Cancer Research in Switzerland - Krebsliga Schweiz

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new drugs that specifically target KRAS and that are now
entering clinical trials. As a corollary, KRAS testing decreases
the cost of the management of these patients.
Project coordinator
Dr. Milo Frattini
Laboratorio di diagnostica molecolare
Istituto cantonale di patologia (ICP)
Via in selva 24
CH-6600 Locarno
Phone +41 (0)91 816 08 05
Fax +41 (0)91 816 07 19
milo.frattini@ti.ch
Gautschi Oliver | Regulation of lD1 expression by Src
in cancer: Clinical implications (KLS 02164-02-2008)
Invasion and metastasis are important hallmarks of cancer,
but only few drugs are currently available that target
these mechanisms in patients. Most anticancer drugs target
cell proliferation and survival. Members of the Src
family of non-receptor tyrosine kinases are part of the
focal adhesion complex, which mediates migration and
invasion in normal and cancer cells. Src is frequently activated
in human cancer by growth factor and cytokine receptors.
Therefore, Src is a promising cancer drug target,
and several Src kinase inhibitors are currently in clinical
trials. Although preliminary results indicate that these
agents have clinical activity against solid tumours including
lung cancer, the activity appears to be limited to a
group of patients. As for many other molecular targeted
agents, predictive factors for Src inhibitors remain to be
identified.
The aim of our project is to better understand the Src signalling
pathway in human lung cancer, which may lead to
a rational development of Src inhibitors in oncology. Using
pharmacological small-molecule Src kinase inhibitors,
viral vectors carrying Src mutant constructs and gene expression
microarrays, we previously identified inhibitor of
differentiation 1 (ID1) as a new and functionally relevant
target gene of Src kinase in human lung cancer cells. The
ID1 gene mediates stem cell function and is a potent regulator
of cancer cell invasion. More recently, using an established
lung cancer biobank, we demonstrated that Src
and ID1 are frequently and strongly co-expressed in primary
human lung cancer, compared with matched lung
tissue. ID1 expression correlated with poor tumour differentiation
and with expression of matrix metalloproteinase
9 (MMP9). Interestingly, ID1 was also overexpressed in
pre-invasive lung lesions. In lung cancer cell lines, forced
expression of ID1 enhanced Matrigel invasion and caused
resistance to Src kinase inhibitors, which was supported
by preliminary animal experiments. Using Src inhibitors
and microarrays, we identified two microRNAs that target
ID1 expression. Manipulation of these microRNAs in lung
cancer cell lines again changed the effect of Src kinase inhibitors
on migration and invasion. Tumour microRNA expression
in patient samples inversely correlated with ID1
expression and with patient survival. These results suggest
that ID1 and microRNAs are dysregulated in lung
cancer and can modulate and predict the activity of Src kinase
inhibitors.
As a consequence, ongoing work includes further experiments
to confirm the predictive value of ID1 and microR-
NAs for Src inhibitors in preclinical models of metastatic
lung cancer. Further efforts are focused on the pharmacological
targeting of microRNAs to develop rational drug
combinations with Src inhibitors and other targeted agents.
Project coordinator
Dr. Oliver Gautschi
Departement für klinische Forschung
Universität Bern
Inselspital
Murtenstrasse 35
CH-3010 Bern
Phone +41 (0)31 632 25 18
Fax +41 (0)31 632 09 46
oliver.gautschi@onkologie.ch
Heim Markus Hermann | Hepatocarcinogenesis
in chronic hepatitis C (OCS 02192-02-2008)
Background
Chronic hepatitis C (CHC) is a major cause of liver disease
worldwide and a risk factor for cirrhosis and hepatocellular
carcinoma (HCC). Regardless of its aetiology, cirrhosis
is a major clinical risk factor for HCC, and indeed, hepatitis
C virus (HCV) associated HCC generally develops in
patients with cirrhosis. There is also evidence for HCV
specific tumourigenic pathways, mainly involving HCV
core and NS5A proteins. However, the molecular pathways
responsible for HCV induced hepatocarcinogenesis
have not yet been characterized. A potential tumourigenic
pathway could involve protein phosphatase 2A (PP2A)
and protein arginine methyltransferase 1 (PRMT1), since
both enzymes are dysregulated in chronic hepatitis C and
both enzymes have been involved in chromatin remodelling
and DNA damage repair.
Aim
The aim of the studies was to elucidate the role of PP2A
overexpression and of PRMT1 inhibition for carcinogenesis.
Methods
We used cell lines that allow the inducible expression of
hepatitis C virus proteins (UHCV57.3) and of the catalytic
subunit of PP2A (UPP2A-C8) as well as Huh7.5 cells
infected with recombinant cell culture-derived HCV
(HCVcc) to study epigenetic histone modifications and
DNA damage repair. We also investigated if the methyl
group donor S-adenosyl-L-methionine (SAMe) could reverse
the HCV induced changes.
Results
The induction of viral proteins, the overexpression of
PP2Ac or the infection of Huh7.5 cells with HCVcc resulted
in an inhibition of histone H4 methylation/acetylation
and histone H2AX phosphorylation in a significantly
changed expression of genes important for hepatocarcinogenesis
and inhibited DNA damage repair. These
changes were partially reversed by the treatment of cells
with the methyl-group donor S-adenosyl-L-methionine
(SAMe).