Current Cancer
Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 6, Number 6, September 2006
Contents
Development and Assessment of Conventional
and Targeted Drug Combinations for Use in the Treatment of
Aggressive Breast Cancers Pp. 455-489
D.N. Waterhouse, K.A. Gelmon, R. Klasa, K. Chi, D. Huntsman,
E. Ramsay, E. Wasan, L. Edwards, C. Tucker, J. Zastre, Y.Z.
Wang, D. Yapp, W. Dragowska, S. Dunn, S. Dedhar and M.B. Bally
[Abstract]
Synthetic Glycopeptides from the Mucin Family
as Potential Tools in Cancer Immunotherapy Pp. 491-517
Torsten Becker, Sebastian Dziadek, Sven Wittrock and Horst
Kunz
[Abstract]
Protein Tyrosine Phosphatases, New Targets for
Cancer Therapy Pp. 519-532
David Easty, William Gallagher and D.C. Bennett
[Abstract]
Knowledge of Epigenetic Influence for Prostate
Cancer Therapy Pp. 533-551
Masatoshi Watanabe, Akimitsu Takagi, Takeshi Matsuzaki,
Daisuke Kami, Minoru Toyota, Yoshifumi Hirokawa and Taizo
Shiraishi
[Abstract]
Implications of Somatic Mutations in the AML1/RUNX1
Gene in Myelodysplastic Syndrome (MDS): Future Molecular Therapeutic
Directions for MDS Pp. 553-563
Hironori Harada, Yuka Harada and Akiro Kimura
[Abstract]
Abstracts
[Back to top]
Development and Assessment of Conventional
and Targeted Drug Combinations for Use in the Treatment of
Aggressive Breast Cancers
D.N. Waterhouse, K.A. Gelmon, R. Klasa, K. Chi, D.
Huntsman, E. Ramsay, E. Wasan, L. Edwards, C. Tucker, J. Zastre,
Y.Z. Wang, D. Yapp, W. Dragowska, S. Dunn, S. Dedhar
and M.B. Bally
Combination chemotherapy has been at the forefront of
cancer treatment for over 40 years. However, the rationale
for selecting drug combinations and the process used to demonstrate
clinical effectiveness has primarily followed trial and error
methodology. Typically, the selection and assessment of combined
drug therapies has been based on the effectiveness of each
agent as monotherapy in treating the neoplasm and avoiding
overlapping toxicities, followed by clinical trials to establish
dose scheduling, toxicity, and efficacy. Unfortunately, this
scheme is inefficient in terms of the time required to complete
and revise these clinical trials based on the outcome to optimize
the drug combination. A more rational approach for the development
of combination oncology products should consider (i) in
vitro assays for assessing therapeutic effects of drug
combinations (antagonistic, additive or synergistic interactions)
when added simultaneously; (ii) methods for measuring these
interactions in vivo; (iii) the importance of understanding
pharmacokinetic and biodistribution parameters when using
drug combinations; (iv) the need to assess pathways known
to contribute to cancer cell survival as well as metastasis;
and (iv) the need to assess the fate of different cell populations
(cancer and stroma) contributing to the development of cancer.
Therefore, the goal of this article is to provide a road map
for the preclinical development of drug combination products
that will have improved therapeutic activity and a high likelihood
of providing beneficial therapeutic outcomes in patients with
aggressive cancers with a specific focus on patients with
breast cancer.
[Back to top]
Synthetic Glycopeptides from the Mucin Family
as Potential Tools in Cancer Immunotherapy
Torsten Becker, Sebastian Dziadek, Sven Wittrock and
Horst Kunz
Compared to glycoproteins of healthy cells, glycoproteins
of tumor cells are often aberrantly glycosylated. Thus, glycopeptide
fragments of surface glycoproteins of tumor cells are of interest
as tumor-associated antigens for the distinction between normal
and tumor cells. Cancer immunotherapy directed at selectively
targeting these tumor-associated glycoprotein structure alterations
– deficient glycosylation and, thus, exposure of peptide
epitopes which are masked in normal cells – is considered
a promising approach for the treatment of cancer.
For this purpose, glycoproteins from the mucin family are
of particular interest. Mucins belong to a class of heavily
O-glycosylated, high-molecular weight glycoproteins
present on the surface of many epithelial cells. The mucin
core protein consists of numerous tandem repeats rich in serine,
threonine and proline. In their tumor-associated forms, epithelial
mucins carry cryptic saccharide structures such as TN-,
T-, sialyl-TN- and sialyl-T antigens and more complex
oligosaccharides (e.g. Lewisy). In contrast to
glycoproteins isolated from natural sources, synthetic glycopeptides
can be obtained in high purity and with exactly defined structure.
In this review, methodologies for the synthesis of mucin-type
glycopeptides containing complex tumor-associated antigen
structures are described. Due to the low immunogenicity often
exhibited by synthetic tumor-associated glycopeptide antigens,
their conjugation to carrier proteins or suitable T-cell epitopes
is essential for the development of anti-tumor vaccines. The
results of immunological evaluations of synthetic (glyco)peptides
and oligosaccharides are described. Some of these synthetic
vaccines show promising activities inducing proliferation
of T-cells and cytotoxic T-cell responses.
[Back to top]
Protein Tyrosine Phosphatases, New Targets
for Cancer Therapy
David Easty, William Gallagher and D.C. Bennett
Cellular growth and development are regulated by reversible
phosphorylation of tyrosine residues in target proteins. Protein
tyrosine phosphatases (PTPs) catalyse removal, and protein
tyrosine kinases (PTKs) the addition of phosphate. Data from
various sources support a role for PTKs in transformation
and it has long been hypothesized that some PTPs will function
as tumour suppressor genes. Specific PTPs are down-regulated
in some tumours, sometimes in association with ectopic expression
of PTKs. Alternatively, other PTPs dephosphorylate and activate
PTKs, and are themselves oncogenic. Much current interest
surrounds the clinical introduction of specific PTK inhibitors,
whereas targeting of PTPs remains largely unexplored. Phosphatases
represent 4% of the drugable human genome and PTPs appear
an important new target for cancer therapy. Here we briefly,
describe PTP structure and function. Secondly, we review experimental
and clinical data, which support a role for PTPs in neoplastic
development. Next, we review current strategies for generation
of agents targeting PTPs; these include re-expression of tumour
suppressor genes (mediated via adenoviral vectors),
and generation of small molecules designed to inhibit oncogenic
activity. Finally, we address the role of PTPs in melanoma,
an increasingly common tumour that may represent an appropriate
target for therapeutic manipulation of PTP activity.
[Back to top]
Knowledge of Epigenetic Influence for Prostate
Cancer Therapy
Masatoshi Watanabe, Akimitsu Takagi, Takeshi Matsuzaki,
Daisuke Kami, Minoru Toyota, Yoshifumi Hirokawa and Taizo
Shiraishi
Prostate cancer is one of the most prevalent cancers in men
in many countries, increasing in frequency with age through
the most advanced years. The standard treatment for newly
diagnosed metastatic tumors is androgen ablation. However,
advanced prostate cancer nevertheless often develops in many
cases. Although hormonal manipulation and chemotherapy have
uncertain value for advanced lesions, especially androgen-independent,
recent studies of docetaxel-based chemotherapy in men with
androgen-independent prostate cancer have shown a survival
benefit. Intensive investigations have shown that aberrant
epigenetic features. including aberrant DNA methylation, make
an important contribution to carcinogenesis as well as genetic
alterations. Hypermethylation of CpG islands in promoter regions
can lead to silencing of tumor-suppressor genes, while hypomethylation
of the genome leads to instability. This review attempts to
provide up-to-date information regarding the significance
of epigenetics for human prostate cancer, with aberrations
offering dues to therapy and possibly also providing targets
for anticancer drugs.
[Back to top]
Implications of Somatic Mutations in the
AML1/RUNX1 Gene in Myelodysplastic Syndrome (MDS): Future
Molecular Therapeutic Directions for MDS
Hironori Harada, Yuka Harada and Akiro Kimura
Myelodysplastic syndrome (MDS) is a clonal disorder of
hematopoietic stem cells characterized by ineffective and
inadequate hematopoiesis. MDS is also a susceptibility to
acute myeloid leukemia (AML) and shown to be extremely resistant
to current therapeutic strategies. MDS in a subset of 10-20%
of patients arise after previous chemotherapy or radiation
exposure for other malignancies. Because MDS is a heterogeneous
disorder, specific gene abnormalities playing a role in the
myelodysplastic process have been difficult to identify. Cytogenetic
abnormalities are seen in half of MDS patients, and generally
consist of partial or complete chromosome deletion or addition,
whereas balanced translocations are rare. Genes more frequently
implicated in the pathogenesis of MDS remain unknown. Although
point mutations of critical genes have been demonstrated to
contribute to the development MDS, there was no strong correlation
between these mutations and clinical features. Recently, we
reported the high incidence of somatic mutations in the AML1/RUNX1
gene, which is a critical regulator of definitive hematopoiesis
and the most frequent target for translocation of AML, in
MDS, especially refractory anemia with excess blasts (RAEB),
RAEB in transformation (RAEBt) and AML following MDS (defined
here as MDS/AML). The MDS/AML patients with AML1 mutations
had a significantly worse prognosis than those without AML1
mutations. Most of AML1/RUNX1 mutants lose trans-activation
potential, which leads to a loss of AML1 function indicating
that AML1/RUNX1 dysfunction is one of the major pathogenesis
of MDS/AML. Normalizing AML1 function or regulating cooperative
gene mutations would provide an important clue for molecular
target therapies.
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