PhD Position of Leukemia Research Group Zurich, Switzerland
Job Description:Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. ALL relapse remains one of the most frequent diagnoses in pediatric oncology. These patients desperately need new treatment options. Combination therapy with new agents that target regulators of programmed cell death constitutes a promising approach to improve treatment of resistant disease. Our own data support the potential of the pan-BCL-2 antagonist obatoclax as chemosensitizer in drug resistant ALL (Bonapace et al., Journal of Clinical Investigation, 120, 1310-23). Subcytotoxic concentrations of obatoclax very effectively resensitized cells from treatment refractory ALL patients to glucocorticoids. Unexpectedly, combination of obatoclax with dexamethasone triggered an alternative non-apoptotic but necroptotic cell death pathway. This alternative cell death pathway was dependent of induction of autophagy. Based on these data, we are now planning a phase I/II trial together with the!
resistant disease committee of the BFM study group and the European Consortium ‘’Innovative Treatment for Childhood Cancer’’ (ITCC) to test obatoclax in combination with dexamethasone for refractory ALL.
Thesis Project: In this PhD thesis project, we propose to explore the mechanisms that underlie the chemosensitzation activity of small molecules such as obatoclax in drug resistant disease. In particular the crosstalk between autophagy, apoptosis and necroptosis will be investigated. Preliminary genetic data suggest an unexpected link to the death receptor complex that warrants intensive investigation. In order to facilitate the planned clinical trial with obatoclax, we also aim at establishing molecular markers as well as predictive markers of response.
Application Deadline 1 July 2010
Scholarship Tags: crosstalk, Leukemia, research, Switzerland, Zurich
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