Transforming Growth Factor-Beta in Cancer Therapy, Volume II: Cancer Treatment and Therapy (Cancer Drug Discovery and Development)

743 Pages·2008·61.7 MB·English

by  Sonia B. Jakowlew, C.-H. Heldin

TRANSFORMING GROWTH FACTOR-B
IN CANCER THERAPY, VOLUME II
CANCER DRUG DISCOVERY AND DEVELOPMENT
Beverly A. Teicher, PhD, SERIES EDITOR
Checkpoint Responses in Cancer Therapy, edited by Cancer Chemoprevention, Volume 2: Strategies for
Wei Dai, 2008 Cancer Chemoprevention, edited by Gary J. Kelloff,
Cancer Proteomics: From Bench to Bedside, edited by Ernest T. Hawk, and Caroline C. Sigman, 2005
Sayed S. Daoud, 2008 Death Receptors in Cancer Therapy, edited by Wafik S.
Transforming Growth Factor-B in Cancer Therapy, El-Deiry, 2005
Volume II: Cancer Treatment and Therapy, edited Cancer Chemoprevention, Volume 1: Promising Cancer
by Sonia Jakowlew, 2008 Chemopreventive Agents, edited by Gary J. Kelloff,
Transforming Growth Factor-B in Cancer Therapy, Ernest T. Hawk, and Caroline C. Sigman, 2004
Volume 1: Basic and Clinical Biology, edited by Proteasome Inhibitors in Cancer Therapy, edited by
Sonia Jakowlew, 2008 Julian Adams, 2004
Microtubule Targets in Cancer Therapy, edited by Nucleic Acid Therapeutics in Cancer, edited by Alan M.
Antonio T. Fojo, 2008 Gewirtz, 2004
Antiangiogenic Agents in Cancer Therapy, Second DNA Repair in Cancer Therapy, edited by Lawrence C.
Edition, edited by Beverly A. Teicher and Lee M. Panasci and Moulay A. Alaoui-Jamali, 2004
Ellis, 2007 Hematopoietic Growth Factors in Oncology: Basic
Apoptosis and Senescence in Cancer Chemotherapy and Science and Clinical Therapeutics, edited by
Radiotherapy, Second Edition, edited by David A. George Morstyn, MaryAnn Foote, and Graham J.
Gerwitz; Shawn Edan Holtz, and Steven Grant, 2007 Lieschke, 2004
Molecular Targeting in Oncology, edited by Howard L. Handbook of Anticancer Pharmacokinetics and
Kaufman, Scott Wadler, and Karen Antman, 2007 Pharmacodynamics, edited by William D. Figg
In Vivo Imaging of Cancer Therapy, edited by and Howard L. McLeod, 2004
Anthony F. Shields and Patricia Price, 2007 Anticancer Drug Development Guide: Preclinical
Cytokines in the Genesis and Treatment ofCancer, edited Screening, Clinical Trials, and Approval, Second
by Michael A. Caligiuri, Michael T. Lotze, and Edition, edited by Beverly A. Teicher and Paul A.
Frances R. Balkwill, 2007 Andrews, 2004
Regional Cancer Therapy, edited by Peter M. Schlag and Handbook of Cancer Vaccines, edited by Michael A.
Ulrike Stein, 2007 Morse, Timothy M. Clay, and Kim H. Lyerly, 2004
Gene Therapy for Cancer, edited by Kelly K. Hunt, Drug Delivery Systems in Cancer Therapy, edited by
Stephan A. Vorburger, and Stephen G. Swisher, Dennis M. Brown, 2003
2007 Oncogene-Directed Therapies, edited by Janusz Rak, 2003
Deoxynucleoside Analogs in Cancer Therapy, edited by Cell Cycle Inhibitors in Cancer Therapy: Current
Godefridus J. Peters, 2006 Strategies, edited by Antonio Giordano and
Cancer Drug Resistance, edited by Beverly A. Teicher, 2006 Kenneth J. Soprano, 2003
Histone Deacetylases: Transcriptional Regulation and Chemoradiation in Cancer Therapy, edited by Hak
Other Cellular Functions, edited by Eric Verdin, Choy, 2003
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Immunotherapy ofCancer, edited by Mary L. Disis, 2006 M. Rustum, 2003
Biomarkers in Breast Cancer: Molecular Diagnostics Targetsfor Cancer Chemotherapy: Transcription Factors
for Predicting and Monitoring Therapeutic Effect, and Other Nuclear Proteins, edited by Nicholas
edited by Giampietro Gasparini and Daniel F. B. La Thangue and Lan R. Bandara, 2002
Hayes, 2006 Tumor Targeting in Cancer Therapy, edited by Michel
Protein Tyrosine Kinases: From Inhibitors to Useful Page, 2002
Drugs, edited by Doriana Fabbro and Frank Hormone Therapy in Breast and Prostate Cancer, edited
McCormick, 2005 by v: Craig Jordan and Barrington J. A. Furr, 2002
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2005 Tumor Suppressor Genes in Human Cancer, edited by
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LaRochelle and Richard A. Shimkets, 2005 Matrix Metalloproteinase Inhibitors in Cancer Therapy,
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Thomas G. Burke and Val R. Adams, 2005 Appelt, 2001
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Potentiators, edited by Gary K. Schwartz, 2005 M. Sebti and Andrew D. Hamilton, 2001
ii
TRANSFORMING
GROWTH FACTOR-P
IN CANCER THERAPY,
VOLUME II
CANCER TREATMENT AND THERAPY
Edited by
SONIA B. JAKOWLE~ PhD
Cancer Training Branch, Office ofCenters, Training and Resources,
National Cancer Institute, Bethesda, MD
Foreword by
CARL-HENRIK HELDIN, PhD
Ludwig Institute for Cancer Research,
Uppsala University, Uppsala, Sweden
~\I', H P
-"1\:: umana ress
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IN MEMORIAM
All of us in the transforming growth factor-f (TGF-J3) research community were
deeply saddened to learn of the death of Anita B. Roberts on May 26, 2006. Ironically,
Anita died from cancer, a disease that is now closely linked to the peptide growth factor
she and her colleagues discovered in the early 1980s and that will forever be associated
with her name. As I reflect on her life and her contributions to science, three memories
stand out that I believe illustrate the extraordinary person that Anita was.
I first met Anita in Mike Sporn's office at the NCI in the summer of 1984. I was a
young scientist working for a biotechnology company in the Bay Area of California.
Our research team had discovered two growth factors, designated Chondrogenic
Induction Factors A and B (CIF-A and CIF-B), that appeared to be highly related to a
growth factor called TGF-J3 that had been recently purified and characterized by Anita.
Several of my colleagues and I met with Mike and Anita to share our data with them
and to discuss how we might collaborate to more clearly elucidate the relationships
between TGF-J3, CIF-A, and CIF-B. Eventually we determined that CIF-A was TGF-J31
and CIF-B was TGF-J32. I clearly remember in my first meeting with Anita, her high
levels of intensity, inquisitiveness, and energy. I was also struck by her scientific rigor
and attention to detail. These were professional characteristics that would become
hallmarks of her scientific career during the next 22 years.
A second memory I have of Anita was related to a Wound Healing Society meeting
we attended together in the early 1990s in Richmond, Virginia. One evening, several of
us ended up in a "drinking establishment" listening to a Blue Grass band. Late in the
evening, Anita and I walked back to the hotel where we were staying, when I asked her
about her family, since all we ever seemed to talk about was science. Anita told me that
she married her husband Bob whom she had first met when she was a freshman in
high school. It was clear to me that she loved her husband and children very much and
was very proud of their accomplishments. It was refreshing for me to see someone who was
both successful in the pursuit of their career and, at the same time, so committed to their
family life.
One of my final memories of Anita was at the 2005 Keystone Symposium on TGF-J3
that Anita, Mike Sporn, and I had co-organized. Shortly after the three of us had agreed
to organize the meeting, Anita was diagnosed with gastric carcinoma. I was stunned by
the news and remember lying awake that night trying to imagine how Anita must feel.
Given her prognosis, I thought it was unlikely she would survive the next 12 months to
even attend the meeting. Much to my amazement, not only did Anita attend, but she sat
with me during the entire meeting completely immersed in the science and reminiscing
about how the TGF-J3 field had progressed during the past 25 years. Anita's attendance
at that meeting and another TGF-J3 meeting held in San Diego in February, 2006,
symbolized her incredible courage, determination, and perseverance.
Anita was truly a remarkable individual. She exhibited an unusual balance of scientific
brilliance and humility. She was a very caring and loving person who changed the lives
of many of the people she touched. For those of us working in the field of TGF-J3, her
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vi In Memoriam
death is a terrible loss. On the other hand, Anita would want us to "press on," to explore
the unknown and determine whether this growth factor she discovered 25 years ago is
a valid therapeutic target for diseases like cancer and pathological fibrosis. This will
continue to be a difficult mission, but remembering Anita's personal and professional
qualities should fortify our efforts and sustain us when we are discouraged. Although
Anita is no longer with us, her indomitable spirit lives on to provide us inspiration
and hope.
John M McPherson, PhD
FOREWORD
Transforming Growth Factor-B in Cancer Therapy, Volume II:
Cancer Treatment and Therapy
The chapters in this volume confer an abundance of knowledge about the current
state of our understanding of transforming growth factor-B (TGF-B) in cancer treatment
and therapy. Unlike several more traditional positive polypeptide growth factors that stim-
ulate cellular proliferation, the prototypical TGF-B is now known to inhibit the growth
of most normal cell types, including those of epithelial and mesenchymal origin. However,
there are examples of cell types that can be stimulated by TGF-B under certain conditions.
TGF-B also induces the accumulation of matrix molecules by stimulating their synthesis
as well as inhibiting their degradation. Moreover, TGF-B induces apoptosis of certain
cell types, thereby restricting their proliferation. Overactivity ofTGF-~ has been linked to
several diseases. For instance, the effect of TGF-~ on matrix accumulation contributes
to fibrotic conditions, like glomerulonephritis, lung fibrosis and liver cirrhosis (1).
TGF-~ has a very complicated role in cancer that is only beginning to be understood.
Initially, TGF-~ is a tumor suppressor since it inhibits the growth of most cell types and
induces apoptosis. However, at later stages of tumorigenesis, TGF-~ has tumor promoting
effects (2). TGF-~ is often produced at high amounts in advanced tumors and such tumor
cells often acquire resistance against the growth inhibitory effects ofTGF-~. TGF-~ also
induces epithelial-to-mesenchymal transition (EMT) which correlates with increased
invasiveness and metastasis (3). Moreover, TGF-B has effects on normal cell types of
tumors which also contribute to tumor progression; it inhibits the immune system and
thereby suppresses the immune surveillance of tumors, and promotes angiogenesis which
is needed for tumor growth. Importantly, high levels of TGF-B have been shown to cor-
relate to poor prognosis for patients with advanced forms of breast cancer, colorectal
cancer, prostate cancer and lung cancer (4).
The present volume contains 46 chapters, which start with a series of 17 informative
chapters that characterize the roles of TGF-~ in different types of developing and
advanced cancers in detail. Next, the reader will have the opportunity to review recent
exciting developments of TGF-~ in cancer treatment and therapy in a full 17 chapters.
The concluding stimulating 12 chapters deal with the development of inhibitors of
TGF-~ signaling for therapy and summarize the current status of this interesting and
rapidly moving field of research.
Thus, the reader will have an opportunity to enjoy an overview of the intriguing role
ofTGF-~ in cancer treatment and therapy. The well-established tumor promoting effect of
TGF-~ in advanced cancers makes TGF-~ signaling antagonists attractive targets for the
development of effective drugs for the treatment of cancer patients. Possible types of
TGF-~ antagonists that may be clinically useful include monoclonal antibodies against
TGF-~ itself or its receptors, soluble forms of the extracellular part of the TGF-~ type II
receptor, which bind and trap the ligand, and low molecular weight compounds, which
inhibit the kinases of TGF-~ type I or type II receptors (1,4). The first generation of
such inhibitors is now available and is being used in tumor models in animals. Some
vii
viii Foreword
encouraging results have already been obtained and are described in some of the
contributing chapters in this volume.
The challenge in the attempt to use TGF-p antagonists in tumor treatment is the fact
that TGF-p has both tumor suppressing and tumor promoting effects. Thus, too efficient
TGF-p inhibition, which obliterates the inhibitory effect of TGF-p on cell growth and
its stimulatory effect on apoptosis, could increase the risk of tumor development. This
risk would be low if there is a difference in dose-dependency for the tumor promoting
and tumor suppressing effects of TGF-p, and if the tumor promoting effects could be
blocked by a partial inhibition of TGF-p signaling, which does not inhibit the tumor
suppressive effects. Whether there is such a difference in dose-dependency remains to
be explored. Alternatively, there is a need to develop more selective TGF-p antagonists
that inhibit only the tumor promoting effects of TGF-p, such as EMT, while leaving the
growth suppressive effects, such as growth inhibition and apoptosis, unperturbed. It is
known that Smad molecules are important both for the tumor suppressive effects
(growth inhibition) and tumor promoting effects (EMT) (1). However, whether it will
be possible to develop inhibitors that antagonize only certain Smad interactions, but not
other interactions, remains to be determined. Moreover, before efficient selective inhibitors
can be developed, we need to learn more about which Smad interactions and other sig-
naling pathways mediate the various effects of TGf-B (5-8). In addition, before we know
whether TGF-p antagonists will be clinically useful, a lot of work remains to be done
for the development and validation of suitable TGF-p antagonists. Thus, the present
volume confers a feast of knowledge about recent advancements in the role of TGF-p
in cancer treatment and therapy, and the reader will be treated to new developments that
are likely to lead to more interesting and exciting treatment and therapy possibilities
in the future.
Carl-Henrik Heldin, PhD
Ludwig Institute for Cancer Research,
Uppsala University, Uppsala, Sweden
REFERENCES
1. Laping NJ, Huet S. TGF-~ receptor kinase inhibitors for treatment of fibrosis. In: Smad signal trans-
duction: Smads in proliferation, differentiation and disease. ten Dijke P and Heldin C-H, eds Springer
Verlag, 2006, pp 443-459.
2. Akhurst RJ, Derynck R. TGF-beta signaling in cancer-a double-edged sword. Trends Cell Biol
2001;II:S44-S51.
3. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. CUff Opin Cell Biol
2003;15:740-746.
4. Lahn M, Berry B, Kloeker S, Yingling JM. TGF-~ receptor kinase inhibitors for the treatment of
cancer. In: Smad signal transduction: Smads in proliferation, differentiation and disease. ten Dijke P
and Heldin C-H, eds Springer Verlag, 2006, pp 415-442.
5. Massague J. How cells read TGF-~ signals. Nat Rev Mol Cell Bioi 2000;1:169-178.
6. Derynck R, Zhang YEo Smad-dependent and Smad-independent pathways in TGF-~ family signalling.
Nature 2003;425:577-584.
7. ten Dijke P, Hill CS. New insights into TGF-~-Smad signalling. Trends Biochem Sci 2004;29:265-273.
8. Moustakas A, Heldin C-H. Non-Smad TGF-~ signals. J Cell Sci 2005;118:3573-3584.
PREFACE
The transforming growth factor-f (TGF-~) superfamily of secreted signaling proteins
shows high conservation among eukaryotes. This superfamily is composed of proteins that
regulate cell fate in development and homeostasis including tissue remodeling, histogenesis
and maintenance of epithelial homeostasis. TGF-~ was originally named for its ability to
induce malignant behavior of normal fibroblasts and it was proposed that TGF-~ might
playa role in uncoupling a cell from normal growth control. Paradoxically, TGF-~ exhibits
a ubiquitous pattern of expression in normal developing and adult tissues, and unlike most
polypeptide growth factors, TGF-~ is produced by, and can act on, nearly every cell type.
Numerous studies have established that the TGF-~ signaling mechanism begins with TGF-~
ligand binding to TGF-~ receptors that causes receptor serine/threonine kinases to phos-
phorylate and activate receptor-regulated Smads, and/or initiate non-Smad signaling
through activation of mitogen-activated protein kinases, phosphatidylinositol 3-kinase and
other mediators. The receptor-regulated Smads heterooligomerize with the common Smad,
Smad4, before translocating to the nucleus, where they regulate gene expression. Mutations
and epigenetic dysregulation of TGF-~ signaling mechanisms occur commonly in major
human diseases including cancer, fibrosis, and immune and vascular diseases. The TGF-~
signaling system controls a wide range of cellular functions that depend on cell type
and physiological or patho-physiological context. In epithelial cells, TGF-~ may play
several roles including inhibition of cell growth, initiation of apoptosis and induction of
epithelial to mesenchymal transition. In contrast, the effects ofTGF-~ on cellular growth
and apoptosis in stromal fibroblasts are minor compared with its potent ability to stimulate
cell-matrix adhesion and matrix remodeling and promotion of cell motility. Elucidation of
cell type- and context-dependent molecular signaling mechanisms that control the varia-
tions in functional specificity of TGF-~ signaling is extremely important in understanding
key processes that occur in normal development and homeostasis and how these processes
change in cancer and disease. With the discovery that TGF-~ is a potent growth inhibitor
of epithelial cells and the identification of inactivating mutations within the TGF-~
signaling pathway in cancer, it has become clear that the TGF-~ signaling system is a
tumor suppressor pathway in early stages of cancer progression. However, many human
cancers show increased expression of TGF-~ that is associated with poor patient prognosis
and increased frequency of metastasis. The stage-specific duality of multifunctional TGF-~
is the emerging paradigm for the role of TGF-~ in cancer and disease and the mechanism
by which the switch of TGF-~ from heroic tumor suppressor to villainous pro-oncogene
occurs is the subject of intense investigation. New therapeutic opportunities may emerge
from a clearer understanding of the molecular and cellular contexts that permit the tumor
suppressor versus oncogenic activities of TGF-~.
It has been nearly 25 years since TGF-~ was discovered and several thousand articles
have been published about the role of TGF-~ in normal and tumor cells. During the
same time, there has been a large increase in our understanding of TGF-~ in cancer and
disease. There has also been a significant change in the general direction of therapeutics'
discovery and development. Both protein therapeutics and small molecule therapeutics are
now described as being molecularly targeted. It is time to review the field of TGF-~ in
cancer and cancer therapy in the post-genomic, molecularly targeted era.
ix