Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

Owen A. O’Connor, M.D., Ph.D. is an American Cancer Society Research Professor at the University of Virginia Comprehensive Cancer Center. He completed his training in Internal Medicine at the New York Presbyterian Hospital at Weill Cornell University Medical School, a Fellowship in Hematology and Oncology at Memorial Sloan Kettering Cancer Center and a Fellowship in Clinical Pharmacology at Weill Cornell. He has been recognized as one of the Top Physicians in Cancer in the U.S. and is recognized by the Irish Government as one of the top 50 Irish Americans in Science and Medicine.

Stephen M. Ansell, M.D., Ph.D. is the Dorotha W. and Grant L. Sundquist Professor of Hematologic Malignancies Research and the Chair of the Division of Hematology at Mayo Clinic. He received his medical degree from the University of Pretoria, South Africa and then completed a fellowship in Hematology and Medical Oncology at Mayo Clinic. His research focuses on optimizing antitumor immune function in B-cell malignancies. He received the Ernst Beutler Award from the American Society of Hematology in 2021 in recognition of his work.

John F. Seymour MBBS Ph.D. heads the Department of Haematology of the Peter MacCallum Cancer Centre & the Royal Melbourne Hospital and is Professor of Medicine at the University of Melbourne. He completed a translational research fellowship at the MD Anderson Cancer Center in Houston, and has received their Distinguished Alumnus award. His work is focused on new drug development in lymphoid malignancies. He was awarded Membership of the Order of Australia, and elected to the Australian Academy of Health and Medical Sciences for his contributions to the field.

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

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

What Are the Hallmarks of Lymphoma? 7

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

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

Genes Involved in DNA Methylation Implicated in Lymphomagenesis 27

The Epigenetic Landscape of Specific Lymphoid Malignancies 28

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

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

PI3K Pathway Effectors 59

Dynamic PI3K Signaling in Lymphocyte Biology 61

Lessons from Monogenic Disorders 64

Corrupted PI3K Signaling in Cancer 65

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

mTOR Inhibitors 116

PI3K and Dual PI3K/mTOR Inhibitors 116

PI3K Isoforms and Expression Throughout the Body 118

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

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

Mechanisms of Resistance to BCL2 Inhibitors 158

Novel Mechanisms to Overcome BCL2 Resistance 159

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

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

Efficacy of Venetoclax in Other B-cell Neoplasms 173

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

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

Mutations Altering Writers of Histone Post-translational Modifications 202

Mutations Altering Higher Order Chromatin Structure 204

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

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

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

Precision Epigenetic Therapy 241

Maximizing the Impact of Emerging Epigenetic Therapies 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

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

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

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

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

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

Immunomodulatory Drugs Affecting Protein Turnover 306

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

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

Clinical Activity of Proteasome Inhibitors in Lymphoid Malignancies 338

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

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

Rationale for Use of Heterobifunctional Degraders in Oncology 373

Clinical Experience with Heterobifunctional Degraders 374

Development of Heterobifunctional Degraders in Lymphoma 375

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 STAT3 388

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

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

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

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

CDK-cyclin Deregulation in Cancer 448

Targeting CDKs in Lymphoid Malignancies 448

Resistance 451

Future Directions 451

Must Read References 452

References 452

Index 457