Main Field(s) of Research, Abstract
Patients with poor risk acute lymphoblastic leukemia (ALL) can be identified most accurately based on their poor response to the initial treatment phase with chemotherapy. This observation implicates that de novo drug resistance of a subpopulation of ALL cells is of central relevance for the occurrence of later relapse. In collaboration with the European ALL-BFM (Berlin-Frankfurt-Muenster) Study Group we have established a leukemia xenograft model that is representative of de novo drug resistant and very high risk ALL in NOD/SCID/gamma null mice. We have extended this model to refractory and relapsed ALL. With this model in place we are investigating the following questions:
- Preclinical validation of new approaches for chemomodulation in drug resistant ALL. Our model is suited to triage amoung hypothesis-driven approaches for targeted therapy in drug resistant ALL. We have recently discovered new ways to specifically trigger a non-apoptotic cell death pathway in the context of glucocorticoid resistance in ALL and are investigating the underlying molecular pathways. In part, this program is in collaboration with the ALL-BFM study group (Martin Stanulla and Martin Schrappe, Kiel Germany) and ALL-BFM-REZ study group (Cornelia Eckert and Arend von Stackelberg, Berlin, Germany)
- Functional characterization of the Leukemia Initiating Cell (LIC) compartment in ALL, comparing pretreatment leukemic cells from patients with very poor or excellent response to initial chemotherapy. Stability of the LIC compartment in the leukemia-xenograft model.
- Identification of new cell surface markers using an unbiased proteomic approach, in collaboration with the group of Bernd Wollscheid at the IMSB at the ETH Zurich. - Identification of critical mediators for leukemia cell survival originating from the microenvironment, using a functional siRNA screen by automated fluorescence microscopy.
- Evaluation of new approaches to target the oncogenic mechanisms in a subtype of high risk ALL with activation of the CRLF2 and JAK/STAT pathways, in collaboration with the group of Shai Izreali, Sheba Medical Center, Tel Aviv, Israel
- Evaluation of antileukemic cytolytic T-cells for the treatment of ALL, in collaboration with Franco Locatelli, Policlinico San Matteo, Pavia, Italy
Based on our preclinical data, we are also developing a Phase I study to evaluate the safety of obatoclax in combination with dexamethasone in relapsed acute lymphoblastic leukemia, in collaboration with the international BFM-study group and the Innovative Therapies for Chilhood Cancer (ITCC) consortium.
Main Fields of Research, Keywords
Leukemia, Drug Resistance, prosurvival and apoptotic signalling, stem cells
Special Techniques and Equipment
All standard techniques of molecular and cellular biology including flow cytometry and cell sorting. Leukemia Xenograft models.
Education and Training
The group is integrated in the research laboratory of the Division of Pediatric Oncology with regular teaching and progress meetings and invited guest speakers for seminars. Our PhD students participate to the Cancer Network PhD Program. We also train master students.