You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
Aim<br />
The THERADPOX project aims at engineering novel and<br />
optimised oncolytic pox- and adenoviruses for cancer therapy,<br />
specifi cally targeting colorectal, pancreatic and ovarian<br />
cancers. The innovative strategy of THERADPOX relies on<br />
the original engineering of OVs to render them safe, specifi c<br />
and effi cient for infection (binding and replication) and for<br />
the destruction of cancer cells through a combination of<br />
virotherapy with non-toxic chemotherapy in vivo. To achieve<br />
an enhancement of tumour cell infectivity of THERADPOX<br />
vectors, tumour-specifi c ligands, for which particular membrane<br />
proteins of cancer cells show high affi nity, will be<br />
incorporated in viral surface proteins and will be optimised.<br />
In addition, by modifying or exchanging ligand expression of<br />
THERADPOX OVs, one can imagine targeting other tumour<br />
types. The viral genome will also be engineered to ensure<br />
that viruses selectively replicate and express therapeutic<br />
proteins in tumour cells and that they spread widely through<br />
the tumour mass. Furthermore, capsid modifi ed oncolytic<br />
Ad vectors will be explored to overcome pre-existing immunity<br />
and delay an induced immune response.<br />
The oncolytic vectors (OVs) will be derived from the viral<br />
platforms described below:<br />
• vaccinia virus (VV): the advantages of VV as OV are a<br />
quick and effi cient life cycle, strong lytic activity and<br />
rapid cell-to-cell spreading. The virus can infect a wide<br />
variety of human tissues but does not cause any known<br />
human disease. VV was the fi rst widely used vaccine<br />
which resulted in the eradication of smallpox. As a result,<br />
the responses, safety profi le and adverse reactions have<br />
been extensively studied and documented;<br />
• myxoma virus (MV): MV causes myxomatosis in European<br />
rabbits but is non-pathogenic in man. However, myxoma<br />
virus productively infects a variety of human tumour<br />
cells (Sypula et al., 2004), suggesting a signifi cant<br />
potential for exploiting MV as a novel OV platform;<br />
• adenovirus (Ad): one of the most extensively studied<br />
viruses which have been engineered for gene therapy<br />
and for virotherapy of cancer, particularly serotypes 2<br />
(Ad2) and 5 (Ad5). The virus is endemic in the human<br />
population and its natural pathogenicity is associated<br />
with mild respiratory infections (common cold). It can be<br />
grown easily and to high titres, and the methodology to<br />
generate recombinant viruses is well established.<br />
Expected results<br />
THERADPOX OVs will be engineered to:<br />
• selectively target cancer cells in vivo (up to a 100-fold<br />
increase of tumour cell infection can be expected: 100 cancer<br />
cells infected for 1 normal cell infected) (M30);<br />
• selectively replicate and propagate in tumour cells in vivo<br />
(expectations are a 100-fold increase of viral yield in<br />
tumour cells versus normal cells) (M32);<br />
• widely spread within tumours in vivo (a statistically significant<br />
increase of the therapeutic index is expected)<br />
(M30);<br />
• specifi cally render cancer cells sensitive to chemotherapy<br />
in vivo: OVs will be engineered to express in the infected<br />
cancer cells prodrug- converting enzymes, enabling the<br />
conversion of a non-toxic molecule (given orally or intravenously)<br />
to toxic compounds (a statistically signifi cant<br />
increase of the therapeutic index is expected) (M36);<br />
• overcome the pre-existing immunity and to delay the<br />
induced adenoviral immune response, concerning oncolytic<br />
Ad (M36).<br />
Potential applications<br />
The THERADPOX project contributes to supporting the<br />
Programme of Community action in the fi eld of public health<br />
(2003-2008) (1786/2002/EC) by:<br />
• promoting and improving health, with a view to reducing<br />
avoidable morbidity: THERADPOX will develop new<br />
OVs to cure patients aff ected with colorectal, pancreatic<br />
and ovarian cancers;<br />
• reacting rapidly to health threats: THERADPOX vectors<br />
are designed to eradicate tumours. Their selectivity for<br />
one tumour type relies on the tumour cell selectivity of<br />
specifi c ligands. Thus, by only changing the ligand in<br />
THERADPOX OVs, one can imagine targeting and effi -<br />
ciently and rapidly eradicating other tumour types that<br />
may be a threat to human health in the future;<br />
• promoting better knowledge and communication fl ows,<br />
thus allowing a greater involvement of individuals in decisions<br />
that concern their health. THERADPOX includes<br />
specifi c tasks for:<br />
• communicating about the knowledge, impacts and<br />
benefi ts of the project;<br />
• disseminating results and information, in a simple,<br />
clear and sound way about the work undertaken<br />
within THERADPOX to the scientifi c community as<br />
well as to the community population, with the ultimate<br />
goal to improve the quality of life.<br />
220 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME