Resistance of Targeted Therapies Excluding Antibodies for Lymphomas

143 Pages·2018·2.79 MB·English

by  Andrés J. M. Ferreri

Resistance to Targeted Anti-Cancer Therapeutics 17
Series Editor: Benjamin Bonavida
Andrés J. M. Ferreri Editor
Resistance of
Targeted Therapies
Excluding
Antibodies for
Lymphomas
Resistance to Targeted Anti-Cancer
Therapeutics
Volume 17
Series Editor:
Benjamin Bonavida
More information about this series at http://www.springer.com/series/11727
Andrés J. M. Ferreri
Editor
Resistance of Targeted
Therapies Excluding
Antibodies for Lymphomas
Editor
Andrés J. M. Ferreri
Department of Onco-Hematology
Unit of Lymphoid Malignancies
IRCCS San Raffaele Scientific Institute
Milan, Italy
ISSN 2196-5501 ISSN 2196-551X (electronic)
Resistance to Targeted Anti-Cancer Therapeutics
ISBN 978-3-319-75183-2 ISBN 978-3-319-75184-9 (eBook)
https://doi.org/10.1007/978-3-319-75184-9
Library of Congress Control Number: 2018935142
© Springer International Publishing AG, part of Springer Nature 2018
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“Resistance to Targeted Anti-Cancer
Therapeutics”: Aims and Scope
Published by Springer Inc.
For several decades, treatment of cancer consisted of chemotherapeutic drugs, radi-
ation, and hormonal therapies. Those were not tumor specific and exhibited several
toxicities. During the last several years, targeted cancer therapies (molecularly tar-
geted drugs) have been developed and consisting of immunotherapies (cell medi-
ated and antibody) drugs or biologicals that can block the growth and spread of
cancer by interfering with surface receptors and with specific dysregulated gene
products that control tumor cell growth and progression. These include several
FDA-approved drugs/antibodies/inhibitors that interfere with cell growth signaling
or tumor blood vessel development, promote the cell death of cancer cells, stimulate
the immune system to destroy specific cancer cells and deliver toxic drugs to cancer
cells. Targeted cancer therapies are being used alone or in combination with conven-
tional drugs and other targeted therapies.
One of the major problems that arise following treatment with both conventional
therapies and targeted cancer therapies is the development of resistance, preexisting
in a subset of cancer cells or cancer stem cells and/or induced by the treatments.
Tumor cell resistance to targeted therapies remains a major hurdle and, therefore,
several strategies are being considered in delineating the underlining molecular
mechanisms of resistance and the development of novel drugs to reverse both the
innate and acquired resistance to various targeted therapeutic regimens.
The new Series “Resistance of Targeted Anti-Cancer Therapeutics” was
inaugurated and focuses on the clinical application of targeted cancer therapies
(either approved by the FDA or in clinical trials) and the resistance observed by
these therapies. Each book will consist of updated reviews on a specific target
therapeutic and strategies to overcome resistance at the biochemical, molecular and
both genetic and epigenetic levels. This new Series is timely and should be of sig-
nificant interest to clinicians, scientists, trainees, students, and pharmaceutical
companies.
Benjamin Bonavida
David Geffen School of Medicine at UCLA
University of California, Los Angeles
Los Angeles, CA 90025, USA
v
Series Editor Biography
Dr. Benjamin Bonavida, PhD (Series Editor) is currently
Distinguished Research Professor at the University of
California, Los Angeles (UCLA). His research career,
thus far, has focused on basic immunochemistry and
cancer immunobiology. His research investigations have
ranged from the mechanisms of cell mediated killing,
sensitization of resistant tumor cells to chemo−/immu-
notherapy, characterization of resistant factors in cancer
cells, cell-signaling pathways mediated by therapeutic
anticancer antibodies, and characterization of a dysregu-
lated NF-κB/Snail/YY1/RKIP/PTEN loop in many can-
cers that regulates cell survival, proliferation, invasion,
metastasis, and resistance. He has also investigated the role of nitric oxide in cancer
and its potential antitumor activity. Many of the above studies are centered on the
clinical challenging features of cancer patients’ failure to respond to both conven-
tional and targeted therapies. The development and activity of various targeting
agents, their modes of action, and resistance are highlighted in many refereed
publications.
Acknowledgements
The Series Editor acknowledges the various assistants who have diligently worked
in both the editing and formatting of the various manuscripts in each volume. They
are Leah Moyal, Kevin Li, and Anne Arah Cho.
vii
Editor’s Biography
Andrés J. M. Ferreri has a degree in Medicine from

the Facultad de Medicina of the Universidad de Buenos
Aires, Argentina (1985), and obtained the degree of
Doctor in Medicine and Surgery in the Facoltà di
Medicina e Chirurgia dell’Università degli Studi di
Parma, Italy, in 1992. He is a Specialist in Clinical
Oncology (Università degli Studi di Milan, Italy,
2005). He was a research fellow at the Divisione di
Oncologia Sperimentale “E” and at the Divisione di
Oncologia Médica “A” of the Istituto Nazionale dei
Tumori of Milan (1989–1994) and vice-director of the Medical Oncology Unit of
the San Raffaele Scientific Institute of Milan, Italy. Currently, Dr. Ferreri is Head of
the Unit of Lymphoid Malignancies of the San Raffaele Scientific Institute of Milan,
and is a Contract Professor of Oncology in the Vita e Salute University, Milan. He
is fully devoted to the research on non-Hodgkin lymphomas and is an opinion leader
in the field of extranodal lymphomas. Dr. Ferreri is Associate Editor of the ESO/
START Project and of “Haematological Oncology” and Faculty of the European
School of Oncology. Dr. Ferreri is a member of EHA, ESMO, ASH, and ASCO.
ix
Preface
Targeted therapies are one of the most important components of the armamentarium
against epithelial malignancies. A fast growth of our knowledge of the molecular
mechanisms and activated pathways in the different lymphoma categories was fol-
lowed by a more diffuse and successful use of targeted therapies. Monoclonal anti-
bodies were the first molecules in this field, whereas several other agents targeting
different key molecules involved in the activated pathways were investigated and
are being used in routine practice. Importantly, most of these agents can be used by
the oral route and the assumption for years is not associated with an increased risk
of severe side effects. However, long-lasting treatment with these drugs is followed
by disease relapse in a high proportion of patients, which is predominantly due to
the development of drug resistance. The knowledge of mechanisms involved in
lymphoma resistance to target therapies is of paramount importance because it will
result in a better selection of patients with sensitive disease, tumor monitoring,
relapse prediction, and establishment of combination of drugs that target different
molecules that could overcome the established resistance.
This book is focused on recently developed targeted therapies other than mono-
clonal antibodies used in lymphoma patients, both in routine practice and in inves-
tigative trials. Expert authors revisit the most relevant aspects of these agents, with
special emphasis on molecular mechanisms and clinical effects of resistance.
Although more space is dedicated to the first-in-class members of each drug family,
other recently developed agents are discussed.
Milan, Italy Andrés J. M. Ferreri
xi
Contents
BTK Inhibitors: Focus on Ibrutinib and Similar Agents . . . . . . . . . . . . . . 1
Mattias Mattsson and Lydia Scarfò
BCL2 Inhibitors: Insights into Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Mary Ann Anderson, Andrew W. Roberts, and John F. Seymour
Proteasome Inhibitors with a Focus on Bortezomib . . . . . . . . . . . . . . . . . . 45
Kevin Barley and Samir Parekh
IMiD: Immunomodulatory Drug Lenalidomide (CC-5013; Revlimid)
in the Treatment of Lymphoma: Insights into Clinical Use
and Molecular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Pashtoon Murtaza Kasi and Grzegorsz S. Nowakowski
mTOR Inhibitors, with Special Focus on Temsirolimus
and Similar Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Teresa Calimeri and Andrés J. M. Ferreri
Inhibitors of the JAK/STAT Pathway, with a Focus on Ruxolitinib
and Similar Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Linda M. Scott
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
xiii
BTK Inhibitors: Focus on Ibrutinib
and Similar Agents
Mattias Mattsson and Lydia Scarfò
Abstract Since Bruton tyrosine kinase (BTK) is a critical effector molecule for B
cell development and lymphomagenesis, BTK inhibitors have been investigated in
B cell malignancies during the last decade. Ibrutinib, a first-in-class, potent, orally
administered covalently-binding inhibitor of BTK was recently approved for the
treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL),
Waldenström’s macroglobulinemia (WM) and marginal-zone lymphoma (MZL). Its
use led to impressive responses in CLL, MCL, WM and MZL with a favorable
safety profile. Mechanisms of resistance to ibrutinib are different according to dis-
ease biology and still need to be fully elucidated. In CLL and WM patients pro-
gressing on ibrutinib, BTK and downstream kinase Phospholipase Cγ2 (PLCγ2)
mutations have been identified leading to resistance. BTK and PLCγ2 mutations are
almost always absent at the beginning of treatment and they are detected at a later
timepoint, suggesting the evolution of clonal dynamics under treatment pressure.
Primary and secondary resistances in MCL are driven by mutations promoting the
activation of the alternative NFκB-pathway and PI3K-AKT pathway. Further work
needs to be done to elucidate the mechanisms behind primary refractory patients, to
define the risk for clonal evolution/new mutations over time on treatment, and to
identify prognostic/predictive markers for patients on BTK inhibitors.
Keywords BTK inhibitors · Ibrutinib · B cell malignancies · Acalabrutinib ·
ONO/GS4059 · BGB-3111 · CC-292
M. Mattsson
Department of Hematology, Uppsala University Hospital and Department of Immunology,
Genetics and Pathology, Uppsala University Uppsala, Uppsala, Sweden
L. Scarfò (*)
Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy
e-mail: [email protected]
© Springer International Publishing AG, part of Springer Nature 2018 1
A. J. M. Ferreri (ed.), Resistance of Targeted Therapies Excluding Antibodies
for Lymphomas, Resistance to Targeted Anti-Cancer Therapeutics 17,
https://doi.org/10.1007/978-3-319-75184-9_1