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 malignanciesTargeting programmed cell death: principles for understanding the many types of cell death and promising combinations of drugs targeting apoptosisTargeting the PI3K pathway: understanding the intricacies of this complex biology and precisely how targeted drugs can be leveraged therapeuticallyTargeting the cancer epigenome: pharmacologic features of drugs targeting the epigenome and future prospects for targeting various aspects of epigenetic controlTargeting 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.

Owen A. OConnor, 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.

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 3Pierre Sujobert, Philippe Gaulard, and Laurence de Leval

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

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

4 Animal Models of Lymphoid Malignancies 40Anjali Mishra

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

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

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

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

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

Section III Targeting Programmed Cell Death 131

10 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. Kelly

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

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

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

Section IV Targeting the Cancer Epigenome 197

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

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

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

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

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

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

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

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

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

Section VI Protein Degraders and Membrane Transport Inhibitors 301

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

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

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

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

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

Section VII Novel Targets and Therapeutic Prospects in Development 381

27 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 Jr

28 Strategies for Targeting MYC 402Jemma Longley and Andrew Davies

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

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

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

References 452

Index 457