Current Cancer
Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 7, Number 3, May 2007
Contents
Glycogen Synthase Kinase-3 Beta; A New Target in Pancreatic
Cancer? Pp. 209-215
G. Garcea, M.M. Manson, C.P. Neal, C.J. Pattenden, C.D.
Sutton, A.R. Dennison and D.P. Berry
[Abstract]
Metastasis-Associated Protein S100A4: Spotlight on
its Role in Cell Migration Pp. 217-228
S. Tarabykina, T.R.L. Griffiths, E. Tulchinsky, J.K. Mellon,
I.B. Bronstein and M. Kriajevska
[Abstract]
Cancer Vaccines for Hormone/Growth Factor Immune Deprivation:
A Feasible Approach for Cancer Treatment Pp. 229-241
G. González and A. Lage
[Abstract]
Non-Homologous DNA End Joining in Anticancer Therapy
Pp. 243-250
Elzbieta Pastwa and Mariusz Malinowski
[Abstract]
The Kinase Inhibitor Imatinib – An Immunosuppressive
Drug? Pp. 251-258
D. Wolf, H. Tilg, H. Rumpold, G. Gastl and A.M. Wolf
[Abstract]
MUC1 is a Promising Therapeutic Target for Prostate
Cancer Therapy Pp. 259-271
Y. Li and P.J. Cozzi
[Abstract]
Current Status and Future of Target-Based Therapeutics
Pp. 273-284
Ryoko Suzuki, Parijatha Rao and Shiro Sasaguri
[Abstract]
Conditionally Replicating Adenoviruses for Cancer
Treatment Pp. 285-301
Youssef Jounaidi, Joshua C. Doloff and David J. Waxman
[Abstract]
Abstracts
[Back to top]
Glycogen Synthase Kinase-3 Beta; A New Target in Pancreatic
Cancer?
G. Garcea, M.M. Manson, C.P. Neal, C.J. Pattenden, C.D.
Sutton, A.R. Dennison and D.P. Berry
Glycogen synthase kinase (GSK) was initially described as
a key enzyme involved in glycogen metabolism. However, since
that time it has been found to regulate a diverse range of
cell functions. In addition to having a major role in the
regulation of the important onco-protein β-catenin,
GSK is also a critical regulator of NF-κB.
NF-κB
comprises a family of transcription factors which activate
the expression of a wide array of genes involved in inflammation,
tumourigenesis, metastasis, differentiation, embryonic development,
apoptosis . Inflammation mediated by the NF-κB
family has been implicated in the initiation of pancreatic
cancer, resistance to chemotherapy and the development of
the debilitating cancer cachexia seen with advanced disease.
Hence, GSK has potential as an important new target both in
the treatment of resectable pancreatic cancer as an adjuvant
to surgery, and in the palliation of inoperable tumours.
[Back to top]
Metastasis-Associated Protein S100A4: Spotlight on
its Role in Cell Migration
S. Tarabykina, T.R.L. Griffiths, E. Tulchinsky, J.K. Mellon,
I.B. Bronstein and M. Kriajevska
S100A4 (also known as Mts1, metastasin, p9Ka,
pEL98, CAPL, calvasculin, Fsp-1, placental calcium-binding
protein) belongs to the family of EF-hand calcium-binding
proteins, whose expression is elevated in a number of pathological
conditions. Although it is well documented that S100A4 is
expressed in cancer cells and contributes to tumor cell motility
and metastatic progression, the exact underlying mechanisms
remain elusive.
An important characteristic feature of S100 proteins is their
dual function, inside and outside the cell. In this review,
we focus on the intracellular function of S100A4.
The review contains structural analysis of S1004 in comparison
with other members of S100 proteins. Possible modes of the
interaction of S100 proteins with targets are described.
Several examples of best-studied molecular interactions involving
S100A4 with heavy chain of nonmuscle myosin IIA, LAR-interacting
protein liprin β1
and tumor suppressor protein p53 are provided. We suggest
that the binding of S100A4 to these molecules is critical
for the S100A4 function. Further studies of the implications
of these interactions in different molecular pathways may
shed additional light on the role of S100A4 protein in the
control of tumor cell motility and migration.
We discuss the approaches for down-regulation of S100A4 expression
and their potential for application in the clinics.
[Back to top]
Cancer Vaccines for Hormone/Growth Factor Immune Deprivation:
A Feasible Approach for Cancer Treatment
G. González and A. Lage
One of the older and most validated cancer treatments is endocrine
therapy. Some tumors are dependent on hormone stimulation
for growth, and therefore therapeutic interventions aiming
to deprive the cells of the hormone are feasible and have
been successful. Tumor growth also depends in some cases on
growth factors, so that the concept of hormone-dependence
can be extended to growth factors deprivation.
Hormone deprivation has been therapeutically achieved up to
now by surgical, radiation and chemical means. However, the
immune system usually can be manipulated to recognize hormones
and growth factors, and in fact some autoimmune diseases exists
involving autoantibodies against hormones. The idea of inducing
a deprivation of hormones and growth factors by active immunizations
is appealing, and initial evidence about the feasibility of
this approach is starting to appear in the literature. Clinical
trials have been initiated using immunization with human chorionic
gonadotrophin (hCG), gastrin, luteinizing hormone releasing
hormone (LHRH) / gonadotropin releasing hormone (GnRH) and
epidermal growth factor (EGF). Preliminary data already show
that antibody titers can be elicited, which results in a decrease
in the concentration of a given hormone or growth factor.
Both the antibody titers and the decrease in the hormone level
are related to survival.
This immunological approach for hormone and growth factor
deprivation creates the possibility of chronic management
of advanced cancer patients.
[Back to top]
Non-Homologous DNA End Joining in Anticancer Therapy
Elzbieta Pastwa and Mariusz Malinowski
Non-homologous DNA end joining (NHEJ) is the major pathway
for the repair of double-strand breaks (DSBs) in human cells.
Proteins involved in NHEJ pathway can become molecular targets
in the treatment of cancer. Inhibition of this pathway leads
to radio- and chemosensitization of cancer cells. This review
will focus on the new therapeutic strategies for NHEJ pathway
inhibition and their application in anticancer therapy.
[Back to top]
The Kinase Inhibitor Imatinib – An Immunosuppressive
Drug?
D. Wolf, H. Tilg, H. Rumpold, G. Gastl and A.M. Wolf
The phenylaminopyrimidine-derivate Imatinib mesylate has been
developed for targeted inhibition of the Abelson kinase (c-ABL),
which is constitutively activated when translocated to the
genetic locus of the breakpoint cluster region (leading to
the BCR/ABL fusion gene), thereby forming the causative pathogenetic
event for the development of chronic myeloid leukemia (CML).
Of note, due to its physico-chemical properties, kinase specificity
of Imatinib is limited. Despite of its well documented clinical
efficacy mediated by inhibition of constitutively activated
tyrosine kinases such as BCR/ABL in CML, PDGF-RA in HES and
mutated c-kit in GIST patients, other tyrosine kinases such
as Flt-3, Lck and mitogen-activated kinases (MAPK) are affected
as well. Accordingly, it has recently been shown that therapeutic
doses of Imatinib also target a variety of immune cells, e.g.
by modulating the differentiation of dendritic cells (DC)
as well as by impeding proper T-cell and macrophage function.
In contrast, combining Imatinib with Interleukin 2 (IL-2)
potently activates NK-cells and led to the description of
a new subclass of DC, so-called IK-DC. The latter mediate
Imatinib/IL-2-induced regression of tumors in pre-clinical
animal models via production of high amounts of IFN-γ
and the death receptor ligand TRAIL. Thus, Imatinib exerts
potent immuno-modulatory effects in vitro and in
vivo, which will be discussed together with their clinical
relevance in detail throughout this review.
[Back to top]
MUC1 is a Promising Therapeutic Target for Prostate
Cancer Therapy
Y. Li and P.J. Cozzi
Prostate cancer (CaP) is one of the most common malignancies
in men, and the incidence of CaP is increasing. Because of
the limitations of current therapeutic approaches, many patients
die of secondary disease (metastases). Mucins are used as
diagnostic markers as well as therapeutic targets due to their
aberrant and unique expression pattern during cancer progression.
There is a growing interest in mucins as treatment targets
in human malignancies, including CaP. So far, 21 mucin genes
have been identified. Of these, MUC1 has been investigated
most extensively. In neoplastic tissues, MUC1 is underglycosylated
compared with that in normal tissues. The reduced glycosylation
permits the immune system to access the peptide core of the
tumor-associated underglycosylated MUC1 antigen (uMUC1) and
reveal epitopes that are masked in the normal cell. This feature
makes it possible to design an antibody that discriminates
between normal and adenocarcinoma cells and target tumor-associated
MUC1 with toxins or radionuclides, or use a vaccine targeting
tumor-associated MUC1 antigen. The results from our recent
study have shown that over-expression of MUC1 plays a very
important role in CaP progression and MUC1 is an ideal target
for targeted therapy to control micrometastases and hormone
refractory disease. This review will cover our current understanding
of the structure and functions of MUC1, summarize its expression
on human CaP tissues and focus on the MUC1-based immunotherapy
for control of metastatic CaP.
[Back to top]
Current Status and Future of Target-Based Therapeutics
Ryoko Suzuki, Parijatha Rao and Shiro Sasaguri
With the beginning of the 21st
century, a new and exciting era for cancer therapy has begun
with the appearance of molecular targeted drugs. Numerous
drugs for chemotherapy have been discovered following careful
screening of natural and synthetic components. After screening,
candidate chemotherapy drugs are examined to determine if
they have sufficiently cytotoxic to function as an anti-tumor
therapeutic. However, the development of molecular targeted
drugs is based on more logical methodologies. First, the target
is determined then a search is conducted for molecules able
to inhibit the target molecule.
Some molecular targeting drugs, such as Glivec (Imatinib,
STI571), have shown amazing effects when compared to currently
used chemotherapy drugs, whereas few others have completely
failed to inhibit tumor development in clinical trials. Thus,
an efficient method for finding effective molecular targeted
drugs is needed. An important question is whether the target
molecule is responsible for tumor growth or metastasis. In
addition, the clinical administration schedule must be suitable
for the component used. The drugs will not be completely successful
in clinical trials if any of the key points are overlooked.
Translational studies are necessary for a complete evaluation
of molecular targeted drugs and, based on the results observed
in clinical applications, the testers must return to their
basic laboratory if necessary and improve the drugs for more
advanced therapy.
In this review we discuss on the current and future status
of molecular target drugs.
[Back to top]
Conditionally Replicating Adenoviruses for Cancer
Treatment
Youssef Jounaidi, Joshua C. Doloff and David J. Waxman
Replication-conditional, oncolytic adenoviruses are emerging
as powerful tools in the warfare on cancer. The ability to
modify cell-specific infectivity or tissue-specific replication
machinery, as well as the possibility of modifying viral-cellular
protein interactions with cellular checkpoint regulators are
emerging as new trends in the design of safer and more effective
adenoviruses. The integration of oncolytic adenoviruses with
mainstream cancer therapies, such as chemotherapy and radiotherapy,
continues to yield significant therapeutic benefits. Adenoviruses
can be armed with prodrug-activating enzymes as well as tumor
suppressor genes or anti-angiogenic factors, thus providing
for enhanced anti-tumor therapy and reduced host toxicity.
Thus far, encouraging results have been obtained from extensive
preclinical and human clinical studies. However, there is
a need to improve adenoviral vectors to overcome unresolved
problems facing this promising anti-cancer agent, chief among
these issues is the adenovirus-triggered immune response threatening
its efficacy. The continued expansion of the knowledge base
of adenovirus biology will likely lead to further improvements
in the design of the ideal oncolytic adenoviruses for cancer
treatment.
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