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