Cancer Research in Switzerland - Krebsliga Schweiz

Thalmann George N. | Impact of therapeutic and
preventive strategies in prostate cancer on prostatespecific
antigen (PSA), gene expression and tumor
cell survival (OCS 01752-08-2005)
Because of the progress made in the treatment of the primary
tumour, mortality in patients with cancer is increasingly
linked to progressive and metastatic disease, which
is often occult at the time of diagnosis/therapy of the primary
tumour. Despite treatment, tumours may progress
by outgrowth of tumour cells resistant to treatment. It is
unclear whether this selection is adaptive or clonal. Therefore,
understanding the effect of preventive or therapeutic
strategies on PSA and the tumour is essential.
Aim of the study
The working hypothesis of the project is that preventive
and therapeutic agents may have an impact on the regulation
and production of PSA and on gene expression
in general. In addition, the cell subpopulation surviving
treatment needs to be isolated and characterized.
Methods and study design
In order to study these interactions we used prostate cancer
cell lines to test whether compounds used or under
evaluation for prevention and treatment of prostate cancer
have an impact on PSA production on the messenger
RNA and protein level and on cancer cell growth. In addition,
primary cell cultures from radical prostatectomy
specimens were cultured under therapeutic conditions,
and the therapy (hormone) refractory population was isolated
and characterized, and tissue was used for the evaluation
of potential novel prognostic markers.
Study results
We demonstrated that several compounds used for the
prevention and therapy of prostate cancer, such as genistein
or bicalutamide, inhibit PSA production, whereas
genistein only inhibited hormone-sensitive cell growth. In
primary cultures the treatment refractory hormone independent
cell population evidenced a cancer stem-/progenitor-like
phenotype that produces little of PSA but
overexpresses genes of self-renewal and proliferation.
Further, genes involved in angiogenesis (development of
blood vessels) could be evaluated for their predictive
value in patients undergoing radical prostatectomy.
Recommendations and patient benefit
Compounds foreseen for use in the prevention or treatment
of prostate cancer should be evaluated for their influence
on PSA expression prior to clinical use. The identification
and characterization of the cell subpopulation
surviving hormonal treatment of prostate cancer may allow
development of novel treatment strategies for this
disease. Finally, markers of neo angiogenesis could be
tested for their predictive value in patients undergoing
radical prostatectomy. A gene expression signature defining
primary tumours with high malignant potential from
such with low malignant potential could be determined.
Project coordinator
Prof. Dr. George Thalmann
Klinik und Poliklinik für Urologie
Inselspital
Anna-Seiler-Haus
CH-3010 Bern
Phone +41 (0)31 632 36 64
urology.berne@insel.ch
Theurillat Jean-Philippe | Synthetic lethality in the
context of autophagy-deficiency (KLS 02014-02-2007)
Autophagy is a normal cellular process that mediates the
breakdown of long-lived proteins. However, if autophagic
activity is pathologically elevated, cells die as a consequence
of self-digestion. Using an RNA-interference approach,
we found that the loss of a specific signal-molecule
termed S6K1 causes an excessive increase in autophagy
flux followed by induction of programmed cell death (apoptosis).
Constitutively, we found that S6K1 activity and
hence survival of cancer cells is positively influenced by
a novel oncogene called URI. Increased URI activity mediates
resistance against many physiological and therapyinduced
stressors.
Study results
We identified and described the function of the URI gene
as an oncogene in ovarian cancer. URI translates into a
protein that acts as a compound of a negative feedback
loop dedicated to regulate S6K1 activity and ultimately
influences the threshold for the induction of cell death
(apoptosis). Normal cells die under physiological stress
conditions, such as low availability of energy through induction
of programmed cell death. However, when URI is
upregulated, apoptosis induction is largely abolished.
We found that about 35 % of patients with ovarian cancer
display an upregulation of URI. One out of ten women
exhibited, furthermore, an amplification of the URI gene.
In the case of gene amplification, the gene is dramatically
multiplied and integrated into the genome, which results
in an increase in activity. Additionally, URI amplification
could be detected in various other cancer types, suggesting
that the importance of the present scientific results is
not restricted to ovarian cancer.
Interestingly, we were able to detect that women harbouring
an amplified URI locus in their cancer genome
were characterized by very aggressive tumour behaviour
and failed to respond to chemotherapeutic treatment. In
contrast to normal cells, URI is in those tumours essential
for the survival of the tumour cells. On a molecular level,
URI inhibits selectively in these tumour cells the inactivating
function of a protein called PP1gamma on S6K1. As a
direct consequence of our molecular understanding, we
expect to find novel, more specific therapeutic approaches
to treat patients with ovarian cancer characterized by URI
amplification who do not respond to the standard chemotherapy
regime.
Patient benefit
These findings will predict in the future the response of
patients with ovarian cancer to a considered chemotherapy
and help to judge whether a patient will benefit or
not. Moreover, the results open up new perspectives for a
more specific and personalized cancer treatment of women
with ovarian cancer. This study, which is a result of collaboration
with ETH Zurich, made a significant step towards
the understanding of a novel oncogene, and will be published
in 2011 in Cancer Cell.
Project coordinator
Dr. Jean-Philippe Theurillat
Institut für klinische Pathologie
UniversitätsSpital Zürich
Schmelzbergstrasse 12
CH-8091 Zürich
Phone +41 (0)44 633 76 58
jean-philippe.theurillat@usz.ch
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