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.

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

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

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

4 Animal Models of Lymphoid Malignancies 40
Anjali Mishra

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

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

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

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

9 PI3 Kinase, AKT, and mTOR Inhibitors 113
Joel 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 133
Sarah T. Diepstraten, John E. La Marca, David C.S. Huang, and Gemma L. Kelly

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

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

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

Section IV Targeting the Cancer Epigenome 197

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

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

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

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

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

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

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

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

21 Promising Combinations of BTK Inhibitors with Other Targeted Agents 287
Nicholas 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 303
Robert Z. Orlowski

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

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

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

26 Heterobifunctional Degraders for the Treatment of Lymphoid Malignancies 372
Ashwin 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 383
David J. Feith, Johnson Ung, Omar Elghawy, Peibin Yue, James Turkson, and Thomas P. Loughran Jr

28 Strategies for Targeting MYC 402
Jemma Longley and Andrew Davies

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

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

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

References 452

Index 457

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