Cancer Research - Europa

Keywords | Therapy | genome | telomerase | diagnosis | drugs |
MOL CANCER MED
Developing molecular medicines
for cancer in the post-genome era
Summary
The cellular immortality enzyme telomerase (one of the most
promising universal cancer markers) and associated telomere
maintenance mechanisms represent novel anti-cancer targets
of enormous therapeutic and diagnostic potential. In
MOL CANCER MED, a multinational EU translational cancer
research consortium has been established, in which expert
cancer geneticists and molecular biologists will interact with
prominent pharmacologists, clinicians and pathologists to
develop these exciting new cellular targets into measurable
pre-clinical advances, within a four-year time-frame.
The project has been structured into three, highly interactive
areas of activity, involving the fundamental evaluation and
pre-clinical validation of:
• telomerase as a target for cancer treatment and diagnosis
based on new molecular knowledge about its expression
and function;
• associated downstream telomere maintenance mechanisms
as additional targets for novel drug design;
• new anti-cancer drugs based on these targets. The consortium
will bring to bear diverse and complementary
technological know-how of considerable power to deliver
the above primary objectives. Eff ective management will
maximise synergies across MOL CANCER MED in order
to produce genuine improvements in the design of new
treatments that promise to be active against a broad
spectrum of common human malignancies.
Problem
Cancer is a leading cause of death in the western world,
second only to cardiovascular disease, and is therefore
a European public health problem of overwhelming human
and economic signifi cance. The incidence of cancer is set to
increase substantially with demographic and possibly environmental
infl uences playing a part. However, there is now an
improved molecular understanding of the key genetic, biochemical
and cellular changes leading to cancer, in signifi cant
part due to the eff orts of diverse groups of world-class EUbased
scientists. With the completion of the human genome
sequence imminent, it is now timely to initiate a major European
coordinated eff ort to translate fundamental scientifi c
knowledge about cancer into safer, more eff ective, therapies
and improved early diagnostic procedures.
MOL CANCER MED is focused on a single group of highly
promising anti-cancer targets associated with telomerase
BIOLOGY
and telomere maintenance. Repression of telomerase in the
somatic tissues of humans, and probably other long-lived
mammals, appears to have evolved as a powerful protective
barrier against cancer. Immortalisation in vitro of normal
human cells that lack telomerase involves the reactivation of
telomerase or, rarely, an alternative (ALT) mechanism for
maintaining telomeres. It is clear that telomerase is obligatory
for continuous tumour cell proliferation, clonal evolution and
malignant progression. Because telomerase is found in around
90 % of human cancers and is essential for the continued proliferation
(and clonal evolution) of cancer cells, it represents
one of the most exciting anti-cancer targets thus far discovered.
Results with a variety of telomerase inhibitory strategies
in human cancer cells have confi rmed that its functional inactivation
results in progressive telomere shortening, leading to
growth arrest and/or cell death through apoptosis. Promising
candidate small molecule inhibitors are beginning to emerge
that will form the basis for anti-telomerase drug development.
MOL CANCER MED is based on successful Framework
5 research concerned with establishing the value of the cellular
immortality enzyme telomerase as an anti-cancer target
(Project: QLG-1999-01341; TACIT) and represents an expansion
and elaboration of this. TACIT yielded results that have
triggered new translational research with clearly defi ned clinical
applications. To this set of activities have been added
carefully selected new EU research teams, notably in the area
of drug development.
Aim
The principal aim of MOL CANCER MED is to fully exploit the
results of recent fundamental advances in understanding the
role of telomerase and telomere maintenance mechanisms in
human cancer development, in order to achieve genuine clinical
benefi t (i.e. in developing both improved diagnostics and
anti-cancer therapies). The principal measurable objectives of
the project, over the complete 48 months period, are:
• to validate further the potential of telomerase and telomere
maintenance systems in cancer therapy and diagnosis;
• to identify novel molecular targets based on telomere
structure, function & stability, that may be of value in treatment
and diagnosis of the common human cancers;
• to create a programme of novel small molecule drug
development based initially on recently identifi ed (but
thus far poorly exploited) targets and, later (from month
12 onwards) exploiting completely new targets identifi ed
during the project.
Expected results
• Novel anti-cancer drug targets and diagnostic methodologies
derived from advances in:
• the understanding and defi nition of biochemical
response pathways underpinning the telomere checkpoint
for somatic cell proliferation;
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