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