Cancer Research - Europa

Keywords | Solid tumours | apoptosis | tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) |
receptor-selective TRAIL mutants | TNF ligand-mimicking peptides | intracellular peptide inhibitors |
computational rational protein design | directed evolution | tailor-made therapy | primary tumour culture |
cell-based delivery systems of anti-cancer genes | GLP/GMP procedures |
TRIDENT
Therapeutic molecules for treatment
of solid tumours by modulating death
receptor-mediated apoptosis
Summary
The effi cacy of current treatments for some types of solid
tumours is disappointingly poor. New therapies using novel
tumour-selective anti-cancer agents are necessary. A major
aim of anti-tumour therapies is to inhibit proliferation and
induce death of tumour cells without aff ecting normal cells.
In this regard, members of TNF ligand/receptor family are
of interest since they regulate both apoptosis (programmed
cell death) and cell proliferation. One TNF family member,
TRAIL, is of particular interest since it selectively induces
death of tumour cells without aff ecting normal cells. Currently,
TRAIL and TRAIL-specifi c antibodies are being
investigated as anti-cancer agents. However, a major drawback
to TRAIL’s effi cacy is that it binds to multiple receptors,
not all of which transduce an apoptotic signal. Previously,
we developed receptor-selective TRAIL variants which are
potent inducers of apoptosis in various tumour cells, are
more effi cacious than native TRAIL, and display synergistic
eff ect in combination with other chemotherapy treatments
or radiotherapy.
This proposal will investigate and characterise TRAIL variants
pre-clinically in solid tumour models and defi ne new
treatment protocols in combination with already proven
treatments. Furthermore, we will elucidate the role of other
TNF receptor family members in signalling in tumour cell
survival/death. Biochemical and structural characterisation
will identify new targets for molecular cancer therapy while
computational design and molecular evolution techniques
will be used to develop novel receptor-selective apoptosisinducing
agonists. We will also develop intracellular acting
agents (intracellular-acting peptides inhibiting pro-survival
signals; intracellular peptide inhibitors), which will block the
unwanted proliferative/anti-apoptotic signals activated by
some TNF members. The tumoricidal activity of these lead
molecules will be tested using conventional, viral and cell
based delivery strategies which will utilise peptide sequences
to specifi cally target them to tumour cells.
TREATMENT
Problem
With almost 3 million new cases each year and 1.7 million
deaths, cancer is an important public health problem in Europe.
The ageing of the European population will cause these numbers
to continue to increase. The most common cancers are
lung, colorectal and breast cancers. The available treatments
for these solid cancers and the outcome of the treatments are
not satisfactory. New therapeutic strategies and novel tumourselective
anti-cancer agents are necessary in order to improve
the treatment of these and other solid tumours.
Aim
The ultimate aim of the TRIDENT project is to develop novel
molecules that target critical apoptotic signalling pathways
important in the formation of various solid tumours.
The specifi c objectives are:
• to develop of novel apoptosis-inducing agonists and proliferation
antagonists using state-of-the art, computer
based rational design and directed evolution techniques;
• to gain in-depth knowledge on the role of the TNF ligand-receptor
family interactions in the carcinogenesis of
solid tumours, both at a molecular and structural level;
The objective of TRIDENT is to channel death receptor activation towards tumour cell apoptosis.
Activation of cell surface death receptors do not only induce apoptosis of the receptor carrying
cell but can simultaneously activate compensatory, pro-survival pathways, which limits the use
of this pathway to kill cancerous cells. The TRIDENT project aims to generate TNF ligand variants
that only bind to the death-inducing members of the TNF receptor family, not to decoy TNF
receptors (selective ligand) and design cell permeable peptide inhibitors (intracellular inhibitors;
IC inh) against anti-apoptotic molecules. These novel molecules used in combination can
maximize tumour cell killing.
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