Acute myeloid leukemia (AML) is an aggressive blood cancer with the median age of 71 years and 80% five years mortality. The excessive mortality is caused by relapse or overt chemoresistance. Using approved medicines for other diseases than licensed, repurposing, has been proposed as an effective way to establish novel therapy. Based on our preliminary data, we will determine the tolerable dose of the novel combination quinacrine and valproic acid in 19 patients with relapsed / refractory AML in a phase I clinical trial. The dosing schedule will be improved in mouse models of human AML, where also the impact of alternate combinations will be determined. Mechanisms of action will be analyzed by gene expression and proteomics, including mapping of phosphorylated proteins involved in intracellular signaling, aiming to identify responding patients. Target validation by quinacrine pull-down experiments of protein followed by functional genetic validation in cell lines. Targets will be examined as biomarker assays for clinical trials. Novel multiparametric mass cytometry will be developed towards clinical laboratory formats. Mass cytometry will be used in single cell immune and signaling profiling of peripheral blood leukocytes for effective monitoring of clonality at diagnosis as well as clonal evolution under therapy. Together, the data from preclinical validation and the dose finding study should propose expansion of the patient cohort and pediatric development.
