Public defence in Chemistry: Jingmei Yang

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Abstract

Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor survival rate and limited therapeutic options. Targeted treatment of other types of cancer, for instance chronic myeloid leukemia (CML) and breast cancer, has seen significant progress. However, when it comes to AML, the outcome is poor with a five-year relative survival of only 20 - 30%. Over the last four years, the FDA has approved nine new drugs for AML patients in the United States. Unfortunately, the median overall survival of AML patients is still fairly low. For patients aged 70 years and older, the median overall survival is only about 10 months. Even for children with AML, the overall 5-year survival rate is 65 - 70%. A major cause of treatment failure is the development of treatment-induced drug resistance. The development of somatic mutations is one of the most common mechanisms of drug resistance.

In AML, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are often present, with an incidence rate of ∼30% of cases. Most of these mutations are internal tandem duplications (ITD), present in approximately 25% of the patients. Patients with a high FLT3-ITD burden often relapse after chemotherapy. In patients with FLT3-ITD mutations, FLT3 has become a promising drug target for therapy. In the past few years, FLT3 inhibitors have led to clinical progress, but there are still some significant problems with their usage. Among these, drug resistance is urgent to overcome.

This thesis mainly focuses on exploring different treatment regimens to overcome drug resistance in human FLT3+ AML cells as a model for the disease. Initially, a drug rotation protocol between two inhibitors which have different resistance profiles was tested. However, the results were not satisfying. Combination therapy between a FLT3 inhibitor and another inhibitor was adopted. This strategy exhibited significant synergy and, more importantly, could postpone the emergence of drug resistance. In further experiments, we examined some newly-developed small molecular compounds, and it turned out some of them had excellent inhibitory activity against established drugresistant AML cell lines. In parallel, we have also studied the cause of resistance in these cells and have identified resistance mutations that have not been described before. Finally, we studied whether FLT3 inhibitors were likely to be synergistic with azacitidine, a hypomethylating agent approved for AML treatment. Such combinations did not display a clear synergistic effect on AML cells, though one combination may be promising. Overall, our studies provided a better understanding of the resistance mechanisms by which FLT3-ITD cells overcome therapy and valuable information about the efficacy of novel inhibitors that are not currently in clinical use, and on combination therapies. To this end, the results will enable to further facilitate the rational development of new strategies to overcome drug resistance in FLT3+ AML.

Keywords: Acute myeloid leukemia, Drug resistance, FLT3 inhibitor, Somatic mutation, Signaling pathway