Precision Cancer Therapies, Volume 1: Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice

Precision Cancer Therapies
Contents
List of Contributors
Volume Foreword
Volume Preface
Series Preface
Section I Biological Basis of the Lymphoid Malignancies
	1 Fundamental Principles of Lymphomagenesis
		Take Home Messages
		Introduction
		How to Study Lymphomagenesis
		Before Lymphoma: The Gray Frontier Between Physiology and Pathology
			Driver Without Disease
			From In Situ Neoplasms to Asymptomatic Lymphomas
			Chronic Antigenic Stimulation as an Early Step of Lymphomagenesis
		The Cell of Origin Concept: A Classification Based on Physiology
		What Are the Hallmarks of Lymphoma?
			Epigenetics and Metabolism
			Apoptosis Escape
			Proliferation
			TCR/BCR Signaling
			Immune Escape
			Trafficking
			Microenvironment
		Conclusion
		Must Read References
		References
	2 Identifying Molecular Drivers of Lymphomagenesis
		Take Home Messages
		Introduction
		Sequencing and Bioinformatics Methods
		Functional Validation of Drivers
		Common Themes in B- and T-cell Lymphoma
		Genetic Landscapes of Lymphomas
			Mature B-cell Lymphomas
			T-cell Lymphomas
		Genomic Subgrouping Approaches in DLBCL
		Challenges of Incorporating Genomic Subgrouping Approaches in Clinical Trials
		Leveraging Underlying Pathophysiology to Inform Therapeutic Consideration
		Conclusion
		Must Read References
		References
	3 Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies
		Take Home Messages
		Introduction: Epigenetics and Lymphoid Malignancies
		Dysregulation of DNA Methylation and Modification of Histone Proteins
		Genes Involved in Histone Modification Implicated in Lymphomagenesis
			Enhancer of Zeste Homolog 2 (EZH2)
			CREB-binding Protein (CREBBP) and Histone Acetyltransferase P300 (EP300)
			The H3K4 Methyltransferase Family
			The Bromodomain and Extra-Terminal Domain (BET) Family
		Genes Involved in DNA Methylation Implicated in Lymphomagenesis
			DNA Methyltransferase 3A (DNMT3A)
			Ten-Eleven Translocation 1/2 (TET1/2)
			Isocitrate Dehydrogenase 2 (IDH2)
		The Epigenetic Landscape of Specific Lymphoid Malignancies
			Follicular Lymphoma
			Diffuse Large B-cell Lymphoma
			Marginal Zone Lymphoma
			Burkitt’s Lymphoma
			Acute Lymphoblastic Leukemia
			Chronic Lymphocytic Leukemia
			Mantle Cell Lymphoma
			Hodgkin’s Lymphoma
			Multiple Myeloma
			Peripheral T-cell Lymphoma – Not Otherwise Specified
			Angioimmunoblastic T-cell Lymphoma and PTCL with TFH Phenotype
			Anaplastic Large Cell Lymphoma
			Adult T-cell Leukemia/Lymphoma
			Intestinal T-cell Lymphoma
			Hepatosplenic T-cell Lymphomas
			NK/T Cell Lymphoma
			Mycosis Fungoides and Sezary’s Syndrome
		Summary
		Must Read References
		References
	4 Animal Models of Lymphoid Malignancies
		Take Home Messages
		Introduction
		Optimal Animal Models to Study Lymphoid Neoplasms
			Zebrafish Model
				Zebrafish Model of T-cell Neoplasms
				Zebrafish Model of B-cell Neoplasms
				Zebrafish Model of NK-cell Neoplasms
				Patient-Derived Xenograft Models in Zebrafish
			Fruit Fly Model
			Non-human Primate Model
			Mouse Models of Lymphoid Neoplasia
		Use of Animal Models in Translational Research
		Conclusions
		Must Read References
		References
Section II Targeting the PI3 Kinase-AKT-mTOR Pathway
	5 Principles of PI3K Biology and Its Role in Lymphoma
		Take Home Messages
		Introduction: Overview
		Four Decades of PI3K Signaling Research
		Class I PI3K Enzymes
			Isoforms
			Structural Organization
			Isoform-specific Functions
			The Essential Phospholipid Second Messenger PIP3
		PI3K Pathway Effectors
			AKT, FOXO, and mTORC1
			TEC Tyrosine Kinases
			Network Topology and Signal Robustness
		Dynamic PI3K Signaling in Lymphocyte Biology
			B-cell Development and Survival
			The Germinal Center (GC) Reaction
			TFH Cell Function
			Naïve and Effector T-cells
		Lessons from Monogenic Disorders
			Genetic PI3Kd Inactivation
			Genetic PI3Kd Hyperactivation
		Corrupted PI3K Signaling in Cancer
			The Success of PI3Kd Inhibition in Lymphoid Malignancies
			Quantitative Biology and Therapeutic Considerations
		Concluding Remarks
		Acknowledgments
		Must Read Reference
		References
	6 Pharmacologic Differentiation of Drugs Targeting the PI3K-AKT-mTOR Signaling Pathway
		Take Home Messages
		Introduction
		PI3K Inhibitors Approved by the US Food and Drug Administration (FDA)
		PI3K Inhibitors in Clinical Development
		AKT Inhibitors
		mTOR Inhibitors
		Conclusions
		Must Read References
		References
	7 Clinical Experience with Phosphatidylinositol 3-Kinase Inhibitors in Hematologic Malignancies
		Take Home Messages
		Introduction
		Idelalisib
		Copanlisib
		Duvelisib
		Umbralisib
		Parsaclisib
		Zandelisib
		Amdizalisib (HMPL-689)
		Conclusion
		Must Read References
		References
	8 Clinical Experiences with Drugs Targeting mTOR
		Take Home Messages
		Introduction
		Rapamycin (Sirolimus) Rapamune® (Pfizer) and Generic Sirolimus
		The Rapamycin Analogs (Rapalogs)
		Temsirolimus (CCI-779; Torisel)
		Everolimus (RAD-001; Afinitor, Zortrees, Evertor)
		Summary of Lymphoma Studies of Everolimus
		Ridaforolimus
		Dual Inhibitors of mTORC1 and mTORC2
		Side Effects of mTORC1 Inhibitors
		Future Directions for mTOR Inhibitors in Lymphoma
		Must Read References
		References
	9 PI3 Kinase, AKT, and mTOR Inhibitors
		Take Home Messages
		Introduction
			PI3K Structure and Functions
			AKT Structure and Functions
			mTOR Structure and Functions
			PTEN as a Regulator of the PI3K/AKT/mTOR Pathway
		mTOR Inhibitors
			Temsirolimus: Phase 3 Trials
		PI3K and Dual PI3K/mTOR Inhibitors
		PI3K Isoforms and Expression Throughout the Body
			Immune Toxicity and Management
			Colitis
			Hepatitis
			Pneumonitis
			Skin Rash
			Homeostatic Toxicity
			Hypertension and Hyperglycemia
			Myelosuppression and Opportunistic Infection
			Myelosuppression
			Atypical Infection
			Vaccination
			Neuropsychiatric Problems
			PI3K Treatment in NHL
		AKT Inhibitors
		Conclusion
		Must Read References
		References
Section III Targeting Programmed Cell Death
	10 Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology
		Take Home Messages
		Introduction
		A Historical Perspective
		Apoptotic Pathways
		Other Cell Death Pathways
		The Role of Intrinsic Apoptosis in Normal Cells – Lessons from Gene Knockout Mice
			BCL2 Family Pro-survival Proteins
				BCL2
				BCL-XL
				MCL-1
				A1/BFL-1
				BCL-W
				Combined Knockout of Pro-survival Proteins
			BCL2 Family Pro-apoptotic Effector Proteins
			BH3-only Proteins
		The Dysregulation of Apoptosis in Cancer
		Must Read References
		References
	11 Pharmacologic Features of Drugs Targeting BCL2 Family Members
		Take Home Messages
		Introduction
		Historical Perspective: From the Discovery of BCL2 to Therapeutic Applications
		BCL2 as a Biomarker
		Targeting BCL2 Family Members
			Antisense Approaches for Targeting BCL2
			Natural Anti-apoptotic Compounds
			Small Molecule Inhibitors of BCL2 Family Members
			Novel BCL2 Inhibitors on the Horizon
		Mechanisms of Resistance to BCL2 Inhibitors
		Novel Mechanisms to Overcome BCL2 Resistance
			Targeting MCL1
			PROTAC Strategies for Targeting Apoptotic Family Members
		Conclusions
		Must Read References
		References
	12 Clinical Experience with Pro-Apoptotic Agents
		Take Home Messages
		Introduction
		Safety and Toxicities of Pro-apoptotic Agents
			Tumor Lysis Syndrome
			Myeloid Compartment Toxicities and Infections
			Gastrointestinal Toxicities
			Thrombocytopenia and Navitoclax
		Efficacy of Venetoclax in Chronic Lymphocytic Leukemia/Small Cell Lymphoma
			Phase 1/2 Studies
			Combining Venetoclax with Conventional Chemotherapy in CLL/SLL
			Phase 3 Studies
			Venetoclax Re-treatment
		Efficacy of Venetoclax in Other B-cell Neoplasms
			Mantle Cell Lymphoma
			Follicular Lymphoma
			Diffuse Large B-cell Lymphoma and Other Aggressive B-cell Lymphomas
			Richter Transformation
			Waldenstrom’s Macroglobulinemia
			Marginal Zone Lymphoma
			Acute Lymphoblastic Leukemia/Lymphoma
			Lessons from Venetoclax in Lymphoid Neoplasms Other than CLL/SLL
		Associations and Mechanisms of Resistance to Pro-apoptotic Agents
		Must Read References
		References
	13 Promising Combinations of Drugs Targeting Apoptosis
		Take Home Messages
		Introduction: Background and Disease Perspective
		Clinical Development of BCL2 Inhibitors
		Venetoclax Monotherapy for CLL
		Venetoclax Plus CD20 Monoclonal Antibody for CLL
		Venetoclax Plus BTK Inhibitor for CLL
		Venetoclax Plus BTK Inhibitor and CD20 Monoclonal Antibody for CLL
		Venetoclax Plus Chemoimmunotherapy
		Venetoclax Toxicities and Side Effects in CLL
			TLS Risk Mitigation and Management in CLL
			Venetoclax-associated Neutropenia
		Risk for Progression and Resistance Mechanisms
		Current Knowledge Gaps and Opportunities for Future Work with Venetoclax
		Must Read References
		References
Section IV Targeting the Cancer Epigenome
	14 The Role of Epigenetic Dysregulation in Lymphoma Biology
		Take Home Messages
		Introduction: Germinal Center B (GCB)-cells and GCB-derived Lymphomas
		Mutations Altering DNA Modifications and Structure
			TET2
		Mutations Altering Writers of Histone Post-translational Modifications
			KMT2D
			CREBBP
			EZH2
		Mutations Altering Higher Order Chromatin Structure
			BAF Chromatin Remodeling Complex
			Linker Histones
		Must Read References
		References
	15 Quantitating and Characterizing the Effects of Epigenetic Targeted Drugs
		Take Home Messages
		Introduction
		Experimental Analysis of the Epigenome
			DNA Methylation
				Bisulfite Conversion Methods
				Affinity-based Methods
				Detection of 5hmC
			Histone Modifications, Histone Variants, and Chromatin-associated Proteins
				Antibody-based Techniques for Mapping the Chromatin State
				Proteomic Analysis of Histones
			Chromatin Accessibility
			Genome Organization
			Emerging Technologies for Epigenomic Analysis of Single Cells
		Molecular and Cellular Effects of Epigenetic Drugs
		Concluding Remarks
		Acknowledgments
		Must Read References
		References
	16 Clinical Experience with Epigenetic Drugs in Lymphoid Malignancies
		Take Home Messages
		Introduction
		Epigenome and Cancer
		Different Epigenetic Classes of Drugs in Hematologic Malignancies
			DNMT Inhibitors
				5-Azacytidine and Decitabine
				Guadecitabine
			HDAC Inhibitors
				Vorinostat
				Romidepsin
				Belinostat
			EZH2 Inhibitors
		Summary
		Must Read References
		References
	17 Future Prospects for Targeting the Epigenome in Lymphomas
		Take Home Messages
		Introduction
		Emerging Epigenetic Therapies
			EZH2- and PRC2-targeted Therapies Are Emerging as Potential Cornerstone Therapies for Lymphomas
			SETD2, a Novel Therapeutic Target for DLBCLs
			LSD1, a Case of Bait and Switch
			A Surprising Indication for KDM5 Histone Demethylase Inhibitors
			New Opportunities Provided by Emerging Histone Deacetylase Inhibitors
			Sirtuins, the “Other HDACs,” Potential Therapeutic Targets in B-cell Lymphomas
			Histone Acetyltransferase Inhibitors, Lacking Selectivity but with Activity in Lymphomas
			Is There a Potential Role for BET Inhibitors for Lymphoma?
			DNA Methyltransferase Inhibitors Are Increasingly Relevant for Treatment of Lymphomas
			Nucleosome Remodeling Complex Inhibitors
		Precision Epigenetic Therapy
		Maximizing the Impact of Emerging Epigenetic Therapies
			Rational Combination of Epigenetic Agents
			Rational Combination with Immunotherapies
		Conclusions
		Acknowledgments
		Disclosures
		Major Papers
		Must Read References
		References
Section V Targeting the B-cell Receptor (BCR)
	18 The Pathologic Role of BCR Dysregulation in Lymphoid Malignancies
		Take Home Messages
		Introduction: The BCR in Normal and Malignant B Lymphocytes
		BCR Signaling
		BCR Signaling in B-cell Malignancies
		B-cell Proliferation in Secondary Lymphatic Organs (SLOs)
		The BCR Complex in Malignant B-cells
			CLL
		BCR Signaling in DLBCL
		Tonic BCR Signaling in Burkitt’s Lymphoma
		BCR Signaling in Follicular Lymphoma (FL)
		BCR Signaling in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL)
		Targeting BCR Signaling
		Bruton’s Tyrosine Kinase (BTK) Inhibitors
		Ibrutinib
		Acalabrutinib
		BTK Inhibitors with Anti-CD20 Antibodies
		Zanubrutinib
		Pirtobrutinib
		Idelalisib
		Conclusions
		Acknowledgments
		Conflict of Interest
		Must Read References
		References
	19 Pharmacologic Features of Drugs Targeting Bruton’s Tyrosine Kinase (BTK)
		Take Home Messages
		Introduction
		BTK and B-cell Activating Factor Receptor (BAFFR) Signaling
		BTK in Cell Signaling Pathways
		BTK Inhibitor Development and Mechanisms of Action
		BTK Inhibitors in Malignancy
		BTK Inhibitors in Solid Cancers
		BTK Inhibitors in Autoimmune Diseases
		Mechanisms of Resistance
		Summary
		Must Read References
		References
	20 Clinical Experience with Drugs Targeting Bruton’s Tyrosine Kinase (BTK)
		Take Home Messages
		Introduction: Chronic Lymphocytic Leukemia (CLL)
			Ibrutinib: Clinical Trials
			Ibrutinib: Real-world Evidence
			Acalabrutinib
			Ibrutinib Versus Acalabrutinib
			Zanubrutinib in CLL
			Pirtobrutinib in CLL
		BTK Inhibition in Indolent B-cell non-Hodgkin’s Lymphoma
		Mantle Cell Lymphoma (MCL)
		Waldenstrom’s Macroglobulinemia (WM)
		Marginal Zone Lymphoma (MZL)
		CNS Involvement with B-cell Malignancies
		Real-world Data
		Conclusions
		Must Read References
		References
	21 Promising Combinations of BTK Inhibitors with Other Targeted Agents
		Take Home Messages
		Introduction
			Limitations of BTK Inhibitor Monotherapy
			Identifying Synergistic Combinations
		Combinations of BTK Inhibitors and Targeted Drugs as the Standard of Care
			BTKi + Anti-CD20 Monoclonal Antibodies
				Waldenstrom’s Macroglobulinemia – iNNOVATE Study
				Chronic Lymphocytic Leukemia (CLL)
				Mantle Cell Lymphoma
			BTKi and BCL2 Inhibitors
				CLL
				Mantle Cell Lymphoma
		The Future: Ongoing Clinical Trials and Additional BTKi Combinations of Interest
			BTKi + CDK4/6 Inhibitors
			BTKi + PI3Kd Inhibitors
			BTKi + Proteasome Inhibitors
			Ibrutinib + Cirmtuzumab, an Anti-ROR1 Monoclonal Antibody
			BTKi + mTOR Inhibitors
			BTKi + SYK Inhibitors
			BTKi + HDAC Inhibitors
			Ibrutinib + Selinexor
		Conclusions
		Must Read References
		References
Section VI Protein Degraders and Membrane Transport Inhibitors
	22 The Biological Basis for Targeting Protein Turnover in Malignant Cells
		Take Home Messages
		Introduction
		Biological Basis for Targeting Protein Turnover
			Approved Drugs Targeting Ubiquitin–Proteasome Pathway
			Pharmacologic Mechanisms of Proteasome Inhibitors
			Other Proteasome Inhibitors
		Immunomodulatory Drugs Affecting Protein Turnover
			Background
			Presently Approved Immunomodulatory Drugs
			Pharmacologic Mechanisms of Currently Approved Immunomodulatory Drugs
			Other Cereblon Modulating Agents
		Conclusions
		Acknowledgments
		Must Read References
		References
	23 Preclinical Overview of Drugs Affecting Protein Turnover in Multiple Myeloma
		Take Home Messages
		Introduction
		Overview of Protein Handling in MM
		Molecular Chaperones in Protein Folding
		Ubiquitin–Proteasome System (UPS)
			Drugs Targeting the UPS
				Proteasome Inhibitors
			Inhibitors of Deubiquitinating Enzymes (DUB)
				Targeting Proteasome Biogenesis
			Molecular Glue Degraders and Proteolysis-targeting Chimera (PROTACs)
		Endoplasmic Reticulum (ER) Stress and the Unfolded Protein Response (UPR)
			Drugs Targeting the UPR
		Autophagy and Aggresome Pathways
		Targeting Nutrient Metabolism to Enhance Proteotoxic Stress
		The Role of Proteasome Inhibition in the Era of Immunotherapy
		Conclusions and Future Perspectives
		Must Read References
		References
	24 Clinical Experience on Proteasome Inhibitors in Cancer
		Take Home Messages
		Introduction to Proteasome Inhibitors (Pis)
		Clinical Activity in Plasma Cell Disorders
			Role of Proteasome Inhibition in Plasma Cells: Mechanisms of Action and Mechanisms of Resistance
			Proteasome Inhibitors with Clinical Activity in Multiple Myeloma
				Bortezomib
				Carfilzomib
				Ixazomib
				Other Oral Proteasome Inhibitors Evaluated for Use in Patients with Multiple Myeloma
			Role of Proteasome Inhibitors in Amyloidosis
			Rationale for Combinations w/ Proteasome Inhibitors
				PI and Cytotoxic Agents
				PI + Immunomodulatory Agents (IMIDS)
				PI and Monoclonal Antibodies
				PI and HDAC Inhibitors
				PI and Nuclear Transport Inhibitor Selinexor
				Future Directions of PI-based Combination Regimens
		Clinical Activity of Proteasome Inhibitors in Lymphoid Malignancies
			Clinical Activity of Bortezomib (BTZ) in Mantle Cell Lymphoma (MCL)
				Bortezomib Phase 2 in R/R MCL Led to Early Approval
				Importing Bortezomib in the Management of MCL
			Clinical Activity of Bortezomib in Indolent Lymphoma (iNHL): Follicular Lymphoma, Marginal Zone, and SLL/CLL Subtypes
			Clinical Activity of Bortezomib in Diffuse Large B-cell Lymphoma (DLBCL)
			Bortezomib in Waldenstrom’s Macroglobulinemia (WM)
			Clinical Activity of Bortezomib in Other Lymphomas
				T-cell Lymphoma
				Hodgkin’s Lymphoma
				Plasmablastic Lymphoma (PBL)
				Lymphoblastic Lymphoma (LL)/Acute Lymphocytic Leukemia (ALL)
			EBV Lymphoproliferative Disorders and Other Immunological Conditions
		Clinical Activity of Proteasome Inhibitors in AML/MDS
		Clinical Activity of Proteasome Inhibitors in Solid Tumors
		Overcoming Resistance to Proteasome Inhibitors in Cancer and Next Steps in Proteasome Inhibition
		Must Read References
		References
	25 Targeting Nuclear Protein Transport with XPO Inhibitors in Lymphoma
		Take Home Messages
		Introduction
		XPO1 Biology
		Pre-clinical and Clinical Data
			Phase 1 Evaluation in Non-Hodgkin’s Lymphoma
			DLBCL
			CLL
			T-cell Lymphoma
			Mantle Cell Lymphoma
			Toxicity
		Mechanisms of Intrinsic and Acquired Resistance to Selinexor and SINE Compounds
		Future Directions
		Must Read References
		References
	26 Heterobifunctional Degraders for the Treatment of Lymphoid Malignancies
		Take Home Messages
		Biology of Protein Degraders
			Ubiquitin–Proteasome System and Protein Degradation
			Targeted Degraders in Clinical Practice
			Heterobifunctional Small Molecule Degraders
			Mechanisms of Resistance
		Rationale for Use of Heterobifunctional Degraders in Oncology
		Clinical Experience with Heterobifunctional Degraders
			Arvinas Phase 1/2 Trials of PR and ER Degraders
				ARV-110
				ARV-471
			Kymera Phase 1 Trial of IRAK4 Degrader KT-474
		Development of Heterobifunctional Degraders in Lymphoma
			IRAKIMiD Degraders
				KT-413
			BTK Degraders
				NX-2127
				NX-5948
				BGB-16673
			STAT3 Degraders
				KT-333
		Conclusions and Future Directions
		Must Read References
		References
Section VII Novel Targets and Therapeutic Prospects in Development
	27 Strategies for Targeting the JAK-STAT Pathway in Lymphoid Malignancies
		Take Home Messages
		JAK-STAT Signaling and Endogenous Regulators
		Alternative Regulation and Function of STATs
		Dysregulated Cytokine Signaling in Lymphoid Malignancies
		Strategies to Target the JAK-STAT Pathway
		Direct Targeting Approaches against STAT3
			Oligonucleotide-based Strategies
			Direct STAT3 Inhibitors as Standalone Agents
			Natural Product Inhibitors of STAT3
			Chemotherapeutic, Cytotoxic Drugs, and Other Modalities that Directly or Indirectly Inhibit STAT3 Pathway
			Inhibition of STAT3 Function in Combination Strategies to Sensitize Tumors and/or Reverse Resistance
		Clinical Trials of STAT3 Inhibitors in Lymphoid Malignancy
		Targeting STAT5 in Lymphoid Malignancy
		Clinical Trials of JAK Inhibitors in Lymphoid Malignancies
		Challenges and Opportunities for Clinical Application of JAK-STAT Targeting Agents
		Acknowledgments
			Conflict of Interest Disclosures
		Must Read References
		References
	28 Strategies for Targeting MYC
		Take Home Messages
		Introduction
		Dysregulation of MYC in B-cell Lymphomas
		Identifying MYC Rearrangement in the Context of HGBL
		Targeting MYC Transcription
		Targeting MYC Translation
		Targeting MYC Stabilization and Downstream Gene Expression
		Initial Therapy in MYC-R DLBCL
		Future Directions
		Must Read References
		References
	29 Targeting NOTCH in Lymphoid Malignancies
		Take Home Messages
		Introduction: NOTCH Signaling
		Role of NOTCH Signaling in B-cell
		Genetic and Microenvironmental Mechanisms of NOTCH Signaling Alteration in CLL and Lymphomas
			Genetic Mechanisms
			CLL (NOTCH1)
			MCL
			FL
			MZL (NOTCH2)
			DLBCL (N1 e N2)
		Other Genes of the Pathway (FBXW7, SPEN)
		Inhibitors Tested at the Preclinical Level
		Must Read References
		References
	30 Targeting NF-κB in Oncology, an Untapped Therapeutic Potential
		Take Home Messages
		Introduction
		Historical Perspective for the Role of NF-κB in Malignancy
		Canonical NF-κB Pathway
		Non-canonical NF-κB Pathway
		NF-κB in Tumorigenesis and Promotion of Malignant Cell Growth
		Oncogenic Alterations in Lymphoma and Other Hematologic Malignancies
		Role of NF-κB in Solid Malignancies
		NF-κB Targeted Therapies
			Approved Drugs
			In Development
		Summary
		Must Read References
		References
	31 Targeting the Cell Cycle and Cyclin-dependent Kinases
		Take Home Messages
		Introduction
		CDK Family and Cyclins
		CDKs Structure
		CDKs Activation
		CDKs Inhibition
		CDKs Function
			Cell Cycle-related CDK-cyclin Complexes
			Transcription-related CDK-cyclin Complexes
			DNA Damage and Repair
		CDK-cyclin Deregulation in Cancer
		Targeting CDKs in Lymphoid Malignancies
			CDK4/6 Inhibitors
			Specific Inhibitors
			CDK7 Inhibitors
			Inhibitors Targeting Multiple CDKs
		Resistance
		Future Directions
		Must Read References
		References
Index
EULA