Digital Public Defence: Dagim Shiferaw Tadele
MSc Dagim Shiferaw Tadele at Institue of Clinical Medicine will be defending the thesis “Development of novel approaches for treatment of leukemia” for the degree of PhD (Philosophiae Doctor).
The public defence will be held as a video conference over Zoom.
The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
Digital Trial Lecture – time and place
- First opponent: Principal Investigator John Brognard, Center for Cancer Research, National Cancer Institute, USA
- Second opponent: Researcher Sigrid Skånland, Institute for Cancer Research, Oslo University Hospital
- Third member and chair of the evaluation committee: Associate Professor June Helen Myklebust, University of Oslo
Chair of the Defence
Professor II Arne Klungland, Faculty of Medicine, University of Oslo
Professor II Jorrit Enserink, Faculty of Medicine, University of Oslo
The BCR-Abl oncoprotein is a hallmark of chronic myeloid leukemia (CML) and is also expressed in 25% of adult acute lymphoblastic leukemia (ALL). In both of these leukemias, BCR-Abl constitutively activates oncogenic signaling pathways and promotes tumorigenesis. Current drug screening efforts are associated with high attrition rates in clinical trials, in part because they do not fully capture the dynamic behavior of cancer cells in vivo, such as the competition between healthy cells and cancer cells. Therefore, we performed a drug screen based on competition between isogenic untransformed cells and BCR-Abl transformed cells, and identified a compound which we referred DJ34. Using a systems approach we discovered that DJ34 induces potent activation of p53 and rapid degradation of c-Myc, which is frequently deregulated in leukemia. We also found that DJ34 acts as a DNA intercalator to block c-MYC transcription and to inhibit topoisomerase II.
Furthermore, we screened for drugs that might be repurposed for treatment of AML patients by performing ex vivo drug sensitivity screens. We identified several compounds that selectively target primary leukemic cells and found that FLT3-ITD+ patient cells are particularly sensitive to HSP90 inhibitors. Importantly, leukemic stem cells are strongly dependent upon HSP90 for their survival, and the HSP90 inhibitor ganetespib causes leukemic stem cell exhaustion in patient-derived mouse xenograft models. Taken together, our data provide proof of principle that combining various drug screening approaches with multi-omics analysis can identify compounds that may have therapeutic potential.
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