Background: Acute myeloid leukaemia (AML) is an aggressive bone marrow derived cancer with haematopoietic stem cell characteristics comprising 3-5 recurrent somatic mutations, but with wide genetically and phenotypically heterogeneity. Approximately 150 patients are diagnosed in Norway per year, with median age 70 years and overall 3 years survival below 20%. More than half of these patients have mutations in intracellular signal transduction pathways involving kinases and protein phosphorylation. The receptor tyrosine kinase FLT3 is affected in 25% with internal tandem mutation in the juxtamembranous region (FLT3-ITD). FLT3-ITD is the strongest marker for disease relapse after therapy. After 40 years without new therapeutic molecules in AML therapy, the first kinase inhibitor midostaurin may be approved for AML in 2018. So far targeting the stroma with leukaemia-supportive cellular subsets is not recognized in AML drug development, but several lines of evidence support stromal targeting as a novel therapy principle in AML patients.
Objective/aim: The aim of this project is to develop low toxicity effective therapy targeting both support cells and dysregulated intracellular signal transduction, providing effective disease control to unfit patients with relapsed / refractory leukaemia. A set of novel inhibitors with sub-nanomolar potency and highly specific efficiency against CSF1R and FLT3 will be developed, additionally used as a step stone for increasing the biological knowledge about these receptor tyrosine kinases in leukaemia. The preclinical models form a framework for development of novel combination, sequences and biomarkers for identification of responders in a phase I trial.