Development of novel targeted therapies against acute myeloid leukemia and novel tools for prediction of treatment efficacy
The aim of the project is to discover novel therapeutic targets for better treatment of acute myeloid leukemia and to develop biomarkers for treatment efficacy. Candidate drugs will be tested in preclinical models before they are taken further into the clinic.
Acute myeloid leukaemia (AML) is an aggressive bone marrow-derived cancer with haematopoietic stem cell characteristics with a wide genetic and phenotypic heterogeneity. Approximately 350 patients are diagnosed in Sweden each year, with median age 70 years and overall 3 years survival below 20%. Thus, there is a need for improved therapy. 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 the juxtamembrane 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 was approved for AML in 2017. However, there are problems with acquired resistance to these drugs. So far stromal targeting in order to attack the soil of growth and leukaemia-supportive cellular subsets has not been recognized in AML drug development. Several lines of evidence suggest stromal targeting for better disease control in AML patients. The large proportion of patients without FLT3 mutation lack today a targeting therapy option.
The aim of this PhD project is to use small molecule screens and shRNA screens on leukemic cell lines (using both FLT3 mutant positive cell lines as well as FLT3 mutant negative cell lines) in order to identify promising candidate molecules. These will be characterized and further optimized for efficacy. The cellular target will be identified with so-called CETSA methodology. Identified targets will be validated both in leukemic cell lines as well as in mice using patient-derived xenografts. The role of the identified target proteins in leukemogenesis will be investigated and the signal transduction pathways involved will be investigated. Their posttranslational modifications (phosphorylation, sumoylation, acetylation etc.) will be identified and their role in leukemogenesis investigated. These posttranslational modification are also candidate biomarkers to be used for prediction of treatment efficacy and whether a certain patient is suitable for treatment with the drug targeting this protein. Modification specific antibodies will be generated (i. e. phosphospecific antibodies, acetylation-specific antibodies etc) and will be validated using flow cytometry protocols.