Acute myeloid leukaemia (AML) is the most common form of acute leukaemia, and it has the lowest 5yr 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 called FLT3, and it 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, suggesting that DNA-PK may be a new therapeutic target. 

Excitingly, we have found that FLT3 mutant AML cells are hyper-sensitive to DNA-PK inhibition, and DNA-PK inhibitors work synergistically with standard AML chemotherapeutics (prelim data). 
DNA-PK is also over activated in B cell non- Hodgkin’s lymphoma (NHL) (generally considered an unfavourable NHL diagnosis) and therefore a potentially valuable target strategy for treating these patients. The tumour suppressor protein PP2A, is inactivated in these tumours and PP2A is responsible for the regulation of DNA-PK activity. Over the last 5 years my team and I have been working on new drugs that have the capacity to turn on the tumour suppressor PP2A on and in a number of leukaemia’s this has been shown to be an effective treatment option, however these studies have not been put into clinical trials as the doses required to kill the cancers may affect other organs. The NHL arm of the project will test if we can target DNA-PK and the tumour suppressor PP2A using in vitro cytotoxicity assays and colony forming assays. The study will provide preliminary data to determine whether this strategy will reduce the dose of tumour suppressor activating compounds needed to kill the cancer whilst not harming healthy organs. 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.

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