Cancer Research in Switzerland - Krebsliga Schweiz

enhances breast cancer cell motility – a finding that has
important implications at later stages of the disease when
tumour cells infiltrate into surrounding tissue and metastasize.
Project coordinator
Prof. Dr Cathrin Brisken
Swiss Institute for Experimental Cancer
Research (ISREC)
School of Life Sciences
Swiss Federal Institute of Technology
Lausanne (EPFL)
NCCR Molecular Oncology
SV2.832, Station 19
CH-1015 Lausanne
Phone +41 (0)21 693 07 81
Fax +41 (0)21 693 07 40
cathrin.brisken@epfl.ch
In collaboration with:
– Dr. Maryse Fiche, Institut universitaire de pathologie,
CHUV, CH-1011 Lausanne
– Prof. Dr. Nancy Hynes, Friedrich Miescher Institute
for Biomedical Research, CH-4058 Basel
Hemmings Brian A. | Development of molecular
strategies for therapeutic interference with glioblastomas
KFP OCS 01613-12-2004
Duration 01.01.2006 – 01.09.2011
CHF 2,076,200.–
Continuation of the project of Merlo Adrian et al. Neurochirurgische
Klinik, Universitätsspital Basel, Basel
Glioblastoma multiforme (GBM) is the most aggressive
and lethal form of brain cancer, with a mean patient
survival time of one year, with less than 10 % of patients
surviving over five years. The high malignancy and low
survival rates of GBM have been attributed to treatment
resistance and invasion to the adjacent normal brain. Past
experimental studies have identified protein kinases as
potential therapeutic targets; however, the response rates
of inhibitors of PDGF, VEGF and EGF receptors (overexpressed
in GBM) have been somewhat disappointing in
clinical studies. Therefore, there is currently a desperate
need to identify the molecular mechanisms of therapy
resistance and driving kinases which might be the Achilles
heel of GBM.
In a search for novel molecular targets, our kinome-focused
microarray analysis identified overexpressed protein
kinase expression in fresh brain tumours including primary
and secondary glioblastoma, astrocytoma and oligodendroglioma.
The study identified targets that have been
previously associated with gliomagenesis (e.g. EGFR or
PDGFR), as well as novel kinases that have not been previously
reported in GBM. Our recent work has focused on
the most promising novel targets that were highly overexpressed
and activated in human gliomas.
MAP kinase-interacting kinase 1 (MNK1) was highly expressed
in GBM compared to normal brain, and its elevated
protein level was confirmed in primary GBMs and in
glioma cell lines. Targeting MNK1 activity together with
rapamycin induced cell cycle arrest and strongly inhibited
global translation and GBM cell proliferation. Furthermore,
MNK1-signalling converged with TGF-� pathways
and regulated glioma cell motility, identifying MNK1
pathway as an attractive point for therapeutic intervention.
TAM family of receptor tyrosine kinases (TAM-TKs)
was shown to be overexpressed in gliomas and promoted
survival in vitro upon etoposide treatment independent
of PI3K/PKB and MAPK signalling. TAM-TK may thus mediate
GBM resistance to therapy, which is a major obstacle
in GBM treatment. Two other tyrosine kinases and
their upstream receptors that are found normally only in
haematopoietic cells were highly overexpressed in brain
tumour samples, GBM cell lines and cancer spheres. Strikingly,
treatment with two specific small molecule inhibitors
strongly blocked basal and EGFR (hyperactivated
in the most of GBMs) mediated proliferation and migration
of GBM cells. Due to the known driving roles of these
kinases, we will further investigate their role in GBM animal
models to establish optimal therapeutic interference.
Our study has analyzed signalling networks and has been
the platform to establish the potential of identified deregulated
pathways for development of novel targeted
thera pies, as well as diagnostics and prognostic markers
for gliomas. If our in vitro results are reflected in in vivo
animal models, then inhibition of these kinases could be
in fact novel therapeutic treatments that will ultimately
improve the life quality of brain cancer patients.
Project coordinator
Dr. Brian A. Hemmings
Friedrich Miescher Institut für
biomedizinische Forschung (FMI)
Maulbeerstrasse 66
CH-4058 Basel
Phone +41 (0)61 697 48 72
Fax +41 (0)61 697 39 76
brian.hemmings@fmi.ch
Krek Wilhelm et al. | Identification of molecular
signatures of human prostate cancer and their validation
in animal models and application in the clinics
KFP OCS 01262-06-2002
Duration: 01.04.2008 – 01.04.2010
CHF 684,900.–
Prostate cancer is a frequent cause of death among men
in Western countries. The causes underlying the development
of prostate cancer are still incompletely defined.
There are several risk factors contributing to prostate cancer
development, including the environment, lifestyle and
genetic predisposition. At early stages, prostate cancer is
asymptomatic. However, as it progresses, it can take on
aggressive behaviour leading ultimately to metastasis. It
would therefore be highly desirable to define highly sensitive
and specific molecular biomarkers that allow precise
early diagnosis of prostate cancer, an accurate prognosis
of the disease and predictions as to the response to specific
therapies.
In this project, researchers from different disciplines ranging
from cancer biology and pathology to proteomics,
computer sciences and clinical oncology collaborated to
develop innovative strategies for the discovery of novel
biomarker signatures for prostate cancer. The starting point
of this project was the PTEN tumour suppressor gene,
which is functionally inactivated in about 60 % of human
prostate cancer patients. The loss of PTEN function in
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