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Precision Cancer Therapies, Volume 1. Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice. Edition No. 1

  • Book

  • 512 Pages
  • May 2023
  • John Wiley and Sons Ltd
  • ID: 5828024
Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

A thorough compilation of the many scientific breakthroughs in the ongoing development of precision cancer therapies related to lymphoma

Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice focuses on lymphoma, an area which has seen a remarkable number of breakthroughs in the ongoing development of precision cancer therapies. Each section on a specific biology or class of drugs has an introductory chapter written by an authority in the field, exclusively focused on the science and its relevance to cancer biology. This approach addresses the need for scientists, physicians, and the private sector to understand the broader context of the extraordinary advances that have produced such astonishing advances in the disease.

The work primarily focuses on how to understand and translate fundamental principles of basic science into information that can be directly applied to patients - hence the subtitle, From Concept to Practice. To aid in readers’ comprehension, the first page of each chapter contains a box entitled ‘Take Home Points’. This short text will highlight the major unique points about the information contained within the chapter. Some of the key topics addressed in the work are as follows: - Biological basis of the lymphoid malignancies: fundamental principles of lymphomagenesis and molecular classification of lymphoid malignancies - Targeting programmed cell death: principles for understanding the many types of cell death and promising combinations of drugs targeting apoptosis - Targeting the PI3K pathway: understanding the intricacies of this complex biology and precisely how targeted drugs can be leveraged therapeutically - Targeting the cancer epigenome: pharmacologic features of drugs targeting the epigenome and future prospects for targeting various aspects of epigenetic control - Targeting the tumour proteome: understanding the mechanisms of protein degradation in cancer including both older drugs like proteasome inhibitors, and newer PROTAC based approaches

Written primarily for scientists and physicians in both the public and private sectors, Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice is a comprehensive reference work for those interested in the growing area of Precision Cancer Therapies. Seamlessly integrating the basic and applied science, this volume will be an indispensable reference for those interested in translating the most important advances in science to innovative novel treatments for patients.

Table of Contents

List of Contributors xix

Volume Foreword xxiv

Volume Preface xxvi

Series Preface xxviii

Section I Biological Basis of the Lymphoid Malignancies 1

1 Fundamental Principles of Lymphomagenesis 3
Pierre Sujobert, Philippe Gaulard, and Laurence de Leval

Take Home Messages 3

Introduction 3

How to Study Lymphomagenesis 3

Before Lymphoma: The Gray Frontier Between Physiology and Pathology 5

Driver Without Disease 5

From In Situ Neoplasms to Asymptomatic Lymphomas 5

Chronic Antigenic Stimulation as an Early Step of Lymphomagenesis 5

The Cell of Origin Concept: A Classification Based on Physiology 6

What Are the Hallmarks of Lymphoma? 7

Epigenetics and Metabolism 7

Apoptosis Escape 8

Proliferation 8

TCR/BCR Signaling 8

Immune Escape 8

Trafficking 8

Microenvironment 8

Conclusion 9

Must Read References 9

References 9

2 Identifying Molecular Drivers of Lymphomagenesis 12
Jennifer Shingleton and Sandeep S. Dave

Take Home Messages 12

Introduction 12

Sequencing and Bioinformatics Methods 13

Functional Validation of Drivers 13

Common Themes in B- and T-cell Lymphoma 14

Genetic Landscapes of Lymphomas 18

Mature B-cell Lymphomas 18

T-cell Lymphomas 18

Genomic Subgrouping Approaches in DLBCL 19

Challenges of Incorporating Genomic Subgrouping Approaches in Clinical Trials 19

Leveraging Underlying Pathophysiology to Inform Therapeutic Consideration 20

Conclusion 22

Must Read References 22

References 22

3 Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies 25
Sean Harrop, Michael Dickinson, Ricky Johnstone, and Henry Miles Prince

Take Home Messages 25

Introduction: Epigenetics and Lymphoid Malignancies 25

Dysregulation of DNA Methylation and Modification of Histone Proteins 26

Genes Involved in Histone Modification Implicated in Lymphomagenesis 27

Enhancer of Zeste Homolog 2 (EZH2) 27

CREB-binding Protein (CREBBP) and Histone Acetyltransferase P300 (EP300) 27

The H3K4 Methyltransferase Family 27

The Bromodomain and Extra-Terminal Domain (BET) Family 27

Genes Involved in DNA Methylation Implicated in Lymphomagenesis 27

DNA Methyltransferase 3A (DNMT3A) 27

Ten-Eleven Translocation 1/2 (TET1/2) 28

Isocitrate Dehydrogenase 2 (IDH2) 28

The Epigenetic Landscape of Specific Lymphoid Malignancies 28

Follicular Lymphoma 28

Diffuse Large B-cell Lymphoma 29

Marginal Zone Lymphoma 30

Burkitt’s Lymphoma 30

Acute Lymphoblastic Leukemia 31

Chronic Lymphocytic Leukemia 31

Mantle Cell Lymphoma 31

Hodgkin’s Lymphoma 31

Multiple Myeloma 32

Peripheral T-cell Lymphoma - Not Otherwise Specified 32

Angioimmunoblastic T-cell Lymphoma and PTCL with TFH Phenotype 32

Anaplastic Large Cell Lymphoma 33

Adult T-cell Leukemia/Lymphoma 33

Intestinal T-cell Lymphoma 33

Hepatosplenic T-cell Lymphomas 33

NK/T Cell Lymphoma 33

Mycosis Fungoides and Sezary’s Syndrome 34

Summary 34

Must Read References 34

References 34

4 Animal Models of Lymphoid Malignancies 40
Anjali Mishra

Take Home Messages 40

Introduction 40

Optimal Animal Models to Study Lymphoid Neoplasms 41

Zebrafish Model 41

Zebrafish Model of T-cell Neoplasms 41

Zebrafish Model of B-cell Neoplasms 42

Zebrafish Model of NK-cell Neoplasms 43

Patient-Derived Xenograft Models in Zebrafish 43

Fruit Fly Model 43

Non-human Primate Model 44

Mouse Models of Lymphoid Neoplasia 44

Use of Animal Models in Translational Research 48

Conclusions 49

Must Read References 49

References 50

Section II Targeting the PI3 Kinase-AKT-mTOR Pathway 53

5 Principles of PI3K Biology and Its Role in Lymphoma 55
Ralitsa R. Madsen

Take Home Messages 55

Introduction: Overview 55

Four Decades of PI3K Signaling Research 55

Class I PI3K Enzymes 56

Isoforms 56

Structural Organization 57

Isoform-specific Functions 57

The Essential Phospholipid Second Messenger PIP 3 58

PI3K Pathway Effectors 59

AKT, FOXO, and mTORC1 59

TEC Tyrosine Kinases 60

Network Topology and Signal Robustness 60

Dynamic PI3K Signaling in Lymphocyte Biology 61

B-cell Development and Survival 61

The Germinal Center (GC) Reaction 61

T FH Cell Function 63

Naïve and Effector T-cells 63

Lessons from Monogenic Disorders 64

Genetic PI3Kδ Inactivation 64

Genetic PI3Kδ Hyperactivation 64

Corrupted PI3K Signaling in Cancer 65

The Success of PI3Kδ Inhibition in Lymphoid Malignancies 65

Quantitative Biology and Therapeutic Considerations 66

Concluding Remarks 67

Acknowledgments 67

Must Read Reference 67

References 67

6 Pharmacologic Differentiation of Drugs Targeting the PI3K-AKT-mTOR Signaling Pathway 71
Inhye E. Ahn, Jennifer R. Brown, and Matthew S. Davids

Take Home Messages 71

Introduction 71

PI3K Inhibitors Approved by the US Food and Drug Administration (FDA) 72

PI3K Inhibitors in Clinical Development 77

AKT Inhibitors 78

mTOR Inhibitors 79

Conclusions 79

Must Read References 79

References 80

7 Clinical Experience with Phosphatidylinositol 3-Kinase Inhibitors in Hematologic Malignancies 86
Alessandro Broccoli and Pier Luigi Zinzani

Take Home Messages 86

Introduction 86

Idelalisib 87

Copanlisib 91

Duvelisib 93

Umbralisib 95

Parsaclisib 97

Zandelisib 97

Amdizalisib (HMPL-689) 98

Conclusion 98

Must Read References 99

References 99

8 Clinical Experiences with Drugs Targeting mTOR 102
Thomas E. Witzig

Take Home Messages 102

Introduction 102

Rapamycin (Sirolimus) Rapamune® (Pfizer) and Generic Sirolimus 103

The Rapamycin Analogs (Rapalogs) 103

Temsirolimus (CCI-779; Torisel) 103

Everolimus (RAD-001; Afinitor, Zortrees, Evertor) 105

Summary of Lymphoma Studies of Everolimus 107

Ridaforolimus 108

Dual Inhibitors of mTORC1 and mTORC2 108

Side Effects of mTORC1 Inhibitors 108

Future Directions for mTOR Inhibitors in Lymphoma 109

Must Read References 110

References 110

9 PI3 Kinase, AKT, and mTOR Inhibitors 113
Joel McCay and John G. Gribben

Take Home Messages 113

Introduction 113

PI3K Structure and Functions 114

AKT Structure and Functions 114

mTOR Structure and Functions 115

PTEN as a Regulator of the PI3K/AKT/mTOR Pathway 115

mTOR Inhibitors 116

Temsirolimus: Phase 3 Trials 116

PI3K and Dual PI3K/mTOR Inhibitors 116

PI3K Isoforms and Expression Throughout the Body 118

Immune Toxicity and Management 119

Colitis 119

Hepatitis 119

Pneumonitis 120

Skin Rash 120

Homeostatic Toxicity 120

Hypertension and Hyperglycemia 121

Myelosuppression and Opportunistic Infection 121

Myelosuppression 122

Atypical Infection 122

Vaccination 122

Neuropsychiatric Problems 122

PI3K Treatment in NHL 122

AKT Inhibitors 123

Conclusion 123

Must Read References 126

References 126

Section III Targeting Programmed Cell Death 131

10 Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology 133
Sarah T. Diepstraten, John E. La Marca, David C.S. Huang, and Gemma L. Kelly

Take Home Messages 133

Introduction 133

A Historical Perspective 133

Apoptotic Pathways 134

Other Cell Death Pathways 137

The Role of Intrinsic Apoptosis in Normal Cells - Lessons from Gene Knockout Mice 137

BCL2 Family Pro-survival Proteins 137

BCL 2 137

BCL -XL 138

MCL- 1 138

A1/BFL- 1 138

BCL -W 139

Combined Knockout of Pro-survival Proteins 139

BCL2 Family Pro-apoptotic Effector Proteins 139

BH3-only Proteins 139

The Dysregulation of Apoptosis in Cancer 142

Must Read References 144

References 144

11 Pharmacologic Features of Drugs Targeting BCL2 Family Members 151
Jennifer K. Lue and Owen A. O’Connor

Take Home Messages 151

Introduction 151

Historical Perspective: From the Discovery of BCL2 to Therapeutic Applications 152

BCL2 as a Biomarker 153

Targeting BCL2 Family Members 154

Antisense Approaches for Targeting BCL2 154

Natural Anti-apoptotic Compounds 154

Small Molecule Inhibitors of BCL2 Family Members 154

Novel BCL2 Inhibitors on the Horizon 158

Mechanisms of Resistance to BCL2 Inhibitors 158

Novel Mechanisms to Overcome BCL2 Resistance 159

Targeting MCL1 159

PROTAC Strategies for Targeting Apoptotic Family Members 160

Conclusions 160

Must Read References 161

References 161

12 Clinical Experience with Pro-Apoptotic Agents 165
Thomas E. Lew and John F. Seymour

Take Home Messages 165

Introduction 165

Safety and Toxicities of Pro-apoptotic Agents 166

Tumor Lysis Syndrome 166

Myeloid Compartment Toxicities and Infections 167

Gastrointestinal Toxicities 168

Thrombocytopenia and Navitoclax 168

Efficacy of Venetoclax in Chronic Lymphocytic Leukemia/Small Cell Lymphoma 168

Phase 1/2 Studies 168

Combining Venetoclax with Conventional Chemotherapy in CLL/SLL 172

Phase 3 Studies 172

Venetoclax Re-treatment 173

Efficacy of Venetoclax in Other B-cell Neoplasms 173

Mantle Cell Lymphoma 173

Follicular Lymphoma 173

Diffuse Large B-cell Lymphoma and Other Aggressive B-cell Lymphomas 177

Richter Transformation 179

Waldenstrom’s Macroglobulinemia 179

Marginal Zone Lymphoma 179

Acute Lymphoblastic Leukemia/Lymphoma 179

Lessons from Venetoclax in Lymphoid Neoplasms Other than CLL/SLL 180

Associations and Mechanisms of Resistance to Pro-apoptotic Agents 180

Must Read References 181

References 181

13 Promising Combinations of Drugs Targeting Apoptosis 186
William G. Wierda

Take Home Messages 186

Introduction: Background and Disease Perspective 186

Clinical Development of BCL2 Inhibitors 187

Venetoclax Monotherapy for CLL 187

Venetoclax Plus CD20 Monoclonal Antibody for CLL 190

Venetoclax Plus BTK Inhibitor for CLL 190

Venetoclax Plus BTK Inhibitor and CD20 Monoclonal Antibody for CLL 191

Venetoclax Plus Chemoimmunotherapy 191

Venetoclax Toxicities and Side Effects in CLL 192

TLS Risk Mitigation and Management in CLL 192

Venetoclax-associated Neutropenia 192

Risk for Progression and Resistance Mechanisms 193

Current Knowledge Gaps and Opportunities for Future Work with Venetoclax 193

Must Read References 194

References 194

Section IV Targeting the Cancer Epigenome 197

14 The Role of Epigenetic Dysregulation in Lymphoma Biology 199
Qing Deng and Michael R. Green

Take Home Messages 199

Introduction: Germinal Center B (GCB)-cells and GCB-derived Lymphomas 199

Mutations Altering DNA Modifications and Structure 200

Tet 2 200

Mutations Altering Writers of Histone Post-translational Modifications 202

KMT2D 202


EZH2 203

Mutations Altering Higher Order Chromatin Structure 204

BAF Chromatin Remodeling Complex 205

Linker Histones 205

Must Read References 206

References 206

15 Quantitating and Characterizing the Effects of Epigenetic Targeted Drugs 209
Emily Gruber, Alexander C. Lewis, and Lev M. Kats

Take Home Messages 209

Introduction 209

Experimental Analysis of the Epigenome 210

DNA Methylation 210

Bisulfite Conversion Methods 210

Affinity-based Methods 211

Detection of 5hmC 211

Histone Modifications, Histone Variants, and Chromatin-associated Proteins 211

Antibody-based Techniques for Mapping the Chromatin State 212

Proteomic Analysis of Histones 212

Chromatin Accessibility 212

Genome Organization 213

Emerging Technologies for Epigenomic Analysis of Single Cells 214

Molecular and Cellular Effects of Epigenetic Drugs 216

Concluding Remarks 221

Acknowledgments 221

Must Read References 221

References 221

16 Clinical Experience with Epigenetic Drugs in Lymphoid Malignancies 225
Enrica Marchi, Ipsita Pal, and John Sanil Manavalan

Take Home Messages 225

Introduction 225

Epigenome and Cancer 225

Different Epigenetic Classes of Drugs in Hematologic Malignancies 226

DNMT Inhibitors 226

5-Azacytidine and Decitabine 227

Guadecitabine 229

HDAC Inhibitors 230

Vorinostat 230

Romidepsin 230

Belinostat 231

EZH2 Inhibitors 231

Summary 232

Must Read References 233

References 233

17 Future Prospects for Targeting the Epigenome in Lymphomas 236
Yusuke Isshiki and Ari Melnick

Take Home Messages 236

Introduction 236

Emerging Epigenetic Therapies 236

EZH2- and PRC2-targeted Therapies Are Emerging as Potential Cornerstone Therapies for Lymphomas 236

SETD2, a Novel Therapeutic Target for DLBCLs 237

LSD1, a Case of Bait and Switch 237

A Surprising Indication for KDM5 Histone Demethylase Inhibitors 238

New Opportunities Provided by Emerging Histone Deacetylase Inhibitors 238

Sirtuins, the “Other HDACs,” Potential Therapeutic Targets in B-cell Lymphomas 239

Histone Acetyltransferase Inhibitors, Lacking Selectivity but with Activity in Lymphomas 239

Is There a Potential Role for BET Inhibitors for Lymphoma? 239

DNA Methyltransferase Inhibitors Are Increasingly Relevant for Treatment of Lymphomas 240

Nucleosome Remodeling Complex Inhibitors 240

Precision Epigenetic Therapy 241

Maximizing the Impact of Emerging Epigenetic Therapies 242

Rational Combination of Epigenetic Agents 242

Rational Combination with Immunotherapies 242

Conclusions 244

Acknowledgments 244

Disclosures 244

Major Papers 244

Must Read References 244

References 244

Section V Targeting the B-cell Receptor (BCR) 249

18 The Pathologic Role of BCR Dysregulation in Lymphoid Malignancies 251
Jan A. Burger

Take Home Messages 251

Introduction: The BCR in Normal and Malignant B Lymphocytes 251

BCR Signaling 251

BCR Signaling in B-cell Malignancies 252

B-cell Proliferation in Secondary Lymphatic Organs (SLOs) 254

The BCR Complex in Malignant B-cells 255

CLL 255

BCR Signaling in DLBCL 256

Tonic BCR Signaling in Burkitt’s Lymphoma 257

BCR Signaling in Follicular Lymphoma (FL) 257

BCR Signaling in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) 257

Targeting BCR Signaling 257

Bruton’s Tyrosine Kinase (BTK) Inhibitors 258

Ibrutinib 259

Acalabrutinib 259

BTK Inhibitors with Anti-CD20 Antibodies 259

Zanubrutinib 260

Pirtobrutinib 260

Idelalisib 260

Conclusions 260

Acknowledgments 261

Conflict of Interest 261

Must Read References 261

References 261

19 Pharmacologic Features of Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 268
Joel McCay and John G. Gribben

Take Home Messages 268

Introduction 268

BTK and B-cell Activating Factor Receptor (BAFFR) Signaling 270

BTK in Cell Signaling Pathways 270

BTK Inhibitor Development and Mechanisms of Action 271

BTK Inhibitors in Malignancy 271

BTK Inhibitors in Solid Cancers 273

BTK Inhibitors in Autoimmune Diseases 273

Mechanisms of Resistance 273

Summary 273

Must Read References 274

References 274

20 Clinical Experience with Drugs Targeting Bruton’s Tyrosine Kinase (BTK) 278
Julia Aronson, Anthony R. Mato, Catherine C. Coombs, Prioty Islam, Lindsey E. Roeker, and Toby Eyre

Take Home Messages 278

Introduction: Chronic Lymphocytic Leukemia (CLL) 278

Ibrutinib: Clinical Trials 278

Ibrutinib: Real-world Evidence 279

Acalabrutinib 280

Ibrutinib Versus Acalabrutinib 281

Zanubrutinib in CLL 281

Pirtobrutinib in CLL 281

BTK Inhibition in Indolent B-cell non-Hodgkin’s Lymphoma 282

Mantle Cell Lymphoma (MCL) 282

Waldenstrom’s Macroglobulinemia (WM) 283

Marginal Zone Lymphoma (MZL) 283

CNS Involvement with B-cell Malignancies 283

Real-world Data 284

Conclusions 284

Must Read References 284

References 284

21 Promising Combinations of BTK Inhibitors with Other Targeted Agents 287
Nicholas J. Schmidt, Michael E. Williams, and Craig A. Portell

Take Home Messages 287

Introduction 287

Limitations of BTK Inhibitor Monotherapy 287

Identifying Synergistic Combinations 288

Combinations of BTK Inhibitors and Targeted Drugs as the Standard of Care 288

BTKi + Anti-CD20 Monoclonal Antibodies 288

Waldenstrom’s Macroglobulinemia - iNNOVATE Study 288

Chronic Lymphocytic Leukemia (CLL) 289

Mantle Cell Lymphoma 291

BTKi and BCL2 Inhibitors 292

CLL 292

Mantle Cell Lymphoma 293

The Future: Ongoing Clinical Trials and Additional BTKi Combinations of Interest 294

BTKi + CDK4/6 Inhibitors 294

BTKi + PI3Kδ Inhibitors 294

BTKi + Proteasome Inhibitors 296

Ibrutinib + Cirmtuzumab, an Anti-ROR1 Monoclonal Antibody 296

BTKi + mTOR Inhibitors 296

BTKi + SYK Inhibitors 296

BTKi + HDAC Inhibitors 297

Ibrutinib + Selinexor 297

Conclusions 297

Must Read References 297

References 297

Section VI Protein Degraders and Membrane Transport Inhibitors 301

22 The Biological Basis for Targeting Protein Turnover in Malignant Cells 303
Robert Z. Orlowski

Take Home Messages 303

Introduction 303

Biological Basis for Targeting Protein Turnover 303

Approved Drugs Targeting Ubiquitin-Proteasome Pathway 304

Pharmacologic Mechanisms of Proteasome Inhibitors 304

Other Proteasome Inhibitors 306

Immunomodulatory Drugs Affecting Protein Turnover 306

Background 306

Presently Approved Immunomodulatory Drugs 307

Pharmacologic Mechanisms of Currently Approved Immunomodulatory Drugs 307

Other Cereblon Modulating Agents 308

Conclusions 309

Acknowledgments 309

Must Read References 309

References 310

23 Preclinical Overview of Drugs Affecting Protein Turnover in Multiple Myeloma 313
Giada Bianchi, Matthew Ho, and Kenneth C. Anderson

Take Home Messages 313

Introduction 313

Overview of Protein Handling in mm 314

Molecular Chaperones in Protein Folding 314

Ubiquitin-Proteasome System (UPS) 314

Drugs Targeting the UPS 318

Proteasome Inhibitors 318

Inhibitors of Deubiquitinating Enzymes (DUB) 319

Targeting Proteasome Biogenesis 319

Molecular Glue Degraders and Proteolysis-targeting Chimera (PROTACs) 320

Endoplasmic Reticulum (ER) Stress and the Unfolded Protein Response (UPR) 321

Drugs Targeting the UPR 321

Autophagy and Aggresome Pathways 321

Targeting Nutrient Metabolism to Enhance Proteotoxic Stress 322

The Role of Proteasome Inhibition in the Era of Immunotherapy 323

Conclusions and Future Perspectives 323

Must Read References 324

References 324

24 Clinical Experience on Proteasome Inhibitors in Cancer 331
Noa Biran, Pooja Phull, and Andre Goy

Take Home Messages 331

Introduction to Proteasome Inhibitors (Pis) 331

Clinical Activity in Plasma Cell Disorders 333

Role of Proteasome Inhibition in Plasma Cells: Mechanisms of Action and Mechanisms of Resistance 333

Proteasome Inhibitors with Clinical Activity in Multiple Myeloma 334

Bortezomib 334

Carfilzomib 335

Ixazomib 336

Other Oral Proteasome Inhibitors Evaluated for Use in Patients with Multiple Myeloma 336

Role of Proteasome Inhibitors in Amyloidosis 336

Rationale for Combinations w/ Proteasome Inhibitors 337

PI and Cytotoxic Agents 337

PI + Immunomodulatory Agents (IMIDS) 337

PI and Monoclonal Antibodies 338

PI and HDAC Inhibitors 338

PI and Nuclear Transport Inhibitor Selinexor 338

Future Directions of PI-based Combination Regimens 338

Clinical Activity of Proteasome Inhibitors in Lymphoid Malignancies 338

Clinical Activity of Bortezomib (BTZ) in Mantle Cell Lymphoma (MCL) 338

Bortezomib Phase 2 in R/R MCL Led to Early Approval 338

Importing Bortezomib in the Management of MCL 342

Clinical Activity of Bortezomib in Indolent Lymphoma (iNHL): Follicular Lymphoma, Marginal Zone, and SLL/CLL Subtypes 345

Clinical Activity of Bortezomib in Diffuse Large B-cell Lymphoma (DLBCL) 346

Bortezomib in Waldenstrom’s Macroglobulinemia (WM) 347

Clinical Activity of Bortezomib in Other Lymphomas 347

T-cell Lymphoma 347

Hodgkin’s Lymphoma 348

Plasmablastic Lymphoma (PBL) 348

Lymphoblastic Lymphoma (LL)/Acute Lymphocytic Leukemia (ALL) 348

EBV Lymphoproliferative Disorders and Other Immunological Conditions 348

Clinical Activity of Proteasome Inhibitors in AML/MDS 349

Clinical Activity of Proteasome Inhibitors in Solid Tumors 349

Overcoming Resistance to Proteasome Inhibitors in Cancer and Next Steps in Proteasome Inhibition 350

Must Read References 352

References 352

25 Targeting Nuclear Protein Transport with XPO Inhibitors in Lymphoma 361
Farheen Manji, Kyla Trkulja, Rob C. Laister, and John Kuruvilla

Take Home Messages 361

Introduction 361

XPO1 Biology 361

Pre-clinical and Clinical Data 362

Phase 1 Evaluation in Non-Hodgkin’s Lymphoma 362


CLL 366

T-cell Lymphoma 367

Mantle Cell Lymphoma 367

Toxicity 367

Mechanisms of Intrinsic and Acquired Resistance to Selinexor and SINE Compounds 368

Future Directions 369

Must Read References 370

References 370

26 Heterobifunctional Degraders for the Treatment of Lymphoid Malignancies 372
Ashwin Gollerkeri, Jared Gollob, and Nello Mainolfi

Take Home Messages 372

Biology of Protein Degraders 372

Ubiquitin-Proteasome System and Protein Degradation 372

Targeted Degraders in Clinical Practice 372

Heterobifunctional Small Molecule Degraders 372

Mechanisms of Resistance 373

Rationale for Use of Heterobifunctional Degraders in Oncology 373

Clinical Experience with Heterobifunctional Degraders 374

Arvinas Phase 1/2 Trials of PR and ER Degraders 375

ARV- 110 375

ARV- 471 375

Kymera Phase 1 Trial of IRAK4 Degrader KT- 474 375

Development of Heterobifunctional Degraders in Lymphoma 375

IRAKIMiD Degraders 375

KT- 413 376

BTK Degraders 376

NX- 2127 377

NX- 5948 377

BGB- 16673 377

STAT3 Degraders 377

KT- 333 377

Conclusions and Future Directions 378

Must Read References 378

References 378

Section VII Novel Targets and Therapeutic Prospects in Development 381

27 Strategies for Targeting the JAK-STAT Pathway in Lymphoid Malignancies 383
David J. Feith, Johnson Ung, Omar Elghawy, Peibin Yue, James Turkson, and Thomas P. Loughran Jr

Take Home Messages 383

JAK-STAT Signaling and Endogenous Regulators 383

Alternative Regulation and Function of STATs 385

Dysregulated Cytokine Signaling in Lymphoid Malignancies 386

Strategies to Target the JAK-STAT Pathway 387

Direct Targeting Approaches against STAT 3 388

Oligonucleotide-based Strategies 389

Direct STAT3 Inhibitors as Standalone Agents 389

Natural Product Inhibitors of STAT 3 389

Chemotherapeutic, Cytotoxic Drugs, and Other Modalities that Directly or Indirectly Inhibit STAT3 Pathway 390

Inhibition of STAT3 Function in Combination Strategies to Sensitize Tumors and/or Reverse Resistance 390

Clinical Trials of STAT3 Inhibitors in Lymphoid Malignancy 391

Targeting STAT5 in Lymphoid Malignancy 391

Clinical Trials of JAK Inhibitors in Lymphoid Malignancies 392

Challenges and Opportunities for Clinical Application of JAK-STAT Targeting Agents 395

Acknowledgments 396

Conflict of Interest Disclosures 396

Must Read References 396

References 396

28 Strategies for Targeting MYC 402
Jemma Longley and Andrew Davies

Take Home Messages 402

Introduction 402

Dysregulation of MYC in B-cell Lymphomas 403

Identifying MYC Rearrangement in the Context of HGBL 403

Targeting MYC Transcription 404

Targeting MYC Translation 405

Targeting MYC Stabilization and Downstream Gene Expression 406

Initial Therapy in MYC-R DLBCL 407

Future Directions 408

Must Read References 408

References 409

29 Targeting NOTCH in Lymphoid Malignancies 411
Deborah Piffaretti, Georgia Alice Galimberti, and Davide Rossi

Take Home Messages 411

Introduction: NOTCH Signaling 411

Role of NOTCH Signaling in B-cell 414

Genetic and Microenvironmental Mechanisms of NOTCH Signaling Alteration in CLL and Lymphomas 415

Genetic Mechanisms 415

CLL (notch1) 415

MCL 417

FL 417

MZL (notch2) 418

DLBCL (N1 e N2) 419

Other Genes of the Pathway (FBXW7, SPEN) 420

Inhibitors Tested at the Preclinical Level 420

Must Read References 421

References 421

30 Targeting NF-κB in Oncology, an Untapped Therapeutic Potential 428
Matko Kalac

Take Home Messages 428

Introduction 428

Historical Perspective for the Role of NF-κB in Malignancy 429

Canonical NF-κB Pathway 429

Non-canonical NF-κB Pathway 431

NF-κB in Tumorigenesis and Promotion of Malignant Cell Growth 431

Oncogenic Alterations in Lymphoma and Other Hematologic Malignancies 432

Role of NF-κB in Solid Malignancies 434

NF-κB Targeted Therapies 435

Approved Drugs 435

In Development 436

Summary 437

Must Read References 437

References 438

31 Targeting the Cell Cycle and Cyclin-dependent Kinases 444
Chiara Tarantelli and Francesco Bertoni

Take Home Messages 444

Introduction 444

CDK Family and Cyclins 444

CDKs Structure 446

CDKs Activation 446

CDKs Inhibition 446

CDKs Function 447

Cell Cycle-related CDK-cyclin Complexes 447

Transcription-related CDK-cyclin Complexes 447

DNA Damage and Repair 448

CDK-cyclin Deregulation in Cancer 448

Targeting CDKs in Lymphoid Malignancies 448

CDK4/6 Inhibitors 448

Specific Inhibitors 449

CDK7 Inhibitors 450

Inhibitors Targeting Multiple CDKs 450

Resistance 451

Future Directions 451

Must Read References 452

References 452

Index 457


Owen A. O'Connor Stephen M. Ansell John F. Seymour