1. Characterization of resistance mechanisms to targeted therapy in acute myeloid leukemia and identification of novel therapy opportunities
Supervisor: Michal Šmída, Ph.D.
Annotation:
Acute myeloid leukemia (AML) is a disease characterized by poor survival and limited therapy options, primarily relying on chemotherapy. Recently, a specific BCL2 inhibitor Venetoclax has triggered high hopes for targeted therapy of AML. Nevertheless, first mechanisms of venetoclax-resistance and AML relapses have been described. Further molecular analyses are urgently required to reveal specific molecular targets whose pharmacologic inhibition would prevent the failures of venetoclax treatments.
The student will investigate the molecular mechanisms of venetoclax-resistance using state-of-the-art techniques like CRISPR/Cas9 genetic knockout screens, RNA sequencing or single-cell RNA sequencing on AML primary cells as well as AML cell lines resistant to venetoclax (generated in our laboratory). Screening a library of approved drugs will propose novel treatments potentially effective on the resistant cells. The student will then explore the molecular mechanisms underlying the observed vulnerabilities and identify specific novel molecular targets that might be proposed for tailored therapy of AML. The efficiency of such therapy will also be evaluated in a mouse model.
Keywords: Acute myeloid leukemia (AML), targeted therapy, CRISPR/Cas9 screening, Precision medicine, therapy resistance.
