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

ISBN-13: 9781119819929 / Angielski / Twarda / 2023 / 400 str.

OA OConnor

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List of Contributors xixVolume Foreword xxivVolume Preface xxviSeries Preface xxviiiSection I Biological Basis of the Lymphoid Malignancies 11 Fundamental Principles of Lymphomagenesis 3Pierre Sujobert, Philippe Gaulard, and Laurence de LevalTake Home Messages 3Introduction 3How to Study Lymphomagenesis 3Before Lymphoma: The Gray Frontier Between Physiology and Pathology 5Driver Without Disease 5From In Situ Neoplasms to Asymptomatic Lymphomas 5Chronic Antigenic Stimulation as an Early Step of Lymphomagenesis 5The Cell of Origin Concept: A Classification Based on Physiology 6What Are the Hallmarks of Lymphoma? 7Epigenetics and Metabolism 7Apoptosis Escape 8Proliferation 8TCR/BCR Signaling 8Immune Escape 8Trafficking 8Microenvironment 8Conclusion 9Must Read References 9References 92 Identifying Molecular Drivers of Lymphomagenesis 12Jennifer Shingleton and Sandeep S. DaveTake Home Messages 12Introduction 12Sequencing and Bioinformatics Methods 13Functional Validation of Drivers 13Common Themes in B- and T-cell Lymphoma 14Genetic Landscapes of Lymphomas 18Mature B-cell Lymphomas 18T-cell Lymphomas 18Genomic Subgrouping Approaches in DLBCL 19Challenges of Incorporating Genomic Subgrouping Approaches in Clinical Trials 19Leveraging Underlying Pathophysiology to Inform Therapeutic Consideration 20Conclusion 22Must Read References 22References 223 Characterizing the Spectrum of Epigenetic Dysregulation Across Lymphoid Malignancies 25Sean Harrop, Michael Dickinson, Ricky Johnstone, and Henry Miles PrinceTake Home Messages 25Introduction: Epigenetics and Lymphoid Malignancies 25Dysregulation of DNA Methylation and Modification of Histone Proteins 26Genes Involved in Histone Modification Implicated in Lymphomagenesis 27Enhancer of Zeste Homolog 2 (EZH2) 27CREB-binding Protein (CREBBP) and Histone Acetyltransferase P300 (EP300) 27The H3K4 Methyltransferase Family 27The Bromodomain and Extra-Terminal Domain (BET) Family 27Genes Involved in DNA Methylation Implicated in Lymphomagenesis 27DNA Methyltransferase 3A (DNMT3A) 27Ten-Eleven Translocation 1/2 (TET1/2) 28Isocitrate Dehydrogenase 2 (IDH2) 28The Epigenetic Landscape of Specific Lymphoid Malignancies 28Follicular Lymphoma 28Diffuse Large B-cell Lymphoma 29Marginal Zone Lymphoma 30Burkitt's Lymphoma 30Acute Lymphoblastic Leukemia 31Chronic Lymphocytic Leukemia 31Mantle Cell Lymphoma 31Hodgkin's Lymphoma 31Multiple Myeloma 32Peripheral T-cell Lymphoma - Not Otherwise Specified 32Angioimmunoblastic T-cell Lymphoma and PTCL with TFH Phenotype 32Anaplastic Large Cell Lymphoma 33Adult T-cell Leukemia/Lymphoma 33Intestinal T-cell Lymphoma 33Hepatosplenic T-cell Lymphomas 33NK/T Cell Lymphoma 33Mycosis Fungoides and Sezary's Syndrome 34Summary 34Must Read References 34References 344 Animal Models of Lymphoid Malignancies 40Anjali MishraTake Home Messages 40Introduction 40Optimal Animal Models to Study Lymphoid Neoplasms 41Zebrafish Model 41Zebrafish Model of T-cell Neoplasms 41Zebrafish Model of B-cell Neoplasms 42Zebrafish Model of NK-cell Neoplasms 43Patient-Derived Xenograft Models in Zebrafish 43Fruit Fly Model 43Non-human Primate Model 44Mouse Models of Lymphoid Neoplasia 44Use of Animal Models in Translational Research 48Conclusions 49Must Read References 49References 50Section II Targeting the PI3 Kinase-AKT-mTOR Pathway 535 Principles of PI3K Biology and Its Role in Lymphoma 55Ralitsa R. MadsenTake Home Messages 55Introduction: Overview 55Four Decades of PI3K Signaling Research 55Class I PI3K Enzymes 56Isoforms 56Structural Organization 57Isoform-specific Functions 57The Essential Phospholipid Second Messenger PIP 3 58PI3K Pathway Effectors 59AKT, FOXO, and mTORC1 59TEC Tyrosine Kinases 60Network Topology and Signal Robustness 60Dynamic PI3K Signaling in Lymphocyte Biology 61B-cell Development and Survival 61The Germinal Center (GC) Reaction 61T FH Cell Function 63Naïve and Effector T-cells 63Lessons from Monogenic Disorders 64Genetic PI3Kdelta Inactivation 64Genetic PI3Kdelta Hyperactivation 64Corrupted PI3K Signaling in Cancer 65The Success of PI3Kdelta Inhibition in Lymphoid Malignancies 65Quantitative Biology and Therapeutic Considerations 66Concluding Remarks 67Acknowledgments 67Must Read Reference 67References 676 Pharmacologic Differentiation of Drugs Targeting the PI3K-AKT-mTOR Signaling Pathway 71Inhye E. Ahn, Jennifer R. Brown, and Matthew S. DavidsTake Home Messages 71Introduction 71PI3K Inhibitors Approved by the US Food and Drug Administration (FDA) 72PI3K Inhibitors in Clinical Development 77AKT Inhibitors 78mTOR Inhibitors 79Conclusions 79Must Read References 79References 807 Clinical Experience with Phosphatidylinositol 3-Kinase Inhibitors in Hematologic Malignancies 86Alessandro Broccoli and Pier Luigi ZinzaniTake Home Messages 86Introduction 86Idelalisib 87Copanlisib 91Duvelisib 93Umbralisib 95Parsaclisib 97Zandelisib 97Amdizalisib (HMPL-689) 98Conclusion 98Must Read References 99References 998 Clinical Experiences with Drugs Targeting mTOR 102Thomas E. WitzigTake Home Messages 102Introduction 102Rapamycin (Sirolimus) Rapamune(r) (Pfizer) and Generic Sirolimus 103The Rapamycin Analogs (Rapalogs) 103Temsirolimus (CCI-779; Torisel) 103Everolimus (RAD-001; Afinitor, Zortrees, Evertor) 105Summary of Lymphoma Studies of Everolimus 107Ridaforolimus 108Dual Inhibitors of mTORC1 and mTORC2 108Side Effects of mTORC1 Inhibitors 108Future Directions for mTOR Inhibitors in Lymphoma 109Must Read References 110References 1109 PI3 Kinase, AKT, and mTOR Inhibitors 113Joel McCay and John G. GribbenTake Home Messages 113Introduction 113PI3K Structure and Functions 114AKT Structure and Functions 114mTOR Structure and Functions 115PTEN as a Regulator of the PI3K/AKT/mTOR Pathway 115mTOR Inhibitors 116Temsirolimus: Phase 3 Trials 116PI3K and Dual PI3K/mTOR Inhibitors 116PI3K Isoforms and Expression Throughout the Body 118Immune Toxicity and Management 119Colitis 119Hepatitis 119Pneumonitis 120Skin Rash 120Homeostatic Toxicity 120Hypertension and Hyperglycemia 121Myelosuppression and Opportunistic Infection 121Myelosuppression 122Atypical Infection 122Vaccination 122Neuropsychiatric Problems 122PI3K Treatment in NHL 122AKT Inhibitors 123Conclusion 123Must Read References 126References 126Section III Targeting Programmed Cell Death 13110 Principles for Understanding Mechanisms of Cell Death and Their Role in Cancer Biology 133Sarah T. Diepstraten, John E. La Marca, David C.S. Huang, and Gemma L. KellyTake Home Messages 133Introduction 133A Historical Perspective 133Apoptotic Pathways 134Other Cell Death Pathways 137The Role of Intrinsic Apoptosis in Normal Cells - Lessons from Gene Knockout Mice 137BCL2 Family Pro-survival Proteins 137BCL 2 137BCL -XL 138MCL- 1 138A1/BFL- 1 138BCL -W 139Combined Knockout of Pro-survival Proteins 139BCL2 Family Pro-apoptotic Effector Proteins 139BH3-only Proteins 139The Dysregulation of Apoptosis in Cancer 142Must Read References 144References 14411 Pharmacologic Features of Drugs Targeting BCL2 Family Members 151Jennifer K. Lue and Owen A. O'ConnorTake Home Messages 151Introduction 151Historical Perspective: From the Discovery of BCL2 to Therapeutic Applications 152BCL2 as a Biomarker 153Targeting BCL2 Family Members 154Antisense Approaches for Targeting BCL2 154Natural Anti-apoptotic Compounds 154Small Molecule Inhibitors of BCL2 Family Members 154Novel BCL2 Inhibitors on the Horizon 158Mechanisms of Resistance to BCL2 Inhibitors 158Novel Mechanisms to Overcome BCL2 Resistance 159Targeting MCL1 159PROTAC Strategies for Targeting Apoptotic Family Members 160Conclusions 160Must Read References 161References 16112 Clinical Experience with Pro-Apoptotic Agents 165Thomas E. Lew and John F. SeymourTake Home Messages 165Introduction 165Safety and Toxicities of Pro-apoptotic Agents 166Tumor Lysis Syndrome 166Myeloid Compartment Toxicities and Infections 167Gastrointestinal Toxicities 168Thrombocytopenia and Navitoclax 168Efficacy of Venetoclax in Chronic Lymphocytic Leukemia/Small Cell Lymphoma 168Phase 1/2 Studies 168Combining Venetoclax with Conventional Chemotherapy in CLL/SLL 172Phase 3 Studies 172Venetoclax Re-treatment 173Efficacy of Venetoclax in Other B-cell Neoplasms 173Mantle Cell Lymphoma 173Follicular Lymphoma 173Diffuse Large B-cell Lymphoma and Other Aggressive B-cell Lymphomas 177Richter Transformation 179Waldenstrom's Macroglobulinemia 179Marginal Zone Lymphoma 179Acute Lymphoblastic Leukemia/Lymphoma 179Lessons from Venetoclax in Lymphoid Neoplasms Other than CLL/SLL 180Associations and Mechanisms of Resistance to Pro-apoptotic Agents 180Must Read References 181References 18113 Promising Combinations of Drugs Targeting Apoptosis 186William G. WierdaTake Home Messages 186Introduction: Background and Disease Perspective 186Clinical Development of BCL2 Inhibitors 187Venetoclax Monotherapy for CLL 187Venetoclax Plus CD20 Monoclonal Antibody for CLL 190Venetoclax Plus BTK Inhibitor for CLL 190Venetoclax Plus BTK Inhibitor and CD20 Monoclonal Antibody for CLL 191Venetoclax Plus Chemoimmunotherapy 191Venetoclax Toxicities and Side Effects in CLL 192TLS Risk Mitigation and Management in CLL 192Venetoclax-associated Neutropenia 192Risk for Progression and Resistance Mechanisms 193Current Knowledge Gaps and Opportunities for Future Work with Venetoclax 193Must Read References 194References 194Section IV Targeting the Cancer Epigenome 19714 The Role of Epigenetic Dysregulation in Lymphoma Biology 199Qing Deng and Michael R. GreenTake Home Messages 199Introduction: Germinal Center B (GCB)-cells and GCB-derived Lymphomas 199Mutations Altering DNA Modifications and Structure 200Tet 2 200Mutations Altering Writers of Histone Post-translational Modifications 202KMT2D 202CREBBP 202EZH2 203Mutations Altering Higher Order Chromatin Structure 204BAF Chromatin Remodeling Complex 205Linker Histones 205Must Read References 206References 20615 Quantitating and Characterizing the Effects of Epigenetic Targeted Drugs 209Emily Gruber, Alexander C. Lewis, and Lev M. KatsTake Home Messages 209Introduction 209Experimental Analysis of the Epigenome 210DNA Methylation 210Bisulfite Conversion Methods 210Affinity-based Methods 211Detection of 5hmC 211Histone Modifications, Histone Variants, and Chromatin-associated Proteins 211Antibody-based Techniques for Mapping the Chromatin State 212Proteomic Analysis of Histones 212Chromatin Accessibility 212Genome Organization 213Emerging Technologies for Epigenomic Analysis of Single Cells 214Molecular and Cellular Effects of Epigenetic Drugs 216Concluding Remarks 221Acknowledgments 221Must Read References 221References 22116 Clinical Experience with Epigenetic Drugs in Lymphoid Malignancies 225Enrica Marchi, Ipsita Pal, and John Sanil ManavalanTake Home Messages 225Introduction 225Epigenome and Cancer 225Different Epigenetic Classes of Drugs in Hematologic Malignancies 226DNMT Inhibitors 2265-Azacytidine and Decitabine 227Guadecitabine 229HDAC Inhibitors 230Vorinostat 230Romidepsin 230Belinostat 231EZH2 Inhibitors 231Summary 232Must Read References 233References 23317 Future Prospects for Targeting the Epigenome in Lymphomas 236Yusuke Isshiki and Ari MelnickTake Home Messages 236Introduction 236Emerging Epigenetic Therapies 236EZH2- and PRC2-targeted Therapies Are Emerging as Potential Cornerstone Therapies for Lymphomas 236SETD2, a Novel Therapeutic Target for DLBCLs 237LSD1, a Case of Bait and Switch 237A Surprising Indication for KDM5 Histone Demethylase Inhibitors 238New Opportunities Provided by Emerging Histone Deacetylase Inhibitors 238Sirtuins, the "Other HDACs," Potential Therapeutic Targets in B-cell Lymphomas 239Histone Acetyltransferase Inhibitors, Lacking Selectivity but with Activity in Lymphomas 239Is There a Potential Role for BET Inhibitors for Lymphoma? 239DNA Methyltransferase Inhibitors Are Increasingly Relevant for Treatment of Lymphomas 240Nucleosome Remodeling Complex Inhibitors 240Precision Epigenetic Therapy 241Maximizing the Impact of Emerging Epigenetic Therapies 242Rational Combination of Epigenetic Agents 242Rational Combination with Immunotherapies 242Conclusions 244Acknowledgments 244Disclosures 244Major Papers 244Must Read References 244References 244Section V Targeting the B-cell Receptor (BCR) 24918 The Pathologic Role of BCR Dysregulation in Lymphoid Malignancies 251Jan A. BurgerTake Home Messages 251Introduction: The BCR in Normal and Malignant B Lymphocytes 251BCR Signaling 251BCR Signaling in B-cell Malignancies 252B-cell Proliferation in Secondary Lymphatic Organs (SLOs) 254The BCR Complex in Malignant B-cells 255CLL 255BCR Signaling in DLBCL 256Tonic BCR Signaling in Burkitt's Lymphoma 257BCR Signaling in Follicular Lymphoma (FL) 257BCR Signaling in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) 257Targeting BCR Signaling 257Bruton's Tyrosine Kinase (BTK) Inhibitors 258Ibrutinib 259Acalabrutinib 259BTK Inhibitors with Anti-CD20 Antibodies 259Zanubrutinib 260Pirtobrutinib 260Idelalisib 260Conclusions 260Acknowledgments 261Conflict of Interest 261Must Read References 261References 26119 Pharmacologic Features of Drugs Targeting Bruton's Tyrosine Kinase (BTK) 268Joel McCay and John G. GribbenTake Home Messages 268Introduction 268BTK and B-cell Activating Factor Receptor (BAFFR) Signaling 270BTK in Cell Signaling Pathways 270BTK Inhibitor Development and Mechanisms of Action 271BTK Inhibitors in Malignancy 271BTK Inhibitors in Solid Cancers 273BTK Inhibitors in Autoimmune Diseases 273Mechanisms of Resistance 273Summary 273Must Read References 274References 27420 Clinical Experience with Drugs Targeting Bruton's Tyrosine Kinase (BTK) 278Julia Aronson, Anthony R. Mato, Catherine C. Coombs, Prioty Islam, Lindsey E. Roeker, and Toby EyreTake Home Messages 278Introduction: Chronic Lymphocytic Leukemia (CLL) 278Ibrutinib: Clinical Trials 278Ibrutinib: Real-world Evidence 279Acalabrutinib 280Ibrutinib Versus Acalabrutinib 281Zanubrutinib in CLL 281Pirtobrutinib in CLL 281BTK Inhibition in Indolent B-cell non-Hodgkin's Lymphoma 282Mantle Cell Lymphoma (MCL) 282Waldenstrom's Macroglobulinemia (WM) 283Marginal Zone Lymphoma (MZL) 283CNS Involvement with B-cell Malignancies 283Real-world Data 284Conclusions 284Must Read References 284References 28421 Promising Combinations of BTK Inhibitors with Other Targeted Agents 287Nicholas J. Schmidt, Michael E. Williams, and Craig A. PortellTake Home Messages 287Introduction 287Limitations of BTK Inhibitor Monotherapy 287Identifying Synergistic Combinations 288Combinations of BTK Inhibitors and Targeted Drugs as the Standard of Care 288BTKi + Anti-CD20 Monoclonal Antibodies 288Waldenstrom's Macroglobulinemia - iNNOVATE Study 288Chronic Lymphocytic Leukemia (CLL) 289Mantle Cell Lymphoma 291BTKi and BCL2 Inhibitors 292CLL 292Mantle Cell Lymphoma 293The Future: Ongoing Clinical Trials and Additional BTKi Combinations of Interest 294BTKi + CDK4/6 Inhibitors 294BTKi + PI3Kdelta Inhibitors 294BTKi + Proteasome Inhibitors 296Ibrutinib + Cirmtuzumab, an Anti-ROR1 Monoclonal Antibody 296BTKi + mTOR Inhibitors 296BTKi + SYK Inhibitors 296BTKi + HDAC Inhibitors 297Ibrutinib + Selinexor 297Conclusions 297Must Read References 297References 297Section VI Protein Degraders and Membrane Transport Inhibitors 30122 The Biological Basis for Targeting Protein Turnover in Malignant Cells 303Robert Z. OrlowskiTake Home Messages 303Introduction 303Biological Basis for Targeting Protein Turnover 303Approved Drugs Targeting Ubiquitin-Proteasome Pathway 304Pharmacologic Mechanisms of Proteasome Inhibitors 304Other Proteasome Inhibitors 306Immunomodulatory Drugs Affecting Protein Turnover 306Background 306Presently Approved Immunomodulatory Drugs 307Pharmacologic Mechanisms of Currently Approved Immunomodulatory Drugs 307Other Cereblon Modulating Agents 308Conclusions 309Acknowledgments 309Must Read References 309References 31023 Preclinical Overview of Drugs Affecting Protein Turnover in Multiple Myeloma 313Giada Bianchi, Matthew Ho, and Kenneth C. AndersonTake Home Messages 313Introduction 313Overview of Protein Handling in mm 314Molecular Chaperones in Protein Folding 314Ubiquitin-Proteasome System (UPS) 314Drugs Targeting the UPS 318Proteasome Inhibitors 318Inhibitors of Deubiquitinating Enzymes (DUB) 319Targeting Proteasome Biogenesis 319Molecular Glue Degraders and Proteolysis-targeting Chimera (PROTACs) 320Endoplasmic Reticulum (ER) Stress and the Unfolded Protein Response (UPR) 321Drugs Targeting the UPR 321Autophagy and Aggresome Pathways 321Targeting Nutrient Metabolism to Enhance Proteotoxic Stress 322The Role of Proteasome Inhibition in the Era of Immunotherapy 323Conclusions and Future Perspectives 323Must Read References 324References 32424 Clinical Experience on Proteasome Inhibitors in Cancer 331Noa Biran, Pooja Phull, and Andre GoyTake Home Messages 331Introduction to Proteasome Inhibitors (Pis) 331Clinical Activity in Plasma Cell Disorders 333Role of Proteasome Inhibition in Plasma Cells: Mechanisms of Action and Mechanisms of Resistance 333Proteasome Inhibitors with Clinical Activity in Multiple Myeloma 334Bortezomib 334Carfilzomib 335Ixazomib 336Other Oral Proteasome Inhibitors Evaluated for Use in Patients with Multiple Myeloma 336Role of Proteasome Inhibitors in Amyloidosis 336Rationale for Combinations w/ Proteasome Inhibitors 337PI and Cytotoxic Agents 337PI + Immunomodulatory Agents (IMIDS) 337PI and Monoclonal Antibodies 338PI and HDAC Inhibitors 338PI and Nuclear Transport Inhibitor Selinexor 338Future Directions of PI-based Combination Regimens 338Clinical Activity of Proteasome Inhibitors in Lymphoid Malignancies 338Clinical Activity of Bortezomib (BTZ) in Mantle Cell Lymphoma (MCL) 338Bortezomib Phase 2 in R/R MCL Led to Early Approval 338Importing Bortezomib in the Management of MCL 342Clinical Activity of Bortezomib in Indolent Lymphoma (iNHL): Follicular Lymphoma, Marginal Zone, and SLL/CLL Subtypes 345Clinical Activity of Bortezomib in Diffuse Large B-cell Lymphoma (DLBCL) 346Bortezomib in Waldenstrom's Macroglobulinemia (WM) 347Clinical Activity of Bortezomib in Other Lymphomas 347T-cell Lymphoma 347Hodgkin's Lymphoma 348Plasmablastic Lymphoma (PBL) 348Lymphoblastic Lymphoma (LL)/Acute Lymphocytic Leukemia (ALL) 348EBV Lymphoproliferative Disorders and Other Immunological Conditions 348Clinical Activity of Proteasome Inhibitors in AML/MDS 349Clinical Activity of Proteasome Inhibitors in Solid Tumors 349Overcoming Resistance to Proteasome Inhibitors in Cancer and Next Steps in Proteasome Inhibition 350Must Read References 352References 35225 Targeting Nuclear Protein Transport with XPO Inhibitors in Lymphoma 361Farheen Manji, Kyla Trkulja, Rob C. Laister, and John KuruvillaTake Home Messages 361Introduction 361XPO1 Biology 361Pre-clinical and Clinical Data 362Phase 1 Evaluation in Non-Hodgkin's Lymphoma 362DLBCL365CLL 366T-cell Lymphoma 367Mantle Cell Lymphoma 367Toxicity 367Mechanisms of Intrinsic and Acquired Resistance to Selinexor and SINE Compounds 368Future Directions 369Must Read References 370References 37026 Heterobifunctional Degraders for the Treatment of Lymphoid Malignancies 372Ashwin Gollerkeri, Jared Gollob, and Nello MainolfiTake Home Messages 372Biology of Protein Degraders 372Ubiquitin-Proteasome System and Protein Degradation 372Targeted Degraders in Clinical Practice 372Heterobifunctional Small Molecule Degraders 372Mechanisms of Resistance 373Rationale for Use of Heterobifunctional Degraders in Oncology 373Clinical Experience with Heterobifunctional Degraders 374Arvinas Phase 1/2 Trials of PR and ER Degraders 375ARV- 110 375ARV- 471 375Kymera Phase 1 Trial of IRAK4 Degrader KT- 474 375Development of Heterobifunctional Degraders in Lymphoma 375IRAKIMiD Degraders 375KT- 413 376BTK Degraders 376NX- 2127 377NX- 5948 377BGB- 16673 377STAT3 Degraders 377KT- 333 377Conclusions and Future Directions 378Must Read References 378References 378Section VII Novel Targets and Therapeutic Prospects in Development 38127 Strategies for Targeting the JAK-STAT Pathway in Lymphoid Malignancies 383David J. Feith, Johnson Ung, Omar Elghawy, Peibin Yue, James Turkson, and Thomas P. Loughran JrTake Home Messages 383JAK-STAT Signaling and Endogenous Regulators 383Alternative Regulation and Function of STATs 385Dysregulated Cytokine Signaling in Lymphoid Malignancies 386Strategies to Target the JAK-STAT Pathway 387Direct Targeting Approaches against STAT 3 388Oligonucleotide-based Strategies 389Direct STAT3 Inhibitors as Standalone Agents 389Natural Product Inhibitors of STAT 3 389Chemotherapeutic, Cytotoxic Drugs, and Other Modalities that Directly or Indirectly Inhibit STAT3 Pathway 390Inhibition of STAT3 Function in Combination Strategies to Sensitize Tumors and/or Reverse Resistance 390Clinical Trials of STAT3 Inhibitors in Lymphoid Malignancy 391Targeting STAT5 in Lymphoid Malignancy 391Clinical Trials of JAK Inhibitors in Lymphoid Malignancies 392Challenges and Opportunities for Clinical Application of JAK-STAT Targeting Agents 395Acknowledgments 396Conflict of Interest Disclosures 396Must Read References 396References 39628 Strategies for Targeting MYC 402Jemma Longley and Andrew DaviesTake Home Messages 402Introduction 402Dysregulation of MYC in B-cell Lymphomas 403Identifying MYC Rearrangement in the Context of HGBL 403Targeting MYC Transcription 404Targeting MYC Translation 405Targeting MYC Stabilization and Downstream Gene Expression 406Initial Therapy in MYC-R DLBCL 407Future Directions 408Must Read References 408References 40929 Targeting NOTCH in Lymphoid Malignancies 411Deborah Piffaretti, Georgia Alice Galimberti, and Davide RossiTake Home Messages 411Introduction: NOTCH Signaling 411Role of NOTCH Signaling in B-cell 414Genetic and Microenvironmental Mechanisms of NOTCH Signaling Alteration in CLL and Lymphomas 415Genetic Mechanisms 415CLL (notch1) 415MCL 417FL 417MZL (notch2) 418DLBCL (N1 e N2) 419Other Genes of the Pathway (FBXW7, SPEN) 420Inhibitors Tested at the Preclinical Level 420Must Read References 421References 42130 Targeting NF-kappaB in Oncology, an Untapped Therapeutic Potential 428Matko KalacTake Home Messages 428Introduction 428Historical Perspective for the Role of NF-kappaB in Malignancy 429Canonical NF-kappaB Pathway 429Non-canonical NF-kappaB Pathway 431NF-kappaB in Tumorigenesis and Promotion of Malignant Cell Growth 431Oncogenic Alterations in Lymphoma and Other Hematologic Malignancies 432Role of NF-kappaB in Solid Malignancies 434NF-kappaB Targeted Therapies 435Approved Drugs 435In Development 436Summary 437Must Read References 437References 43831 Targeting the Cell Cycle and Cyclin-dependent Kinases 444Chiara Tarantelli and Francesco BertoniTake Home Messages 444Introduction 444CDK Family and Cyclins 444CDKs Structure 446CDKs Activation 446CDKs Inhibition 446CDKs Function 447Cell Cycle-related CDK-cyclin Complexes 447Transcription-related CDK-cyclin Complexes 447DNA Damage and Repair 448CDK-cyclin Deregulation in Cancer 448Targeting CDKs in Lymphoid Malignancies 448CDK4/6 Inhibitors 448Specific Inhibitors 449CDK7 Inhibitors 450Inhibitors Targeting Multiple CDKs 450Resistance 451Future Directions 451Must Read References 452References 452Index 457

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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.