Cancer Research - Europa

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