|
Current Cancer
Therapy Reviews
ISSN: 1573-3947
Current Cancer Therapy Reviews
Volume 3, Number 1, February 2007
Contents
Transcription Factors as Targets for Cancer Therapy:
AP-1 a Potential Therapeutic Target Pp.
1-6
Virna D. Leaner, Howard Donninger and Michael J. Birrer
[Abstract] [Full
Text Article]
Cellular Senescence as a Target in Cancer Control
Pp. 7-15
Amancio Carnero
[Abstract] [Full
Text Article]
The HOX Gene Network as a Potential Target for Cancer
Therapy Pp. 17-24
Monica Cantile, Giulia Schiavo, Luigi Terracciano and
Clemente Cillo
[Abstract] [Full
Text Article]
Molecular and Genetic Profiling of Prostate Cancer:
Implications for Future Therapy Pp. 25-36
Gregory Saia, Min Zhang, Vincent Depalo, Tim Lautenschläger
and Arnab Chakravarti
[Abstract] [Full
Text Article]
Haploidentical Stem Cell Transplantation in Childhood
Pp. 37-44
Peter Bader, Andre Willasch, Dietrich Niethammer and Thomas
Klingebiel
[Abstract] [Full
Text Article]
A Review of the Use of Stents for Palliation of Esophageal
and Lung Cancer Pp. 45-60
Costas S. Bizekis, Harvey I. Pass and Michael D. Zervos
[Abstract] [Full
Text Article]
The Role of Antioxidant Enzymes in the Growth of Pancreatic
Carcinoma Pp. 61-65
Nazee Jabbari and Joseph J. Cullen
[Abstract] [Full
Text Article]
Aromatase Inhibitors for Treatment of Breast Cancer
Pp. 67-79
John R. Benson and Oduru Ravisekar
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Transcription Factors as Targets for Cancer Therapy: AP-1
a Potential Therapeutic Target
Virna D. Leaner, Howard Donninger and Michael J. Birrer
[Full
Text Article]
The field of cancer therapy is rapidly moving forward
with the development of numerous prospective new agents designed
to inhibit cellular factors involved in signal transduction,
cell proliferation, and the onset of apoptosis. At the core
of these biological processes are transcription factors that
are the functional mediators of these effects. Transcription
factors are the downstream targets of numerous signal transduction
pathways that are central to the process of carcinogenesis.
The Activator Protein-1 (AP-1) complex is one such factor
that has a central role in multiple processes involved in
tumorigenesis including proliferation, migration, invasion
and metastasis. The focus of this review is, using AP-1 as
a model, to discuss transcription factors as targets for cancer
therapy. The feasibility of targeted disruption of AP-1 by
various agents such as dominant-negative mutants, small molecule
inhibitors, transcription factor decoys (TFD), chemotherapeutic
drugs, chemoprevention agents, siRNA and natural products
will be explored.
[Back to top]
Cellular Senescence as a Target in Cancer Control
Amancio Carnero
[Full
Text Article]
Somatic cells show a spontaneous decline in growth rate in
continuous culture. This is not related to elapsed time but
to an increasing number of population doublings, eventually
terminating in a quiescent but viable state, termed replicative
senescence. These cells are commonly multinucleated and
do not respond to mitogens or apoptotic stimuli. Cells displaying
characteristics of senescent cells can also be observed in
response to other stimuli, such as oncogenic stress, DNA damage
or cytotoxic drugs, and have been reported to be found in
vivo. Most tumors show unlimited replicative potential,
leading to the hypothesis that cellular senescence is a natural
antitumor program. Recent findings suggest that cellular senescence
is a natural mechanism to prevent undesired oncogenic stress
in somatic cells that has been lost in malignant tumors. Given
that the ultimate goal of cancer research is to find the definitive
cure for as many tumor types as possible, exploration of cellular
senescence to drive towards antitumor therapies may decisively
influence the outcome of new drugs. In the present work we
will review the potential of cellular senescence to be used
as target for anticancer therapy.
[Back to top]
The HOX Gene Network as a Potential Target for Cancer
Therapy
Monica Cantile, Giulia Schiavo, Luigi Terracciano and
Clemente Cillo
[Full
Text Article]
Although Hox genes have been identified as master regulatory
genes controlling embryonic development, an alternative view
on the role of the Hox gene network suggests that it regulates
crucial processes at cellular level in eukaryotic organisms.
The Hox network acts at the nuclear cell level as a decoding
system for external inductive signals to activate specific
genetic programs. Cancer can be considered as an anomalous
structure growing inside the human body and following, from
an architectural viewpoint, the rules controlling body shape
as occurs during embryonic development. As a consequence of
this viewpoint, it has been proposed that the whole HOX gene
network is involved in controlling phenotype cell identity
and three-dimensionality of tissues and organs and, furthermore,
that specific HOX genes or groups of genes are implicated
in the neoplastic alterations of organs and tissues such as
kidney, colon, lung, skin, bladder, breast, prostate. Despite
our limited understanding of the mechanisms involved, it has
already been possible to identify the specific HOX genes perturbed
in certain types of human cancers with greater benefit for
cancer patients than for better known oncogenes. Here we foresee
the start of clinical trials with the purpose of targeting
specific HOX genes in order to achieve a therapeutic effect
in cancer patients.
[Back to top]
Molecular and Genetic Profiling of Prostate Cancer:
Implications for Future Therapy
Gregory Saia, Min Zhang, Vincent Depalo, Tim Lautenschläger
and Arnab Chakravarti
[Full
Text Article]
Prostate cancer is predicted to be the most common cancer
diagnosed in American men in 2006 with an estimated 230,000
new cases in the United States alone [1]. It is likely to
result in over 27,000 deaths in 2006, and the average male
will have a one in six chance of developing this malady in
his lifetime [1]. These statistics illustrate the need to
have screening and treatment systems in place that possess
both a high degree of sensitivity as well as proven effectiveness.
With the recent strides made in the field of molecular and
cellular biology, it is now possible to analyze and tailor
treatments to an individual’s tumor. As the methods
of analysis become more refined, researchers are better able
to sift through the vast amounts of data and hone in on promising
new targets. Molecular prognostic markers are already beginning
to appear as a result of modern genomic analysis, and more
are on the way. These markers are appearing in a variety of
pathways including signal transduction, apoptosis, cell cycle
regulation, angiogenesis, and cell adhesion. The emergence
of viable prognostic markers indicative of specific tumor
types holds the potential of greatly improving cancer screening
methods as well as overall patient survival.
[Back to top]
Haploidentical Stem Cell Transplantation in Childhood
Peter Bader, Andre Willasch, Dietrich Niethammer and Thomas
Klingebiel
[Full
Text Article]
Allogeneic stem cell transplantation has become an important
treatment option for many children with malignant and non
malignant diseases during the past decades. However, this
therapy was for a long time restricted to patients having
an “HLA identical donor”. In most recent years
donor registries all over the world have extended and the
numbers of registered volunteers have substantially increased
during the last 20 years. In spite of this progress, there
is still a substantial number of children lacking a well matched
donor. Virtually all little patients have at least one “haploidentical”
parent who could potentially serve as a stem cell donor. These
donors are immediately available, are highly motivated and
could be asked for a further time if the graft would have
been rejected. In the post transplant course parents are repeatedly
available for additional donor cell transfusions for preemptive
immunotherapy. Moreover using haploidentical parents as donors
can avoid the inauguration of new registries and banking expenditures
in countries whose population is not very much represented
in existing large donor registries. For long years, graft
rejection, graft versus host disease (GVHD) and delayed recovery
of the immune system used to be the limiting factors for haploidentical
transplantation. Substantial progress has been made in the
clinical application of haploidentical stem cell transplantation
in children with leukemia as well as non malignant diseases
in the last years. Recurrence of the underlying disease and
delayed immune recovery, however, remained major cause for
treatment failure yet to overcome to offer this procedure
to a wider range of patients. Nevertheless, haploidentical
stem cell transplantation has become a valuable alternative
procedure for patients lacking an HLA identical donor. The
development and recent advance is reviewed in the following.
[Back to top]
A Review of the Use of Stents for Palliation of Esophageal
and Lung Cancer
Costas S. Bizekis, Harvey I. Pass and Michael D. Zervos
[Full
Text Article]
According to the American Cancer Society, there will be an
estimated 14,520 new cases of esophageal cancer and 174,470
new cases of lung cancer in 2005 [1]. Close to 60% of these
patients with esophageal cancer will present at an advanced
stage not amenable to cure, but still will require palliation
of their dysphagia [2].
Conventional plastic stents (CPS) were used initially, and
with continuous improvement in technology, insertion of self-expanding
metal stents (SEMS) has become the palliative treatment of
choice in the majority of these patients [3-7]. SEMS are effective
in palliating malignant dysphagia in 85%-100% of patients
[7-9]. More recently, a new self-expanding plastic stent (SEPS)
has been designed which in early studies has been very effective
in palliating dysphagia [10-13].
Similarly, the majority of patients with lung cancer will
present at an advanced stage and approximately 20% of these
patients will have an endobronchial component requiring some
form of palliation for relief of airway obstruction [14].
Currently airway stents are either made of self-expanding
metal for more permanent use, or silicone if a more temporary
solution is needed. Complications similar to the esophageal
stents may arise.
The purpose of this article is to provide an evidence based
review of stents in the palliative setting for esophageal
and lung cancer and briefly explore their potential use and
expanding indications in the neoadjuvant setting.
[Back to top]
The Role of Antioxidant Enzymes in the Growth of Pancreatic
Carcinoma
Nazee Jabbari and Joseph J. Cullen
[Full
Text Article]
Adenocarcinoma of the pancreas is the fourth leading cause
of cancer death in the United States. Because of the poor
therapeutic responsiveness of pancreatic cancer to surgery,
chemotherapy, and radiation therapy, survival beyond five
years is rare with median survival less than six months.
K-ras mutations have been identified in up to 95% of
pancreatic cancers, implying their critical role in the molecular
pathogenesis. Ras overexpression leads to increased
production of reactive oxygen species (ROS) through activation
of the NADPH oxidase system resulting in downstream propagation
of mitogenic signaling leading to cell growth and tumor progression.
The superoxide dismutases (SOD) convert O2.- into
H2O2. Extracellular SOD (ECSOD) is the
only isoform of SOD that is expressed extracellularly, manganese-containing
superoxide dismutase (MnSOD) is localized in the mitochondria,
and copper- and zinc-containing superoxide dismutase (CuZnSOD)
in the cytoplasm. The catalases and peroxidases convert H2O2
into water. Catalase is located in peroxisomes and cytoplasm
and peroxidases are in many subcellular compartments. Antioxidant
enzymes that scavenge specific ROS have inhibited the in
vitro and in vivo growth of pancreatic cancer.
Additionally, food-derived polyphenols, which may act by scavenging
reactive oxygen species, can also inhibit pancreatic cancer
growth. This review will concentrate on the sophisticated
antioxidant defense system, which may shed insight into the
etiology, diagnosis, and treatment of pancreatic cancer.
[Back to top]
Aromatase Inhibitors for Treatment of Breast Cancer
John R. Benson and Oduru Ravisekar
[Full
Text Article]
Breast cancer remains the commonest malignancy amongst women
and its incidence continues to increase worldwide. This inexorable
rise in numbers of women suffering from the disease is particularly
notable in those countries which previously had a relatively
low incidence of breast cancer but have now adopted Western
lifestyles with changes in reproductive behaviour and greater
usage of the oral contraceptive pill. These epidemiological
observations emphasize the hormone dependency of breast cancer
and the importance of endocrine factors for tumour initiation
and promotion. There has been a resurgence of interest in
hormonal therapies with the advent of third generation aromatase
inhibitors (AI) which represent the most significant advance
in endocrine management of breast cancer since the introduction
of tamoxifen 3 decades ago.
This article will recount the historical development of endocrine
therapies and the biological rationale for hormonal manipulation
as a therapeutic goal. The application of AI’s in the
clinical setting will be critically discussed with citation
of seminal studies. Like many novel agents for treatment of
breast cancer, AI’s were initially used in the advanced
disease setting where they offered advantages over tamoxifen
and progestins as first- and second-line therapies respectively.
Aromatase inhibitors are widely used in the neoadjuvant setting
for hormone sensitive tumours and can permit subsequent breast
conservation surgery when mastectomy would otherwise have
been indicated. However, it is in the adjuvant setting that
AI’s have stimulated much interest and generated an
element of uncertainty in the optimum form of adjuvant hormonal
therapy for post-menopausal women with oestrogen receptor
positive tumours. It seems likely that any blanket policy
is no longer appropriate and a selective strategy with tailoring
of therapy based on risk of relapse is the preferred option.
Those patients at greatest risk of relapse may benefit most
from an upfront AI whilst those with lower hazard rates for
relapse may be best treated with an ‘early switch’
regimen involving tamoxifen for 2 – 3 years followed
by an AI for a total duration of 5 years. Benefits in terms
of disease-free and overall survival must be balanced against
longer term adverse effects on bone health and cognitive function
as well as cost. Some patients at very low risk of relapse
may derive minimal additional benefit from incorporation of
an AI into their treatment schedule and should receive tamoxifen
only.
The three oral AI’s are of comparable efficacy and are
potentially interchangeable. Longitudinal studies must be
undertaken with gathering of longer term data on side-effect
profiles before any definitive pronouncements on clinical
utility. There are particular concerns about severe oestrogen
depletion amongst women receiving an AI for chemoprevention
and ongoing evaluation of treatment related morbidity is essential.
|
