fails?	115
	Extramedullary Relapse	117
	New Drugs	118
	Conclusions	119
	References	119
	Down Syndrome and Acute Myeloid Leukemia: An Unique Genetic Sensitivity to Chemotherapy	127
	Introduction	127
	Chemotherapy Sensitivity and Down Syndrome	129
	The Role of Chromosome 21-Localized Genes and Chemotherapy Sensitivity in Down Syndrome AMkL	130
	Relationship Between GATA1 and Chemotherapy Drug Sensitivities	133
	Differential Gene Expression Studies and Down Syndrome AMkL	134
	Future Challenges	135
	Conclusion	136
	References	136
	Targeting RAS Signaling Pathways in Juvenile Myelomonocytic Leukemia (JMML)	141
	GM-CSF and Deregulated RAS Signaling in Pathogenesis of JMML	142
	Mouse Models	145
	Targeted Therapeutics	146
	RAF/MEK/ERK	148
	PI3K/AKT/mTOR	150
	PTPN11/SHP-2	151
	JAK2-STAT5	151
	Conclusion	152
	References	152
	Chronic Myeloid Leukemia: Pathophysiology and Therapeutics	157
	Pathophysiology of Bcr-Abl in CML	157
	Clinical Phases	160
	Targeted Therapies	161
	Imatinib in Children	163
	Monitoring	163
	Resistance to Kinase Inhibitors and New Therapeutic Strategies	165
	Indications for Transplantation	167
	Future Therapies	168
	References	168
	Molecularly Targeted Therapies in Pediatric Myelodysplastic Syndromes	172
	Introduction	172
	Myelodysplastic Syndromes	173
	Incidence	173
	Classification	173
	Etiology	174
	The Relationship Between Acute Myeloid Leukemia and MDS	180
	Chromatin-Based Transcriptional Therapy	181
	DNA Methyltransferase (DNMT) Inhibitors	181
	Histone Deacetylases (HDACs) and HDAC Inhibitors (HDACi)	183
	Maturation-Directed Therapies	184
	Immunomodulatory Drugs (IMiDs) and Anti-angiogenic Agents	184
	Other Targeted Therapies	185
	Combination Therapies	185
	Stem Cell Transplantation for Myelodysplastic Syndromes	186
	Conclusions	187
	References	188
	New Therapeutic Frontiers for Childhood Non-Hodgkin Lymphoma	194
	Introduction	194
	Diffuse Large B-Cell Lymphoma	195
	Burkitt Lymphoma	205
	Anaplastic Large Cell Lymphoma	209
	Lymphoblastic Lymphoma	215
	Summary and Future Directions	222
	References	223
	Molecular Targeting of Post-transplant Lymphoproliferative Disorders	231
	Introduction	231
	Epstein–Barr Virus Infection of Humans	233
	Host Immune Response Against EBV	234
	EBV Targets Apoptotic Resistance	236
	Molecular Targets for EBV-PTLD	237
	Vaccines	237
	Anti-Viral Medications	237