Current Cancer
Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 5, Number 8, December 2005
Contents
Mechanisms of Lymphangiogenesis: Targets
for Blocking the Metastatic Spread of Cancer Pp.
561-571
Bradley K. McColl, Stephen J. Loughran, Natalia
Davydova, Steven A. Stacker and Marc G. Achen
[Abstract]
Novel Therapeutic Approaches Targeting Vascular Endothelial
Growth Factor and its Receptors in Haematological Malignancies
Pp. 573-578
Domenico Ribatti and Angelo Vacca
[Abstract]
Anti-Angiogenic and Anti-Inflammatory Effects
of Statins:
Relevance to Anti-Cancer Therapy Pp. 579-594
Józef Dulak and Alicja Józkowicz
[Abstract]
Nuclear Proteins: Promising Targets for Cancer
Drugs Pp. 595-610
Y.-L. Yao and W.-M. Yang
[Abstract]
Therapeutic Cancer Vaccines: At Midway Between
Immunology and Pharmacology Pp. 611-627
A. Lage, R. Perez and L. E. Fernandez
[Abstract]
Mechanisms of Focal Adhesion Kinase Regulation
Pp. 629-643
Lee A. Cohen and Jun-Lin Guan
[Abstract]
Abstracts
[Back to top]
Mechanisms of Lymphangiogenesis: Targets for Blocking
the Metastatic Spread of Cancer
Bradley K. McColl, Stephen J. Loughran, Natalia
Davydova, Steven A. Stacker and Marc G. Achen
The lymphatic vasculature is an important route of metastatic
spread in cancer and recent studies have demonstrated that
lymphangiogenesis (the growth of lymphatic vessels) associated
with tumors promotes metastasis via the lymphatics.
Therefore, the molecular mechanisms that drive lymphangiogenesis
are attractive targets for development of novel therapeutics
designed to restrict cancer metastasis. Such therapeutics
would be of high priority as metastasis is the most lethal
aspect of tumor biology. Research over the past seven years
has identified protein growth factors and cell surface receptors
that signal for lymphangiogenesis during embryonic development,
in adult tissues and in cancer. Proteases that process and
thereby activate lymphangiogenic growth factors have also
been defined. Lymphangiogenic growth factors, the enzymes
that activate them and the cell surface receptors signalling
for growth of lymphatic vessels are prime targets for anti-lymphangiogenic
drugs designed to restrict cancer metastasis. Agents targeting
some of these proteins have already shown promise for blocking
tumor lymphangiogenesis and lymphatic metastasis in animal
models. This article focuses on current and emerging targets
for blocking these processes that have been defined in recent
studies of the molecular mechanisms controlling lymphangiogenesis.
Strategies to block the actions of these proteins in cancer
are also explored.
[Back to top]
Novel Therapeutic Approaches Targeting Vascular Endothelial
Growth Factor and its Receptors in Haematological Malignancies
Domenico Ribatti and Angelo Vacca
The existence of specific angiogenesis inhibitors was first
postulated by Judah Folkman in 1971. The term "antiangiogenesis"
was introduced to describe treatments designed to prevent
the induction of new blood vessels and perhaps reduce the
number of those already present. Several approaches inhibit
tumor angiogenesis and more than 60 antiangiogenic compounds
have been clinically evaluated. Because tumor-associated angiogenesis
takes place in a physiological context, its inhibition should
not induce resistance and should potentiate the oncostatic
effect, because each neovessel supplies hundreds of tumor
cells. Inhibitors may be synthetic or semi-synthetic agents,
endogenous inhibitors, or biological antagonists of the angiogenic
cascade.
Several direct and indirect vascular endothelial growth factor
(VEGF) and VEGF receptor (VEGFR) inhibitor strategies are
under clinical investigation for treatment of solid tumors
and hematological malignancies. Approaches to disrupt the
VEGF/VEGFR signalling pathways range from small-molecule ATP
competitive VEGFR inhibitors to biological agents such as
soluble receptors, anti-VEGF and anti-VEGFR antibodies, small
molecule inhibitors, and VEGF transcription inhibitors. This
review summarizes the literature on the use of these molecules
in the treatment of hematological malignancies.
[Back to top]
Anti-Angiogenic and Anti-Inflammatory Effects of Statins:
Relevance to Anti-Cancer Therapy
Józef Dulak and Alicja Józkowicz
Angiogenesis is indispensable for the growth of solid tumors
and angiogenic factors are also involved in the progression
of hematological malignancies. Targeting the formation of
blood vessels is therefore regarded as a promising strategy
in cancer therapy. Interestingly, besides demonstration of
some beneficial effects of novel anti-angiogenic compounds,
recent data on the activity of already available drugs point
to their potential application in anti-angiogenic therapy.
Among these are the statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme
A reductase. Statins are very efficient in the treatment of
hypercholesterolemia in cardiovascular disorders; however,
their effects are pleiotropic and some are not directly related
to the inhibition of cholesterol synthesis. Some reports particularly
highlight the pro-angiogenic effects of statins, which are
caused by low, nanomolar concentrations and are regarded as
beneficial for the treatment of cardiovascular diseases. On
the other hand, the anti-angiogenic activities, observed at
micromolar concentrations of statins, may be of special significance
for cancer therapy. Those effects are caused by the inhibition
of both proliferation and migration and induction of apoptosis
in endothelial cells. Moreover, the statin-mediated inhibition
of vascular endothelial growth factor synthesis, the major
angiogenic mediator, may contribute to the attenuation of
angiogenesis.
It has been suggested that the anti-cancer effect of statins
can be potentially exploited for the cancer therapy. However,
several clinical trials aimed at the inhibition of tumor growth
by treatment with very high doses of statins did not provide
conclusive data. Herein, the reasons for those outcomes are
discussed and the rationale for further studies is presented.
[Back to top]
Nuclear Proteins: Promising Targets for Cancer Drugs
Y.-L. Yao and W.-M. Yang
Recent progress in cancer drug therapy has recognized that
the nucleus of the eukaryotic cell is an active site for many
cellular processes important to the development of cancer.
Many of these processes take place in specialized compartments
of the nucleus. One of such sub-nuclear compartments is the
promyelocytic leukemia nuclear body (PML NB). In acute promyelocytic
leukemia (APL), PML forms a fusion protein with the retinoic
acid receptor (RAR) alpha as a result of chromosomal translocation.
This PML-RAR alpha fusion protein is responsible for the proliferative
and de-differentiated phenotype of the leukemic cells and
is the target of all-trans retinoic acid (ATRA). Another example
of the specialized sub-nuclear compartments important in the
targeting of cancer is the nucleolus. Recently, it has been
proposed that the nucleolus serves as a stress sensor for
the cell, and the molecular mechanism underlying this proposal
has been discovered. Moreover, many anti-cancer drugs target
specific protein-protein interactions within the nucleus.
We will discuss current development surrounding two such target
proteins: the hypoxia-inducible factor 1 alpha (HIF-1alpha)
and FKBP25. Furthermore, chromatin structure, which is affected
by modifications of core histones, has become a target of
anti-cancer drugs. In this review, we will emphasize the significance
of nuclear proteins as promising targets for cancer drug therapy
by discussing a few key ideas, in three broad categories of
specialized sub-nuclear compartments, protein-protein interactions,
and the modifications of the chromatin structure.
[Back to top]
Therapeutic Cancer Vaccines: At Midway Between Immunology
and Pharmacology
A. Lage, R. Perez and L. E. Fernandez
The pursuit of active specific immunotherapy of cancer re-emerged
vigorously in the 90s. More than 50 vaccines are currently
under clinical testing, and more than 400 clinical trials
have been conducted. This wave of enthusiasm is rooted in
fundamental immunology, as new paradigms, such as the dominant
tolerance through T-regulatory cells and the instructive role
of the innate immune system on the adaptive immune system,
opened the possibility that an efficient cancer vaccination
could be achieved even without the need of cancer neoantigens,
provided that antigen presentation could be increased, and
that regulatory circuits could be controlled.
However, recent failures in some large trials have brought
disappointment and have highlighted the differences between
experiments in young, healthy mice with small transplanted
tumours, and clinical testing in aged, ill patients with advanced
spontaneous tumours, driving the attention to issues such
as tumour editing, tumour-induced immunosuppression, and immunosenescence.
The molecular basis of these phenomena is only partially known.
Additionally, the inherent complexity of the immune system
as a network of multiple interactions and redundant control
loops among a huge diversity of components sets another barrier
to the translation of in vitro reductionist knowledge
into rationally designed clinical trials. All this calls for
a new therapeutic paradigm in cancer vaccines, moving beyond
the analogy with the classic drug-target approach, and targeting
the immune system regulation as a whole, and its interaction
with the tumour, in all its complexity. Early mathematical
modelling of cancer immunotherapy has suggested how to go
about it. This re-evaluation of the cancer vaccine landscape,
suggests that future successful cancer immunotherapy will
be combined immunotherapy, will be exquisitely schedule-dependent
and will need new experimental models allowing for the exploration
of the mechanisms of resistance and tumour escape, such as
tumour editing and tumour induced immunosuppression, in the
context of the physiology of the immune system of the elderly.
These shifts will put cancer vaccines closer to pharmacology
than to conventional preventive vaccinology, or at least at
the midway. A change in the design and the ultimate goals
of the clinical trials will also be needed, identifying long
term stabilization of the disease and quality of life as main
endpoints, again closer to the clinical management of most
chronic noncommunicable diseases.
[Back to top]
Mechanisms of Focal Adhesion Kinase Regulation
Lee A. Cohen and Jun-Lin Guan
Focal adhesion kinase (FAK) is a tyrosine kinase whose phosphorylation
state and activity is tightly linked to cell adhesion to the
extracellular matrix through integrin receptors. FAK’s
regulation by adhesion places it in a key position to be able
to influence cellular events that are either dependent on
cell adhesion like cell proliferation and survival, or that
require modulation of cell adhesion like cell migration. FAK’s
involvement in cellular pathways that regulate cell growth
and cell movement suggests that it may contribute to the development
of cancer or other diseases. FAK’s possible involvement
in these pathways makes it a potential drug target. In this
review we will focus on the developing view how FAK’s
activity and phosphorylation are regulated within the cell.
Specifically, we will address the contribution of integrins
and growth factor dependent pathways to FAK’s activation.
The role of the tyrosine kinase Src in FAK’s regulation
will be discussed. The contribution of various negative regulators
of FAK’s phosphorylation on its regulation including
phosphatases and proteases will be discussed. Lastly, the
emerging role of FAK’s amino terminal FERM like domain
in FAK’s regulation will be explored. FAK’s function
within a cell are tightly linked to its phosphorylation state,
thus understanding its normal regulation in the cell will
provide important insight into drug development by highlighting
novel regulatory mechanisms within FAK that potentially may
be exploited.
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