Prof. Michel Duchosal, Full Professor

Medicine Department Hematology CHUV Rue du Bugnon 46 CH-1011 Lausanne Tel:  +41 21 314 42 15 Fax: +41 21 314 07 91 E-mail: michel.duchosal@chuv.ch 2 post-doctoral fellows

Research activities :

• Molecular characterization and treatment of haematological malignancies

Research key words :

• Transplantation, hematopoietic cancer, lymphoma, leukaemia, gene profiling, apoptosis

Link to our web site

The main research topics of the laboratory are:

1) PRE-CLINICAL EVALUATION OF A NOVEL ANTI-TUMOR AGENT IN HEMATOLOGICAL MALIGNANCIES.
Activation of molecules leading to apoptosis originate through cell surface death receptors or from mitochondria. This latter pathway is targeted by APO 866 which inhibits specifically nicotinamide phosphoribosyltransferase (NAPRT), a key mitochondrial enzyme generating NAD. NAD depletion induces high levels of apoptosis, particularly in cancer cells. The scientific objective is to test the efficacy of APO866 alone or in combination with chemotherapeutic drugs on a panel of hematological cancers. Furthermore, the project will identify cell biomarkers as indicators of APO866 sensitivity.
This objective will be reached by addressing the following specific aims:
1. Test the efficacy of APO866 on cell lines and primary tumor samples derived from different hematological malignancies both in vitro, and in vivo using mouse-human xenochimeric models of human hematological malignancies.
2. Compare gene expression profiles between sensitive and resistant cells treated with or without APO866.
3. Evaluate the combinatorial effects of APO866 with chemotherapeutic drugs. This will be assessed in in-vitro and in-vivo laboratory models (immunodeficient mice grafted with human tumors).

2) MOLECULAR CHARACTERIZATION OF POST-TRANSPLANTATION LYMPHOMAS.
Solid organ and hematopoietic stem cell transplanted patients may suffer from (posttransplant) lymphoproliferative diseases (PTLD). PTLD development is linked to immunosuppression, and is often induced by uncontrolled growth of B cell infected by the Epstein-Barr virus (EBV). The in vivo steps leading to such lymphomas are poorly characterized.
The aim of our project is to characterize molecular signatures associated with the development of PTLD.
We will apply molecular biology techniques such as DNA microarray and RT PCR on a laboratory model of aggressive human B cell PTLD. Indeed immunodeficient mice transplanted with human lymphocytes generate such human PTLD.
The study may provide new diagnostic and prognostic tools for the management of this disease, as it has been the case in other types of lymphomas. The study may also help to design new therapeutic strategies aiming at preventing the development of or at treating overt lymphomas in the context of immunosuppression and transplantation.
Practically, the project contemplates to:
1 - Generate human PTLD using a model available in the laboratory.
2 - Perform microarray analyses, and if necessary specific gene amplifications by the polymerase chain reaction method on developing tumors. We will particularly focus on genes associated with T helper cells that are essential for tumour development, and on genes expressed physiologically in germinal center or in activated B lymphocytes, and on oncogenes which predict the aggressivemness of some lymphomas in humans. Together these data will present a coordinated view of the different factors that together are responsible for the development of PTLD associated lymphomas.

References :

• Nahimana, A., Aubry, D., Butcher, S., and Duchosal, M.A. NAD targeting efficiently kills hematological cancer cells. 2009. Blood 113(23) : 6037-6038.

• Nahimana, A., Attinger, A., Aubry, D., Greaney, P., Ireson, C., Dawson, K., Dupuis, M., and Duchosal, M.A. The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies. 2009. Blood 113(14): 3276-3286.

• Greaney, P., Nahimana, A., Lagopoulos, L., Etter, A.-L., Aubry, D., Attinger, A., Bassi, I., Sordat, B., Demotz, S., Dupuis, M., and Duchosal, M.A. A novel Fas agonist induces high levels of apoptosis in haematological malignancies. 2006. Leukemia Research 30: 415-426.