Medizinische Universität Graz - Research portal
Selected Publication:
Gallob, FM.
Functional assessment of novel molecularly targeted drug combinations in pediatric acute myeloid leukemia (AML), A study on the effects of novel drug combinations in a 3D, long-term setting ex vivo.
[ Diplomarbeit/Master Thesis (UNI) ] TU Graz; 2020.
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- Authors Med Uni Graz:
- Advisor:
- Prokesch Andreas
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- Abstract:
- Pediatric acute myeloid leukemia (AML) is a rare hematopoietic cancer that accounts for about 20% of pediatric acute leukemias. It is characterized by the clonal expansion of myeloid precursor cells and without treatment, the disease leads to a fatal outcome within weeks. In the past decades refinements in standard chemotherapy have yielded immense improvements regarding disease outcome and current 5-year survival rates have plateaued at 70%. However, 25 to 35% of patients relapse with a considerable worse prognosis and the need for a more targeted approach has become apparent. So far, several targetable genetic aberrations have been identified but the lack of progress in AML therapy based on these insights has only underscored that in addition to genetic data a functional approach is needed. Since most functional drug discovery programs in this field are focused on short-term high throughput single drug screens there is a lack of understanding for non-immediate cytotoxic effects as well as for effects of drug combinations. Therefore, this thesis aimed to identify drug combinations of promising FDA-approved drugs and study their effects on primary AML cells ex vivo in a long-term setup using a functional approach. To that end, we first screened AML cell lines for susceptibility to combinations from a preselection of agents and quantified synergistic effects by using the bliss-independence model. To maximize clinical translation, we only used FDA approved drugs in concentrations not surpassing their respective Cmax. In total, we tested 15 different combinations that were chosen based on the non-interaction of the targeted pathways. (...)