Cancer Research in Switzerland - Krebsliga Schweiz

of transporters with respect to chemosensitivity and
chemoresistance in the various tumour cell subpopulations
will contribute to a more efficient chemotherapy.
Project coordinator
Dr. Pascale Anderle Pedone
Institut für Biochemie und molekulare Medizin
Universität Bern
Bühlstrasse 28
Postfach
CH-3000 Bern 9
Phone +41 (0)31 631 47 39
Fax +41 (0)31 631 37 37
pascale.anderle@mci.unibe.ch
Bertoni Francesco | Anaplastic large cell lymphoma:
One or more entities? (KLS 02403-02-2009)
Duration: 01.08.2009 – 01.08.2011
The recent 2008 World Health Organization (WHO) classification
divides anaplastic large cell lymphoma (ALCL)
into two distinct subgroups based mainly on the presence
or absence of translocations affecting the anaplastic lymphoma
kinase (ALK) gene. It is well accepted that patients
with ALK positive ALCL are a distinct group sharing
unique phenotypic and well-defined genetic and clinical
features. Although the general clinical presentations and
peculiar translocations and/or genetic events differ in the
ALK positive and ALK negative ALCL subgroups, the question
as to how related the two types of ALCL are and
whether ALK negative ALCL may represent a subset of
‘peripheral T-cell lymphomas, not otherwise specified
(PTCL, NOS)’ remains open.
The aim of this project is to focus on the genetic events
underlying the pathogenesis of ALCL. The dual aim is to
provide better tools to differentiate the individual lymphoma
types and to identify genes that might represent
new therapeutic targets.
Material and methods
The study is being performed on a large series of ALK positive
and ALK negative ALCL clinical samples; this has
been made possible thanks to an international network of
collaborating investigators. For genomic profiles we are
using Affymetrix Human Mapping SNP6 Arrays and for
gene expression profiling Affymetrix U133 plus 2.0. We
are also data mining a very large dataset of proprietary
and public T-cell NHL gene expression profiles.
Results
Ongoing are: data mining, validation of regions of interests
and characterization of a gene identified by data mining
of the gene expression profiles. The project is proceeding
according to plan.
Project coordinator
Dr. Francesco Bertoni
Laboratorio di oncologia sperimentale
Istituto oncologico della Svizzera italiana (IOSI)
Via Vincenzo Vela 6
CH-6500 Bellinzona
Phone +41 (0)91 820 03 67
Fax +41 (0)91 820 03 97
frbertoni@mac.com
Bourquin Jean-Pierre | Pre-clinical evaluation of a
new pharmacological approach using obatoclax for
chemosensitization of drug resistant childhood
acute lymphoblastic leukemia (KFS 02453-08-2009)
Duration: 01.03.2010 – 01.03.2011
Using a preclinical model that is based on representative
cases with highly resistant disease, we have established
a new rationale for chemosensitization in acute lymphoblastic
leukaemia (ALL). A small molecule that is thought
to act as an antagonist of critical regulators of programmed
cell death, obatoclax mesylate, very effectively
restored the response to conventional chemotherapeutic
agents in ALL cells that were otherwise completely refractory
to these conventional chemotherapeutic agents. Unexpectedly,
combination of obatoclax with dexamethasone,
one of the most important drugs for ALL treatment,
triggered a new type of programmed cell death specifically
in resistant leukaemia cells but not in chemosensitive
ALL cells, providing a strong rationale for a selective therapeutic
targeting of resistant leukaemia cells. Interestingly,
combination of obatoclax with other cytotoxic
agents triggered a classical cell death pathway, the mitochondrial
apoptotic pathway, suggesting that this agent
interferes with critical mechanisms at the interface of two
cell death pathways.
Based on our work, which is in part published in the Journal
of Clinical Investigation, a proposal for a clinical
phase I trial was developed under the auspices of the
leading group of experts in Europe, regrouped in the resistant
disease committee of the international BFM Study
Group (BFM stands for Berlin-Frankfurt-Münster to credit
the important contribution of the first founders who
paved the way to successful chemotherapy regimen for
ALL). The aim of this study is to evaluate toxicity and gain
first evidence for activity of the combination of obatoclax
and dexamethasone in patients with relapsed or refractory
ALL. This approach would then be taken forward as
an investigational phase II window for high risk patients in
first relapse to evaluate clinical activity. This trial will also
contribute to designing an experimental therapy with several
chemotherapeutic agents for patients with refractory
disease. This proposal has received a lot of attention in the
field and was declared as one of the priorities for drug development
for refractory ALL by IBFM.
To further improve and accelerate the clinical development
of obatoclax as chemosensitizer, we established a
larger number of cases with relapsed and refractory B-cell
precursor (BCP) and T-cell ALL using our leukaemia xenograft
model. The aim was to understand whether resistance
to chemosensitization with obatoclax could occur in
this patient population and to identify biomakers that
would help predict a response to the drug. Interestingly,
we could not find any case that would not respond to the
combination of obatoclax with chemotherapeutic agents
in BCP-ALL but detected several resistant cases in T-ALL.
Sensitization activity to the glucocorticoid drug dexamethasone
using obatoclax was clearly associated with
inhibition of mTOR kinase activity, an important signalling
node that integrates signals from different pathways to
promote tumour growth. We used our leukaemia xenograft
model to test the possibility to follow mTOR kinase
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