Cancer Research - Europa

GROWTHSTOP
Identifi cation, development and
validation of novel therapeutics
targeting programmed cell death
in tumours
Summary
Mounting evidence indicates that the acquired ability to
resist apoptosis is a hallmark of most, and perhaps all types
of cancer. As scientists learn more about how apoptosis is
thwarted by cancer cells, they are also gaining a greater
understanding of why many tumours are resistant to the
apoptosis-inducing eff ects of radiation and chemotherapy.
These insights will guide eff orts to overcome treatment
resistance and off er important clues about new drugs that
target genes and protein products in the apoptosis pathways
to encourage selective cell death.
GROWTHSTOP is exploring how apoptosis is regulated and
how it can be selectively triggered to induce suicide in cancer
cells while sparing normal cells. The GROWTHSTOP
Consortium applies a combination of high resolution bioimaging
techniques, proteomics, cellular models, and in vivo
tumour models towards:
• the understanding of the pathways that signal apoptosis
in solid tumours;
• their validation as viable targets for tumour suppression
or regression in animal models in vivo;
• the discovery and validation of a novel, alternative class
of inhibitors that specifi cally targets protein interactions
rather than, or in addition to, enzyme activity. The goal
of the GROWTHSTOP project is to exploit apoptotic
pathways as a viable therapeutic strategy.
Importantly, more than 30 % of the applied EU budget will
be reserved for SMEs that deliver expertise and chemical
screening in order to ensure a rapid translation of novel
screens and assays into an effi cient search for specifi c drugs
manipulating pro-apoptotic pathways.
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Keywords | Apoptosis | cell death | cell imaging | tumour models | kinase inhibitors | pharmacophore inhibitors |
scaff old inhibitors |
Problem
Cancer is a major challenge to European health care. Each
year nearly two million people are diagnosed with cancer in
the EU, and over one million deaths result from this disease.
Each case can have a tremendous impact on the health and
wellbeing of the aff ected person, his or her family and personal
environment. In addition, a high percentage of cases
have major economic impacts, both for the individual and
for the health care provider. As a result, improvements in
cancer therapy remain of prime importance for the wellbeing
of Europeans and for the future development of the
Union.
Cancer is caused by mutations in a relatively small and identifi
able number of genes, which fall into two categories:
proto-oncogenes, which provide critical proliferative or survival
signals to cells and which are inappropriately activated
by mutation during tumourigenesis; and tumour-suppressor
genes, which restrain cell growth and proliferation, and which
are lost or inactivated by mutations during the development
of a tumour.
Importantly, mutations in individual genes do not cause
tumours, since the human genome harbours failsafe mechanisms
that protect normal cells from the consequences of
deregulated proliferative stimuli. Two such failsafe mechanisms
are known. The fi rst is an irreversible growth arrest,
termed cellular senescence, which is activated by deregulated
oncogenic signals through the Ras pathway: one key
example is the often lifelong lack of proliferation of melanocytic
naevi despite the presence of mutations in B-Raf,
a downstream eff ector of Ras proteins. The second is apoptosis,
or programmed cell death, which is activated by many
forms of de-regulated proliferative signals. Tumours can
only develop when secondary mutations that disable these
failsafe programmes arise; as a consequence, many mutations
that are found in human tumours are involved in
pathways that control either senescence or apoptosis.
Aim
Strategies that aim at restoring these failsafe programmes,
in particular apoptosis, in established solid tumours have
emerged as an important approach to cancer therapy. The
promise of this approach is that such strategies create
a therapeutic window, killing tumour cells while sparing
normal cells. The key aim of this project is therefore to
devise, test and implement strategies that restore apoptosis
as a failsafe programme to solid human tumours.
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME