Acute myeloid leukaemia (AML) is the most common form of acute leukaemia, accounting for approximately 30% of all leukaemia diagnoses in Australia and it has the lowest 5 year survival rate at a dismal 24%.
Recently, improved technologies have enabled researchers to identify a number of mutations that recur in AML. The most common mutation in AML is within a molecule located on the cell surface of premature blood cells. This molecule called FLT3, is mutated in 1/3rd of all AML patients.
Patients diagnosed with FLT3 mutations have a very poor prognosis. The FLT3 mutation causes the leukaemia cells to generate excessive chemical molecules, known as reactive oxygen species (ROS). This ROS further damages the DNA of the leukaemia cells, inducing more errors in the gene sequences of the cell. If this damage is not repaired properly the leukaemia cells acquire additional mutations making the cancer even harder to treat.
In exciting new data we have discovered that in AML patients diagnosed with FLT3 mutations, their cells have a decreased ability to accurately repair damage caused by increased ROS. These patients display over-activation of an error-prone DNA repair pathway. We have discovered that in FLT3 mutant patients a protein called DNA-protein kinase (DNA-PK), a key regulator of the error prone repair pathway, is hyper-activated. DNA-PK may be a new therapeutic target for the treatment of AML.
Excitingly, we have found that FLT3 mutant AML cells are hyper-sensitive to DNA-PK inhibition and our preliminary data has shown that DNA-PK inhibitors work synergistically with standard AML chemotherapeutic.
Hypothesis: We propose that inhibition of DNA-PK will have anti-leukaemic effects in FLT3-mutant AML, and will enhance the therapeutic effects of standard chemotherapy.
Aims: To test the preclinical efficacy of DNA-PK inhibitors alone and in combination with chemotherapy and novel targeted FLT3 therapies (tyrosine kinase inhibitors) in AML cells with FLT3 mutations, using models (in vivo) to help get our therapies into clinical trials.
Significance: This project will further our understanding of DNA damage repair pathways in AML benefitting patients. Given repair of DNA damage is fundamental to every cell type, this knowledge will also be of broad interest and widely applicable to medical professionals. We will determine if targeting DNA-PK is a therapeutic option in AML, using clinically relevant pre-clinical models including patient-derived AML xenografts. A number of DNA-PK inhibitors are currently in clinical trials for other indications therefore successful completion of this project could see the timely introduction of clinical trials for AML patients.
AI Enjeti, a clinical haematologist at the Newcastle Mater Hospital who heads the AML trials at this site, will provide our patient samples and is poised to translate our laboratory