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Research Focus: Using repurposed drugs to repair the damage that causes AML

Leukaemia is the most common childhood cancer.

Project title: Targeting mutant NRAS in paediatric AML

Lead investigator: Dr Kyle Matchett, Ulster University
Funded by the Little Princess Trust in partnership with CCLG
Awarded January 2019

Award: £74,933

Leukaemia is the most common childhood cancer. The survival rate for acute myeloid leukaemia (AML) is very poor with only 60% of children diagnosed expected to survive more than 5 years. This is compounded by severe treatment side effects including vomiting and hair loss. Our work is focused on finding new drugs that are both effective in fighting the leukaemia and spare young patients these side effects.

A group of experts from the USA recently published the first detailed roadmap of childhood AML, called the TARGET study. The group performed detailed analysis of AML in 1,023 children, and were able to identify the genes, proteins and other changes that are important in AML development. One of the most common alterations found was in a gene called NRAS. Not only were changes in NRAS among the most common alterations found in childhood AML, but these changes were specific to childhood AML and are much rarer in the adult disease. Finding new therapies to target childhood AML (or any cancer) that is ‘driven’ by NRAS has been challenging. In this project, we will take a new approach, called drug repurposing, to find a possible new therapy for NRAS-driven childhood AML.

Drug repurposing is the process of using drugs already approved for a specific disease in new diseases. Drug repurposing is attractive because the time from discovery to patient is quicker and there is reduced cost and risk in drug development.

To do this, we will first take childhood AML cells with the specific NRAS change and ‘repair’ this change. We will use a state of the art technique called CRISPR-Cas9 as genetic ‘scissors’ to make the repair. We will then use these two cell lines – one with the altered/’faulty’ NRAS and one with the repaired NRAS, to find effective drugs by screening. This project will continue from our first screening proposal and recent drug combination (MuSIC) project, both funded by Little Princess Trust/CCLG, and will be our first project with the focus of identifying a targeted therapy for a specific type of childhood AML.

Our three aims are to:

  1. Generate the two NRAS cell lines using CRISPR-Cas9 – we will use this technology to repair the specific NRAS alteration in childhood AML cells, providing two cell lines – one with the altered version and one with the healthy version. These will then be checked and confirmed before the next step.
  2. Identify repurposed drugs that specifically target NRAS altered cells – the NRAS alteration plays a key role in AML, so we want to target these. We will use a large library of approved drugs and test these in both cell lines to find drugs that are more specific for the AML cells with altered NRAS. We will also test these hits in sorted normal cells to identify NRAS-mutant specific drugs that have minimal toxicity.
  3. Investigate how the drug hits are working – we will take the most promising NRAS-specific drugs forward for further testing to understand how they are killing these AML cells, by looking at a range of cell processes, such as the cell cycle.

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The MBE for voluntary groups was awarded to The Little Princess Trust by Her Majesty Queen Elizabeth.