Contents
p53: Fighting Cancer Pp.385-402
Galina
Selivanova
Novel Strategies in Cancer Therapeutics:
Targeting Enzymes Involved in Cell Cycle Regulation and Cellular Proliferation Pp.403-424
M.C.
Liu, J.L. Marshall and R.G. Pestell
Harnessing Changes in Cellular Glycosylation
in New Cancer Treatment Strategies Pp.425-442
M.V.
Dwek and S.A. Brooks
Carcinoembryonic Antigen as a Target to
Induce Anti-Tumor Immune Responses Pp.443-454
P.
Sarobe, E. Huarte, J.J. Lasarte and F. Borras-Cuesta
Antiandrogens in Prostate Cancer Endocrine
Therapy Pp.455-461
Z.
Culig, G. Bartsch and A. Hobisch
[Back to top] p53:
Fighting Cancer
Galina Selivanova
p53 is a key tumor
suppressor that plays a critical role in coordinating the response of cells to
a diverse range of stress conditions, e.g. oncogenic activation, hypoxia or DNA
damage. Induction of cell death by apoptosis in response to stress by p53 is
crucial for the prevention of tumor development as well as for the response to
anticancer therapy. p53 triggers apoptosis through multiple mechanisms,
including mitochondrial and death receptor pathways, cytoskeleton changes,
suppression of survival signalling, and induction of hypoxia. Lesions in the
p53 pathway occur so frequently in cancer, regardless of patient age or tumor
type, that they appear to be part of the life history of a majority of cancer
cells. Given an extremely high potency of apoptosis induction by functional
p53, it appears that anti-cancer strategies based on p53 reactivation should be
efficient and applicable in a wide range of human tumors. Tumor cells are prone
to p53-induced apoptosis due to oncogene activation. Therefore it is
conceivable that p53-based therapeutic strategies will not require selective
targeting of tumor cells.
[Back to top] Novel Strategies in Cancer Therapeutics:
Targeting Enzymes Involved in Cell Cycle Regulation and Cellular Proliferation
M.C.
Liu, J.L. Marshall and R.G. Pestell
Tumor development,
growth, and progression depend on some combination of altered cell cycle
regulation, excessive growth factor pathway activation, and decreased
apoptosis. Understanding the complex molecular mechanisms that underlie these
processes should therefore lead to the identification of potential targets for
therapeutic intervention. The estrogen receptor and HER-2/neu were among the
earliest targets investigated, ultimately leading to the widespread use of
tamoxifen and trastuzumab, respectively, in the treatment of breast cancer.
Major research advances have since led to other classes of targeted therapies,
including cyclin-dependent kinase inhibitors, histone deactylase inhibitors,
and receptor tyrosine kinase inhibitors. The following review provides a
discussion of the molecular biology associated with each of these types of
therapies as well as a detailed summary of the preclinical and clinical data
published on selected compounds from each of these subgroups.
[Back to top] Harnessing Changes
in Cellular Glycosylation in New Cancer Treatment Strategies
M.V.
Dwek and S.A. Brooks
The majority of
proteins are modified in post-translational events and one of the most common
of these is glycosylation. Many reports describe alterations to the normal
cellular glycosylation in cancer but detailed knowledge of the underlying
structures and mechanisms that result in the altered glycosylation of cancer
glycoproteins have been hindered by the inherent complexity of glycans
themselves. Improved analytical tools for the study of glycosylation and
application of molecular techniques for the characterisation of the genes
encoding glycosyltransferases have, however, enabled the structural
identification of some of the cancer-associated changes in glycosylation. The
observed alterations in protein glycosylation in cancer have led to clinical
trials in which glycans on cancer cell-surface proteins are targeted. These new
approaches to cancer treatment include immunotherapy and
carbohydrate-processing inhibitor-based strategies. Compounds that mimic
glycans involved in the metastatic dissemination of cancer are also actively
sought. The results that have been obtained and the long-term potential of
these new approaches are discussed in this review article.
[Back to top] Carcinoembryonic Antigen as a Target to Induce
Anti-Tumor Immune Responses
P. Sarobe, E. Huarte, J.J. Lasarte and F. Borras-Cuesta
Identification of
relevant targets for cancer therapy is a major goal in cancer research. In this
field, the identification of tumor antigens has opened the possibility of inducing
specific anti-tumor immune responses. Among these antigens, carcinoembryonic
antigen (CEA) is especially relevant because CEA is expressed in a wide variety
of adenocarcinomas such as colon, rectum, pancreas, gastric, breast, etc. The
present review focuses on different strategies to induce anti-CEA immune
responses. In a first group of strategies, the antigen is administered using
viral and bacterial vectors expressing CEA, dendritic cells loaded with CEA
protein, or dendritic cells transfected with DNA or RNA expressing CEA. A
second group of strategies is based on immunizations with antigenic peptide
determinants from CEA, rather than with immunogens containing the whole
protein. This has been possible due to the identification of different peptide
determinants from CEA, which when presented by MHC class I molecules, are
recognized by T cytotoxic lymphocytes. More recently, due to the importance of
CD4+ T cells in the induction of immune responses, T helper peptides
presented by MHC class II molecules have also been identified. To overcome the
poor immunogenicity of CEA-derived peptide determinants, a common feature of
self-antigens, their sequence has been modified to improve binding to MHC
molecules or recognition by T cell receptors. Finally, in order to enhance
immunization efficacy, some of these strategies have combined the
administration of immunogens and cytokines or co-stimulatory molecules. Some of
the immunization protocols developed are being tested in clinical trials with
promising results. Thus, CEA may prove to be a valuable target antigen for the
therapy of a high number of malignancies.
[Back to top] Antiandrogens in Prostate Cancer Endocrine
Therapy
Z.
Culig, G. Bartsch and A. Hobisch
Prostate cancer is
the most frequently diagnosed tumor in industrialized countries. Endocrine
therapy, which is based on interference with androgen signaling is only
palliative. Drugs used in prostate cancer therapy are luteinizing hormone
releasing hormone (LHRH) agonists and antiandrogens. Application of LHRH
agonists leads to suppression of the levels of circulating androgens, and
antiandrogens block the function of the androgen receptor (AR). The steroidal
antiandrogen cyproterone acetate and nonsteroidal compounds hydroxyflutamide
and bicalutamide are used most frequently. They prevent acquisition of a
transcriptionally active conformation of the AR. It became clear that tumors
progress to therapy resistance in the presence of the AR which might be structurally
altered. These mutations generate receptors that respond to other steroids and
antiandrogens by increased activation. In addition, AR expression increases
during endocrine treatment. AR is also activated by nonsteroidal compounds such
as growth factors, interleukin-6, and neuropeptides. Therefore, new
experimental approaches are needed to antagonize AR expression and function
more efficiently. The AR associates with a number of proteins, coactivators and
corepressors. There are indications that expression of some of these proteins
is altered in prostate cancer, a fact which might be important for improvement
of endocrine therapy.