Table Of ContentAdvances in Experimental Medicine and Biology 1100
Julio A. Aguirre-Ghiso Editor
Biological
Mechanisms of
Minimal Residual
Disease and
Systemic Cancer
Advances in Experimental Medicine
and Biology
Volume 1100
Editorial Board
IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel
ABEL LAJTHA, N.S.Kline Institute for Psychiatric Research, Orangeburg,
NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy
NIMA REZAEI, Children’s Medical Center Hospital, Tehran University of
Medical Sciences, Tehran, Iran
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Julio A. Aguirre-Ghiso
Editor
Biological Mechanisms
of Minimal Residual
Disease and Systemic
Cancer
Editor
Julio A. Aguirre-Ghiso
Division of Hematology and Oncology,
Department of Medicine, Department
of Otolaryngology, Department of
Oncological Sciences, Tisch Cancer
Institute, Black Family Stem Cell
Institute, Mount Sinai School
of Medicine
Icahn School of Medicine at Mount Sinai
New York, NY, USA
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-319-97745-4 ISBN 978-3-319-97746-1 (eBook)
https://doi.org/10.1007/978-3-319-97746-1
Library of Congress Control Number: 2018958003
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Preface
Understanding and Targeting Minimal Residual
Disease: A Path to Change Cancer Patient
Outcomes
Technologies of early detection continue to improve, and therapies are now
more than ever better tailored to treat specific cancers and their subtypes.
With these improvements the survival curves for different cancers are show-
ing rightward shift toward later relapse. In some cancers such as ER+ breast
and prostate cancer, late relapses can span more than a decade and in some
studies in ER+ breast cancer more than two decades. In hematological malig-
nancies, late relapse spanning > 10 years is also documented. In diseases like
melanoma, ultra-late recurrence is not uncommon, and even in HNSCC and
renal cell carcinoma, these late recurrences are also observed. However,
despite this progress, large fractions of patients bearing hematological and
solid tissue malignancies relapse with refractory and lethal disease. This is
due to the ability of residual cancer cells that do not proliferate to persist
undetected by the immune system and unscathed by therapies.
Work by several labs in the last 20 years have shed light into the mecha-
nisms by which cancer cells that otherwise should be in perpetual growth stop
to enter a dormant state that then is interrupted to fuel relapses. The data has
led to the notion that microenvironmental and epigenetic mechanisms may be
responsible for maintaining residual cancer cells in a dormant state. These
include control by the immune system or by niches that normally keep dif-
ferentiated or adult quiescent stem cells in a growth arrest.
In patients, minimal residual disease (MRD) is monitored using different
technologies. Hematological malignancies studies have pioneered the moni-
toring of residual cancer cells by specific markers combined with the detec-
tion of genetic alterations (commonly the driver mutated genes) that provide
a molecular readout of the status of MRD. Other cancers such as prostate
cancer rely on soluble markers in circulation such as PSA but do not directly
interrogate the status of the residual cancer cells and their heterogeneity. This
is in fact a major shortcoming in monitoring and understanding residual can-
cer cell biology in solid cancers. The detection of circulating tumor cells
(CTCs, in blood) or disseminated tumor cells in some target organs (DTCs, in
lymph nodes or bone marrow) has changed how we monitor the progression
of disease. Still major efforts are needed to better characterize this residual
disease to make clinical decisions and tailor therapies in order to prevent
recurrences.
In this book nine chapters delve deep into the basic mechanisms of resid-
ual disease dormancy and recurrence in solid cancer and in hematological
malignancies. These chapters have also dedicated effort to explain and
v
vi Preface
analyze the methods and technologies being developed to monitor MRD in
different cancers.
Pisarsky et al. explore the role of vascular biology in controlling meta-
static progression and how anti-angiogenic therapies may in fact alter vascu-
lar homeostasis and awaken dormant residual cancer in various cancers, with
an emphasis in breast cancer. Carlini et al. explore the basic microenviron-
mental and epigenetic mechanisms driving residual cancer cell dormancy
with a focus on developmental mechanisms and therapy effects on dormancy
programs. Cackowski et al. focus on MRD in prostate cancer and how bone
marrow niches control DTC dormancy while also exploring the clinical per-
spectives of CTC detection. Lin et al. provide insight into MRD in both mela-
noma and breast cancer and how the use of CTCs cell-free DNA and cell-free
microRNA detection are being adapted for monitoring residual disease in
these cancers. With a focus in solid cancers as well Sproll et al. provide a
detailed analysis of routes of dissemination that create MRD in HNSCC and
esophageal cancer with the clinical perspective and mechanistic advances
that are helping understand how to detect CTCs and DTCs and better manage
recurrences in this cancer type.
Four chapters provide a comprehensive and insightful analysis of MRD in
hematological malignancies covering acute myeloid leukemia (AML)
(Gomez et al.), childhood acute lymphoblastic leukemia (ALL) (Jeremias
et al.), chronic lymphocytic leukemia (Bhatia et al.), and multiple myeloma
(Berger et al.). These chapters provide an in-depth look into the monitoring
of MRD in the clinic. These chapters are revealing how advanced the detec-
tion of MRD is in hematological malignancies, compared to solid cancers.
They also explain how this technology and consensus development in meth-
ods has benefited from a longer research experience and unified monitoring
procedures that can be shared and compared across centers in the world
allowing for consistent optimization and data sharing. These chapters also
offer input into the biological basis of MRD in these hematological malig-
nancies. They explore the genetic basis of these hematological malignancies
and how they allow for detection of remnant clones and the role of the micro-
environment and also stem cell programs in the control of MRD persistence
in an inactive state followed by reactivation.
By bringing together experience in solid cancer, basic mechanism analysis
of MRD, and dormancy and hematological malignancies studies, this book
fills a niche for cross comparing how MRD is studied and understood in these
cancers. The book not only provides biological insight but importantly a
strong clinical perspective that must always guide the exploration of the bio-
logical mechanisms. Overall, the chapters in this book offer an insightful
view of the current status of MRD and the mechanisms of dormancy and
progression during the residual stage of the disease. Understanding this biol-
ogy is key to target MRD and provide therapeutic opportunities to prevent
recurrences. This is without doubt one of the biggest challenges in modern
oncology that will provide improved outcomes for patients.
New York, NY, USA Julio A. Aguirre-Ghiso
Acknowledgments
I would like to thank the authors for their exceptional chapter contributions.
Without these we could have not accomplished this project that brings needed
new views and ideas to the minimal residual cancer field.
vii
Contents
1 Epigenetic and Pluripotency Aspects of Disseminated
Cancer Cells During Minimal Residual Disease ......................... 1
Maria Jose Carlini, Nitisha Shrivastava, and Maria Soledad Sosa
2 Anti-angiogenic Therapy- Mediated Endothelial
Damage: A Driver of Breast Cancer Recurrence? ...................... 19
Laura Pisarsky and Cyrus M. Ghajar
3 Minimal Residual Disease in Prostate Cancer ............................ 47
Frank C. Cackowski and Russell S. Taichman
4 Minimal Residual Disease in Head and Neck Cancer
and Esophageal Cancer ................................................................. 55
Christoph Sproll, Georg Fluegen, and Nikolas H. Stoecklein
5 Detection of Minimal Residual Disease and Its Clinical
Applications in Melanoma and Breast Cancer Patients ............. 83
Selena Y. Lin, Javier I. J. Orozco, and Dave S. B. Hoon
6 Preservation of Quiescent Chronic Myelogenous Leukemia
Stem Cells by the Bone Marrow Microenvironment .................. 97
Mansi Shah and Ravi Bhatia
7 Minimal Residual Disease in Acute Myeloid Leukemia ............. 111
Alexandra Gomez-Arteaga and Monica L. Guzman
8 Characteristics and Therapeutic Targeting
of Minimal Residual Disease in Childhood
Acute Lymphoblastic Leukemia ................................................... 127
Irmela Jeremias and Denis M. Schewe
9 Minimal Residual Disease in Multiple Myeloma:
Impact on Response Assessment, Prognosis
and Tumor Heterogeneity .............................................................. 141
Natalie Berger, Seunghee Kim-Schulze, and Samir Parekh
Index ...................................................................................................... 161
ix
1
Epigenetic and Pluripotency
Aspects of Disseminated Cancer
Cells During Minimal Residual
Disease
Maria Jose Carlini, Nitisha Shrivastava,
and Maria Soledad Sosa
Abstract Keywords
Our understanding of the minimal residual Quiescence · Dormancy · Pluripotency ·
disease (MRD) in solid cancers indicates that Epigenetics · Minimal residual disease · Early
it can persist in the system for years or even dissemination · Metastasis · Disseminated
decades. We now know that the persistence of cancer cells
MRD might depend on the dormancy of the
disseminated cancer cells (DCCs). Once
DCCs exit dormancy, they become metastatic
and the survival rates of the patients inevitably Abbreviations
decrease. Thus, innovative treatments are
required to extend the asymptomatic phase of ADT androgen depletion therapy
MRD after the initial therapeutic intervention. AR androgen receptor
With the latest advances in cancer research, ATG autophagy-related gene
there is a greater need to explore and under- atRA all trans retinoic acid
stand the biology, timing of dissemination, BET bromodomain and extraterminal
and origin of DCCs during tumor progression. domain
These important aspects of DCCs impact the BM bone marrow
selection, design, administration, and timing BMP bone morphogenetic proteins
of effective therapies. Herein, we summarize BP bisphosphonate
the current understanding of MRD biology in CAF cancer associated fibroblasts
solid tumors, with a focus on epigenetics and CCC circulating cancer cells
pluripotency, presenting an overall view of the CNV copy number variations
direction the field is taking to reach the goal of CSC cancer stem cells
reducing cancer-related mortalities that result CUP cancer of unknown primary origin
from metastasis. DCC disseminated cancer cells
DNMT1 DNA methyltransferase 1
E2 estradiol
ECM extracellular matrix
M. J. Carlini · N. Shrivastava · M. S. Sosa (*)
EGFR epithelial growth factor receptor
Department of Pharmacological Sciences,
Icahn School of Medicine at Mount Sinai, EMT epithelial-to-mesenchymal transition
New York, NY, USA
e-mail: [email protected]
© Springer Nature Switzerland AG 2018 1
J. A. Aguirre-Ghiso (ed.), Biological Mechanisms of Minimal Residual Disease and Systemic
Cancer, Advances in Experimental Medicine and Biology 1100,
https://doi.org/10.1007/978-3-319-97746-1_1
