Resistance to Proteasome Inhibitors in Cancer: Molecular Mechanisms and Strategies to Overcome Resistance

396 Pages·2014·6.685 MB·English

by  Q. Ping Dou (eds.)

Resistance to Targeted Anti-Cancer Therapeutics
Q. Ping Dou Editor
Resistance to
Proteasome
Inhibitors in
Cancer
Molecular Mechanisms and Strategies
to Overcome Resistance
Resistance to Targeted Anti-Cancer Therapeutics
Series Editor
Benjamin Bonavida, Los Angeles, CA, USA
More information about this series at h ttp://www.springer.com/series/11727

Q. Ping Dou
Editor
Resistance to Proteasome
Inhibitors in Cancer
Molecular Mechanisms and Strategies
to Overcome Resistance
Editor
Q. Ping Dou
Wayne State University
Detroit , MI , USA
ISSN 2196-5501 ISSN 2196-551X (electronic)
ISBN 978-3-319-06751-3 ISBN 978-3-319-06752-0 (eBook)
DOI 10.1007/978-3-319-06752-0
Springer Cham Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014947541
© Springer International Publishing Switzerland 2014
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This book is dedicated to my loving
family—my wife, Anna; my daughter,
Eva; and my son, Dan.

Pref ace
A balance of protein synthesis and degradation is tightly regulated in our bodies in
order to keep us healthy. Most intracellular proteins are degraded via the ubiquitin-
proteasome pathway (UPP), and dysfunction of the UPP has been linked to the
occurrence of many human diseases, including cancers. The clinical introduction
of the fi rst US Food and Drug Administration (FDA)-approved proteasome inhibi-
tor bortezomib for the treatment of multiple myeloma (MM) and mantle cell lym-
phoma is an example of using the UPP as an anticancer target which has been met
with success. Now, bortezomib-based therapies have become a staple for the MM
treatment, contributing to a two- to threefold increase in the survival rate of the
MM patients.
H owever, not all patients respond to bortezomib treatment and relapse occurs in
many patients who initially responded. Also, bortezomib-based therapies had mini-
mal effects in treating most of hematologic malignancies and almost all of the solid
tumors. Furthermore, some neurotoxicities (such as peripheral neuropathy) were
found to be associated with bortezomib treatment. Therefore, bortezomib resistance
(both intrinsic and acquired) is a critical barrier to progress in bortezomib therapy
for MM and other cancers.
T his book, Resistance to Proteasome Inhibitors in Cancer: Molecular mecha-
nisms and strategies to overcome resistance, focuses on the mechanisms of action
and resistance of the proteasome inhibitor bortezomib in human cancers (including
MM, mantle cell lymphoma, acute leukemia, and various solid tumors) and on cut-
ting-edge strategies to overcome bortezomib clinical resistance. The second-gener-
ation 20S proteasome inhibitors carfi lzomib, ixazomib, delanzomib, oprozomib,
and marizomib, with different pharmacological properties and broader anticancer
activities, have shown great promise in this respect; carfi lzomib, the second FDA-
approved proteasome inhibitor drug, induces responses in a minority of MM patients
relapsed from or refractory to bortezomib. The potential reversal strategies for bort-
ezomib resistance also include developing novel combinational therapies and iden-
tifying new targets in the UPP, such as ubiquitin E3 ligases, deubiquitinases, 26S
proteasomal ATPases, histone deacetylases, oxidative stress and proteotoxic stress
pathways, and pharmacogenomic signature profi ling in resistant cancer cells. While
vii
viii Preface
bortezomib resistance could be reversed by several aforementioned strategies in
several preclinical models, the confi rmation under clinical settings is needed. There
are high hopes in the fi eld that the discovery of the mechanisms of proteasome
inhibitor resistance will help illuminate the future of cancer treatment.
Due to the timely nature and keen interest in the subject matter of this book, it is
my wish that this book will serve as an important resource for physicians, clinician
scientists, translational researchers, basic researchers, graduate and medical stu-
dents, patients, consumers, and pharmaceutical companies.
I would like to thank the authors, who are among the top leaders in their areas of
research, for their exceptional contributions. This volume represents one in a new
book series entitled R esistance of Targeted Anti-Cancer Therapeutics of which
Professor Benjamin Bonavida of the University of California, Los Angeles, serves
as the Series Editor (published by Springer Publishing Company). I wish to thank
Professor Bonavida for his encouragement. I am also indebted to Ms. Fiona Sarne,
the Editor of Cancer Research for Springer Science + Business Media, for her great
effort and assistance.
Detroit, MI , USA Q. Ping Dou, Ph.D.
Contents
1 Proteasome Inhibitors and Lessons Learned
from Their Mechanisms of Action and Resistance
in Human Cancer .................................................................................... 1
Sara M. Schmitt, Rahul R. Deshmukh, and Q. Ping Dou
2 Resistance to Proteasome Inhibitors in Multiple Myeloma ................ 47
Francesca Cottini, Anna Guidetti, Claudia Paba Prada,
Teru Hideshima, Michelle Maglio, Cindy Varga,
Dharminder Chauhan, Jacob Laubach, Kenneth C. Anderson,
and Paul G. Richardson
3 Overcoming Bortezomib Resistance: A Review
of the Second-Generation Proteasome Inhibitor
Carfi lzomib in the Treatment of Multiple Myeloma ............................ 81
Hans C. Lee and Robert Z. Orlowski
4 Proteasome Inhibitors in the Treatment of Multiple Myeloma
and AL Amyloidosis ................................................................................ 99
Jeffrey A. Zonder
5 Profi ling Bortezomib Resistance in Multiple Myeloma:
Implications in Personalized Pharmacotherapy .................................. 117
Amit Kumar Mitra, Holly Stessman, John Shaughnessy,
and Brian Van Ness
6 Targeting Mantle Cell Lymphoma with a Strategy
of Combined Proteasome and Histone Deacetylase Inhibition ........... 149
Michael Batalo, Prithviraj Bose, Beata Holkova, and Steven Grant
7 Preclinical Studies on the Molecular Basis of Bortezomib
Resistance and Modalities to Overcome Resistance
in Hematological Malignancies .............................................................. 181
Jacqueline Cloos, Denise Niewerth, and Gerrit Jansen
ix