Cancer Research - Europa

PRIMA
Prostate Cancer
Integral Management Approach
Summary
Prostate cancer is one of the most common malignancies in
the western male population. In Europe, approximately
40 000 men die of prostate cancer each year and, due to
the ageing population, that number is likely to increase to
around 60 000 men in 2020. Therefore prostate cancer is
a signifi cant medical problem with which the European
Community will be confronted increasingly in the oncoming
decades. For localised prostate cancer, radical therapies,
aiming at eradicating all malignant processes in the prostate
gland, are available, which can cure the patient.
However, if the malignant process has locally or distantly
spread, no curative medical intervention is currently in
existence. Since the early 1940s, androgen ablation therapy
has been the mainstay in an attempt to control prostate
neoplasms, but unfortunately this is only of a palliative
nature and tumour progression is inevitable, due to the
expansive growth of cancer cells that are unresponsive to
currently available hormone therapies. Furthermore, prostate
cancer cells have a strong tendency to spread to
the bone, a site where metastases cause great morbidity,
ultimately leading to a painful death.
Problem
There has been little progress in the management of metastatic
prostate cancer since Huggins and Hodges proposed
endocrine treatment of the disease. It has become clear that
the treatment is palliative and not curative. Therefore, new
targets for therapy need to be identifi ed, and methods to
interfere with these to change the course of the disease
have to be developed and tested pre-clinically in (animal)
model systems.
Aim
The main aim is the identifi cation of appropriate targets for
therapy for advanced prostate cancer. Two hypothesis-driven
approaches are combined with target discovery eff orts
using state-of-the-art, highthroughput, molecular profi ling
technologies. The identifi ed targets are validated at two levels,
i.e. phenotypically and functionally (high-throughput small
interfering RNA screens). Once identifi ed, validated targets
are used to screen for low molecular weight compounds,
which are subsequently tested in animal models for bone
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Keywords | Prostate cancer | androgen receptor | bone metastasis | high-throughput target identifi cation and validation |
high-throughput low molecular weight compound screening |
metastatic prostate cancer. In the PRIMA project, a multidisciplinary
eff ort is proposed to explore pathways that lead
to the most lethal aspect of prostate cancer, i.e. hormonetherapy-unresponsive
bone metastatic lesions. It has become
clear that in the majority of advanced prostate cancers, the
androgen receptor-signalling pathway is active even in the
absence of androgens. European research teams with a leading
role in androgen receptor research will integrate their
eff orts to exploit androgen receptor-mediated signalling as
a therapeutic target.
This should be achieved by:
• targeting the androgen receptor itself;
• interfering with androgen receptor-activation by nonsteroids;
• studying non-transcriptional functions of the androgen
receptor;
• targeting essential androgen-receptor co-factors overexpressed
in prostate cancer;
• inhibiting those androgen receptor target genes that
regulate prostate cancer cell growth, survival and
diff erentiation.
The androgen receptor teams will join forces with European
investigators that study interactions between prostate cancer
cells and the bone microenvironment.
Expression profi ling of members of the transforming growth
factor superfamily and signal transduction molecules in
cell lines, animal models and clinical specimens should provide
more insight into the role of these molecules in the
development of bone metastatic lesions. Furthermore, epithelium-
mesenchymal transition will be extensively studied. The
exploration of pathways leading to hormone therapy-unresponsive
bone metastatic disease will use functional genomics
and expression profi ling as technology platforms. These technology
platforms will also be used to identify novel candidate
targets for treatment and a specifi c bioinformatics platform
will be developed to analyse all collected data. In the targeted
discovery phase, candidate target genes will be identifi ed
that, in addition to already available targets from earlier collaborative
programmes, need to be phenotypically and/or
functionally validated. Phenotypical validation will be performed
in archival material of patients with a well-documented
follow-up in all stages of the disease process. In addition, highthroughput
functional, cell-based analysis and molecular
target validation will be performed by knocking down genes
that are over-expressed in hormone refractory or metastatic
prostate cancers using RNA interference. The knowledge
obtained from the targeted discovery phase and validation
phase will be used to establish assays, which will, in turn, be
used for highthroughput screening of low molecular weight
compounds (i.e. more than 25 000 compounds). The assays
will use easy-to-upscale formats and reporters that can be
easily read out. The fi nal phase of the project will be the testing
of interesting compounds for their ability to interfere
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME