Targeting Mitochondrial Metabolism for the Treatment of Chronic and Acute Myeloid Leukaemias (360G-Wellcome-211821_Z_18_Z)

Tyrosine Kinase Inhibitors (TKIs) as a standard treatment of Chronic and Acute Myeloid Leukemia mainly target differentiated cells, leaving a population of leukemic stem cells (LSCs) behind, which support relapse of disease. Based on knowledge that cancer cells acquire energy to satisfy their high energy requirements by rewiring metabolic pathways, a previous study at Dr. Helgason's laboratory identified upregulation of oxidative phosphorylation metabolism as vital for LSC survival in Chronic Myeloid Leukemia (CML), providing potential selective targets for elimination of LSC by drugs interfering with mitochondrial function. In order to reduce time needed for treatment to enter clinical trial, Helgason's laboratory carried out drug-repurposing screening for suitable FDA-approved drugs targeting oxidative phosphorylation and identified a strong candidates for validation. The aim is to functionally validate these inhibitors as means to sensitise CML and Acute Myeloid Leukemia cells to TKI treatment in vitro in order to facilitate elimination of the LSC moiety while leaving healthy haematopoietic stem cells unaffected. Mechanism of action of promising candidates will then be studied using CRISPR-mediated genetic inhibition. Successful candidates will then be offered for translation into the clinic.