Cancer Research in Switzerland - Krebsliga Schweiz

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A novel method was developed for the reconstruction of
a voice with more natural fundamental frequency and increased
voice quality. It became obvious that the variability
in the fundamental frequency may not be sufficient to
restore prosody. This finding led to the development of
a multi-resolution approach, where voluntary variations
in the voice are restored based on different vocal cues
on different time scales.
The algorithmic solutions developed in the framework of
the project represent a significant step in the understanding
and processing of pathological voices. However, the
results obtained also highlighted the difficulty and complexity
of the restoration process. The actual restoration
results are not yet sufficient to be integrated in a device
aiming at improving the quality of life of laryngectomees
(vocal aid, improvement of telephone calls, public audience
amplification, etc.), but the research work is still underway.
Project coordinator
Dr Philippe Renevey
Centre suisse d’électronique et
de microtechnique (CSEM)
Rue Jaquet-Droz 1
CH-2007 Neuchâtel
Phone +41 (0)32 720 55 27
prv@csem.ch
Schäfer Beat W. | Oncogenic fusion proteins as
therapeutic targets in pediatric sarcomas
(OCS 02264-08-2008)
Childhood sarcomas are aggressive tumour entities. This
is especially true of the type of sarcomas that are characterized
by the presence of a chromosomal translocation
and include rhabdomyosarcoma and Ewing’s sarcoma.
Several previous studies from different laboratories demonstrated
that the fusion proteins produced by chromosomal
translocations are important for both tumour development
and tumour cell survival. Therefore, these
oncogenic transcription factors represent important target
molecules for the development of novel treatment
strategies. Unfortunately, this development is challenging
due to the nature of the proteins involved, and for this
reason it is not actively pursued by industry.
The aim of the current project was therefore to develop a
method by which the activity of these fusion proteins can
be measured and subsequently inhibited by small-molecule
chemical compounds. The method developed for this
relies on measuring transcriptional activity based on a few
carefully selected target genes. We successfully implemented
and validated such a method. Next, we screened a
library composed of small-molecule chemical compounds
and a library composed of the latest drugs under development
in oncology. Interestingly, we first identified a novel
drug called fenretinide, a retinoic acid analogue that is
now under development for Ewing’s sarcoma and neuroblastoma,
as also being effective for rhabdomyosarcoma.
Equally interesting were results from the second library,
which is mainly composed of very specific kinase inhibitors
that allow targeting of specific signalling pathways.
Using Ewing’s sarcoma cells, we identified drugs targeting
the PI3K/mTOR pathway as being the most effective.
Strikingly, rhabdomyosarcoma cell did not react that well
on this group of inhibitors but was most sensitive to drugs
targeting components of the cell cycle. We found that an
important cell cycle kinase is directly involved in stabilizing
the fusion protein. Both drugs are now being further
evaluated for anti-tumourigenic activity in an in vivo
mouse model.
The results of this project represent the first step towards
improvement of current therapies for sarcomas by inhibiting
the activity of the fusion proteins lying at the centre
of tumourigenicity. These drugs now need to be further
developed in pre-clinical models.
Project coordinator
Prof. Dr. Beat W. Schäfer
Abteilung Onkologie
Kinderspital Zürich
Universitäts-Kinderkliniken
Steinwiesstrasse 75
CH-8032 Zürich
Phone +41 (0)44 266 75 53
Phone +41 (0)44 634 88 52
beat.schaefer@kispi.uzh.ch
Schäfer Beat W. | Prognostic classification of
rhabdomyosarcoma: A combined retro- and prospective
study (OCS 1944-08-2006)
Childhood sarcomas are aggressive tumour entities. When
metastatic, these tumours often have a fatal course despite
aggressive treatment with chemo- and radiotherapy.
Therefore, there is an urgent need to improve therapy
in this tumour group. The most frequently occurring sarcoma
in childhood and adolescence is rhabdomyosarcoma.
The aim of our study was to simplify pathological classification
into different rhabdomyosarcoma subgroups that
are based on biological criteria. Historically, subgroup
classification is based on histological analysis and divides
rhabdomyosarcoma into tumours with embryonal and
alveolar histology. Biological analysis in the past also revealed
two subgroups: One subgroup is characterized by
the presence of a specific genetic aberration, a chromosomal
translocation that is lacking in the other subgroup.
These two genetic groups only partially overlap with the
ones based on histology. However, identification of this
genetic aberration is crucial, since treatment and prognosis
depend by and large on its presence. Whereas genetic
methods are clearly able to identify the aberration, applying
those methods can be sophisticated.
To improve recognition of the genetic aberration, we
therefore searched for biomarkers that would be indicative
on simple histological sections. In our previous work,
we could indeed identify four biomarkers based on gene
expression profiles that fulfilled all criteria necessary. In
the present project, we have now validated these markers
on a large cohort of patients with rhabdomyosarcoma in
collaboration with the German Cooperative Soft Tissue