Precision Cancer Therapies

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(r) (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-kappaB in Oncology, an Untapped Therapeutic Potential 428 Matko Kalac Take Home Messages 428 Introduction 428 Historical Perspective for the Role of NF-kappaB in Malignancy 429 Canonical NF-kappaB Pathway 429 Non-canonical NF-kappaB Pathway 431 NF-kappaB in Tumorigenesis and Promotion of Malignant Cell Growth 431 Oncogenic Alterations in Lymphoma and Other Hematologic Malignancies 432 Role of NF-kappaB in Solid Malignancies 434 NF-kappaB 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